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Yong JP, Mu XY, Zhou CF, Zhang KK, Gao JQ, Guo ZZ, Zhou SF, Ma Z. Radiofrequency ablation of liver metastases in a patient with pancreatic cancer and long-term survival: A case report. World J Clin Cases 2025; 13:100169. [DOI: 10.12998/wjcc.v13.i20.100169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 09/05/2024] [Accepted: 03/06/2025] [Indexed: 04/09/2025] Open
Abstract
BACKGROUND According to the GLOBCAN2022 database, pancreatic cancer has become the 6th leading cause of cancer-related death worldwide. The latest statistics suggest that the incidence of pancreatic cancer is increasing at a rate of 0.5% to 1.0% per year, and it is expected to become the 2nd leading cause of tumor-related deaths in the United States by 2030. More than 50% of pancreatic cancer patients have already developed distant metastases at the time of diagnosis, with the liver being the most common site. Patients with pancreatic cancer with liver metastasis (PCLM) have a worse prognosis than those with locally progressed pancreatic cancer, with a median survival of less than six months. Therefore, the outcome of liver metastases is often a vital determinant of the prognosis of patients with PCLM. There are few successful cases of localized treatment for PCLM patients. Our department recently performed local radiofrequency ablation (RFA) treatment for a PCLM patient through an evidence-based medicine approach, with remarkable therapeutic effects.
CASE SUMMARY The patient was admitted to the hospital on May 03, 2018, 3 weeks after pancreatic cancer surgery. In October 2017, the patient presented with lower back pain. No abnormalities were detected via computed tomography (CT), colonoscopy, or gastroscopy. However, on March 18, 2018, the patient was investigated in a foreign hospital via CT, which suggested occupational lesions in the descending part of the duodenum, and magnetic resonance imaging suggested pancreatic occupancy. He was considered to be suffering from pancreatic cancer. He underwent laparoscopic-assisted pancreatic + duodenum + superior mesenteric vein partial resection and reconstruction under general anesthesia on March 26, 2018 at The Affiliated Hospital of Xuzhou Medical University. The pancreas and duodenum were partially resected. Postoperative pathology showed adenocarcinoma of the pancreas (moderately differentiated), partly mucinous carcinoma, invading the mucosal layer of the duodenum; the tumor size was 4.5 cm × 4 cm × 4 cm. There was no apparent nerve or vascular invasion. There was no cancer or involvement of the pancreas section or expected hepatic duct margins. There was no cancer involvement in the gastric and duodenal sections. There was no cancer metastasis to the peripheral lymph nodes of the pancreas (0/9). No metastasis to the gastric lesser curvature or more significant curvature lymph nodes (0/1, 0/5) was detected, and the peri-intestinal lymph nodes showed no cancer metastasis (0/4). Although the gallbladder showed signs of chronic cholecystitis, there was no cancer involvement, and the lymph nodes in Groups 12 and 13 also showed no cancer metastasis (0/6, 0/1). His postoperative recovery was acceptable. CT was performed on May 2018 at our hospital and found the following: (1) Double lung bronchial vascular bundles slightly heavier than normal; (2) Postoperative changes in the pancreas and a retention tube shadow in front of the head of the pancreas; (3) Small cysts in the right lobe of the liver; (4) Abdominopelvic effusion; and (5) Para splenic enlargement. pTNM stage: PT3N0M0. The patient was in the second stage of postoperative pancreatic cancer, with a potential risk of recurrence considering the patient's postoperative body quality deviation. The patient was unable to tolerate the standard multidrug combination and underwent six cycles of single-agent gemcitabine chemotherapy from May 10, 2018 to August 31, 2018 (the specific drug dosage was 1.4 g/d1/d8 gemcitabine injection, which was repeated every 21 days). Efficacy was determined to be stable disease after 2, 4, and 6 cycles. The side effects during treatment were tolerable.
CONCLUSION This case suggests that RFA can serve as a viable local treatment modality for selected patients with PCLM, offering a chance for long-term survival. Such localized interventions, when carefully tailored, may complement systemic therapies in controlling metastatic pancreatic cancer.
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Affiliation(s)
- Jin-Peng Yong
- Department of Oncology, The Second Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou 450000, Henan Province, China
| | - Xiao-Yan Mu
- Department of Oncology, Longhua Hospital Affiliated with Shanghai University of Traditional Chinese Medicine, Shanghai 20001, China
| | - Chao-Feng Zhou
- Department of Oncology, The Second Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou 450000, Henan Province, China
| | - Ke-Ke Zhang
- Department of Oncology, The Second Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou 450000, Henan Province, China
| | - Jie-Qiong Gao
- Department of Oncology, The Second Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou 450000, Henan Province, China
| | - Zhi-Zhong Guo
- Department of Oncology, The Second Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou 450000, Henan Province, China
| | - Shi-Fan Zhou
- Department of Oncology, The Second Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou 450000, Henan Province, China
| | - Zhen Ma
- Department of Neurology, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou 450000, Henan Province, China
- Department of Oncology, Henan Hospital of Traditional Chinese Medicine, Zhengzhou 450000, Henan Province, China
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Wang X, Gong M, Zhu Z, Zhang B, Han L, Li W, Wu Z, Ma Q, Wang Z, Qian W. Rutin protects the pancreas from inflammatory injury and oncogene-driven tumorigenesis by inhibiting acinar to ductal metaplasia. Eur J Pharmacol 2025; 998:177536. [PMID: 40120793 DOI: 10.1016/j.ejphar.2025.177536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 03/19/2025] [Accepted: 03/20/2025] [Indexed: 03/25/2025]
Abstract
Rutin is a valuable traditional Chinese medicine known for its anti-inflammatory and anticancer effects. It has been shown to be effective in treating various inflammation-associated diseases. Here, we investigated the influence of rutin on acute pancreatitis and tumorigenesis. Using C57BL/6J mice and Kras mutant transgenic mice, we induced pancreatitis and acinar regeneration models. Pancreatic malondialdehyde (MDA), superoxide dismutase (SOD) activity and reduced glutathione (GSH) contents were measured for oxidative stress. Histological staining and a pancreatic acinar 3D culture model were used to clarify the influence of rutin on ADM in vivo and in vitro. Western blotting was adopted to detect ADM markers amylase and CK19. We found that rutin ameliorated inflammatory injury to the pancreas in both caerulein- and arginine-induced AP. Then, we revealed that the anti-damage effect of rutin may be due to its inhibition of oxidative stress. In addition, an acinar 3D culture model showed that rutin inhibited the formation of ADM by activating AMPK in acinar cells. Finally, the activation of AMPK is believed to be a potential mechanism by which rutin exerts inhibitory effects on Kras-driven tumorigenesis. Rutin inhibited AP-induced pancreatic injury and oncogenic Kras-driven tumorigenesis by inhibiting ADM.
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Affiliation(s)
- Xueni Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China; Pancreatic Disease Center of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Mengyuan Gong
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China; Pancreatic Disease Center of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Zeen Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China; Pancreatic Disease Center of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Bo Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China; Pancreatic Disease Center of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Liang Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China; Pancreatic Disease Center of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Wei Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China; Pancreatic Disease Center of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Zheng Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China; Pancreatic Disease Center of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Qingyong Ma
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China; Pancreatic Disease Center of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Zheng Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China; Pancreatic Disease Center of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Weikun Qian
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China; Pancreatic Disease Center of Xi'an Jiaotong University, Xi'an, 710061, China.
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Miao H, Zhang B, Li Y, Ma X, Yang Y, Lin Z, Liu Y. Rosuvastatin inhibits carcinogenesis through Ca 2+ triggered endoplasmic reticulum stress pathway in pancreatic cancer. Cell Signal 2025; 131:111753. [PMID: 40107481 DOI: 10.1016/j.cellsig.2025.111753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2025] [Revised: 02/17/2025] [Accepted: 03/16/2025] [Indexed: 03/22/2025]
Abstract
BACKGROUND Pancreatic cancer remains one of the most challenging malignancies to treat due to its late-stage diagnosis, aggressive progression, and high resistance to existing therapies. Rosuvastatin (ROV), known for its hypolipidemic effects, which significantly inhibited clonogenic capacity and epithelial-mesenchymal transition (EMT) in prostate cancer cells. However, the anti-cancer mechanisms of ROV in PC have not yet been fully explored. PURPOSE This study aimed to investigate the potential anti-cancer effects of ROV on PC cells and to elucidate the underlying mechanisms. METHODS Cytotoxicity was detected via MTT assay, while epithelial-mesenchymal transition (EMT) markers, Ca2+ levels, and endoplasmic reticulum (ER) stress were observed with fluorescence microscopy. RNA-seq analysis was used to identify significantly changed mRNA expression following ROV treatment. Additionally, western blotting and immunohistochemistry (IHC) were conducted to examine proteins involving in the cell cycle, EMT, Ca2+ signaling, and endoplasmic reticulum stress (ERS) in vitro and in vivo. RESULTS ROV inhibited PC cell proliferation by arresting the cell cycle at the G1/S phase and partially reducing cell mobility during the EMT process. A total of 1336 significantly different RNAs (P < 0.05 and |logFC|>1) were identified and analyzed through RNA-seq, revealing the Ca2+ and ER pathways in PC cells treated with ROV. ROV treatment significantly altered the level of intracellular Ca2+, triggering the ERS pathway and modulating the Ca2+/CaM/CaMKII/ERK pathway. Furthermore, ROV inhibited key proteins within the Ca2+ and ERS pathways, leading to reduced cell proliferation, mobility and G1/S phase arrest. In tumor tissues, the expression of Ki67, EMT markers, Calmodulin, and ATF6 corroborated the in vitro findings. CONCLUSION ROV inhibited proliferation and metastasis in PC cells by inhibiting the EMT process through the Ca2+/CaM/CaMKII/ERK and Ca2+-mediated ERS pathways, highlighting its potential as a prophylactic and therapeutic agent for PC.
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Affiliation(s)
- Hui Miao
- Central Laboratory, Yanbian University Hospital, Yanji 133000, China; Dunhua City Hospital, Dunhua 133700, China
| | - Baojian Zhang
- Central Laboratory, Yanbian University Hospital, Yanji 133000, China; Key Laboratory of Pathobiology (Yanbian University), State Ethnic Affairs Commission, Yanji 133002, China
| | - Yue Li
- Central Laboratory, Yanbian University Hospital, Yanji 133000, China; Key Laboratory of Pathobiology (Yanbian University), State Ethnic Affairs Commission, Yanji 133002, China
| | - Xiao Ma
- Central Laboratory, Yanbian University Hospital, Yanji 133000, China; Key Laboratory of Pathobiology (Yanbian University), State Ethnic Affairs Commission, Yanji 133002, China
| | - Yang Yang
- Key Laboratory of Pathobiology (Yanbian University), State Ethnic Affairs Commission, Yanji 133002, China
| | - Zhenhua Lin
- Central Laboratory, Yanbian University Hospital, Yanji 133000, China; Key Laboratory of Pathobiology (Yanbian University), State Ethnic Affairs Commission, Yanji 133002, China
| | - Yanqun Liu
- Central Laboratory, Yanbian University Hospital, Yanji 133000, China; Key Laboratory of Pathobiology (Yanbian University), State Ethnic Affairs Commission, Yanji 133002, China.
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Sun G, Wu Y, Li J, Yang M, Xu H, Li Y, Tong P, Shao R, Liu Y, Kong X. Quercetin liposomes conjugated with hyaluronidase: An efficient drug delivery system to block pancreatic cancer. J Control Release 2025; 382:113642. [PMID: 40127723 DOI: 10.1016/j.jconrel.2025.113642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 02/03/2025] [Accepted: 03/15/2025] [Indexed: 03/26/2025]
Abstract
Pancreatic cancer characterized with intense hydraulic tissue in tumor extracellular matrix (ECM) resists most of chemotherapeutic drugs. Increased levels of hyaluronic acid (HA) represent the primary component of the hydraulic tissue, rendering tumors protective from drug targeting. Quercetin (Que), a natural flavonoid, has the ability to inhibit tumor cell growth in a number of cancers; however, its poor water solubility and low bioavailability largely limit its application in cancer therapy. Hence, we developed an efficient drug delivery system by encapsulation of Que. into liposomes and conjugation with hyaluronidase (HAase) at liposome surface, termed as HQL. In the presence of HAase, HQL were predominantly accumulated at tumor with enhanced permeability and retention effect. Treatment of xenografted tumor mice with HQL gave rise to suppressed tumor growth, while no toxic effects were observed in mice. HQL demonstrated the strong ability to inhibit cell proliferation, promote cell apoptosis, and induce arrest at G2/M cell cycle in pancreatic cancer lines, three-dimensional cultured cell spheroids and pancreatic ductal adenocarcinoma (PDAC)-derived organoids. Mechanistically, HQL downregulated expression of cell cycle-associated protein (CCNB1, CDK1 and PLK1) and cell apoptosis-associated factors PI3K/AKT and Bcl-2. In summary, HQL degraded HA in the tumor microenvironment to enhance nano-particle penetration and inhibited tumor cell growth, eliciting efficacy of anti-tumor therapy. Thereof, HQL may provide a novel efficient drug delivery approach for the adjuvant treatment of pancreatic cancer.
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Affiliation(s)
- Ge Sun
- Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China; Shanghai University of Medicine & Health Sciences, Shanghai 201318, China; Shanghai Key Laboratory of Systems Regulation and Clinical Translation for Cancer, Shanghai 200127, China; State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Shanghai 200127, China
| | - Ying Wu
- Shanghai Key Laboratory of Systems Regulation and Clinical Translation for Cancer, Shanghai 200127, China; State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Shanghai 200127, China
| | - Jiekai Li
- Department of Hematology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Mingjie Yang
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Hang Xu
- Shanghai Key Laboratory of Systems Regulation and Clinical Translation for Cancer, Shanghai 200127, China; State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Shanghai 200127, China
| | - Yiping Li
- Department of Oncology, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan 430065, China
| | - Peilin Tong
- Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Rong Shao
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Shanghai 200127, China; Shanghai Key Laboratory of Biliary Tract Diseases, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China; Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Yingbin Liu
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China; Department of General Surgery, Jiading Branch, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 201800, China; Shanghai Key Laboratory of Systems Regulation and Clinical Translation for Cancer, Shanghai 200127, China; State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Shanghai 200127, China.
| | - Xianming Kong
- Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China; Shanghai University of Medicine & Health Sciences, Shanghai 201318, China.
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Park Y, Hwang DW, Lee JH, Song KB, Jun E, Lee W, Sung MK, Kim SC. Oncological outcomes of palliative minimally invasive distal pancreatectomy for unexpected metastatic pancreatic ductal adenocarcinoma: A single-center experience. Surgery 2025; 182:109331. [PMID: 40138876 DOI: 10.1016/j.surg.2025.109331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 02/19/2025] [Accepted: 02/20/2025] [Indexed: 03/29/2025]
Abstract
BACKGROUND The benefits of palliative minimally invasive distal pancreatectomy for patients with unexpectedly metastatic pancreatic ductal adenocarcinoma have not been previously studied. This retrospective study compared the outcomes of palliative minimally invasive distal pancreatectomy with those of minimally invasive biopsy in these patients. METHODS We reviewed the records of 46 patients with unexpected metastasis of left-sided pancreatic ductal adenocarcinoma that were discovered during surgery between 2005 and 2019. Nineteen patients underwent palliative resection (minimally invasive distal pancreatectomy group), whereas 27 patients underwent only minimally invasive biopsy (minimally invasive biopsy group). Demographic, clinical, and operative data, as well as survival rates, were compared between the 2 groups. RESULTS Major complications (Clavien-Dindo grade ≥3) were comparable between the 2 groups (11.8% vs 5.6%; P = .603). Postoperative chemotherapy was administered to 84.2% of the minimally invasive distal pancreatectomy group and 77.8% of the minimally invasive biopsy group (P = .716). The minimally invasive distal pancreatectomy group had a higher completion rate of first-line palliative chemotherapy (42.9% vs 8.7%; P = .007) and a higher 2-year survival rate (36.8% vs 18.8%; P = .004). In multivariate analysis, survival was associated with completion of first-line chemotherapy (hazard ratio: 2.962; P = .003) and maintenance chemotherapy for over 12 months (hazard ratio: 2.339; P = .010). Gastric outlet obstruction was less prevalent in the minimally invasive distal pancreatectomy group (5.3% vs 25.9%, P = .037). CONCLUSION Palliative minimally invasive distal pancreatectomy may improve survival and facilitate the continuation of chemotherapy in selected patients with unexpected metastatic pancreatic ductal adenocarcinoma. However, the small sample size and potential selection bias limit the generalizability of these findings. Larger, prospective, multicenter studies are needed to confirm the role of minimally invasive distal pancreatectomy and to establish optimal management strategies for these patients.
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Affiliation(s)
- Yejong Park
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Dae Wook Hwang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jae Hoon Lee
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Ki Byung Song
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Eunsung Jun
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Department of Convergence Medicine, Asan Institute for Life Sciences, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Republic of Korea
| | - Woohyung Lee
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Min Kyu Sung
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Song Cheol Kim
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, BK21 Project, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
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Wang C, Song W, Zhang Y, Deng H, Zhou Z, Zhu J, Wang X. SKIL Promotes Pancreatic Cancer Metastasis by Inhibiting TSPYL2 to Activate the TGF-β Pathway. CANCER INNOVATION 2025; 4:e70011. [PMID: 40391200 PMCID: PMC12086372 DOI: 10.1002/cai2.70011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2025] [Revised: 03/24/2025] [Accepted: 04/07/2025] [Indexed: 05/21/2025]
Abstract
Background Pancreatic adenocarcinoma (PAAD) represents a highly fatal form of cancer. The 5-year survival rate for patients with this disease is only around 10%. A significant hurdle in its management is the absence of characteristic early-stage symptoms. As a result, a large majority of pancreatic cancer patients are diagnosed when the disease has reached an advanced stage or has metastasized. Consequently, taking measures to suppress the occurrence of metastasis in pancreatic cancer can bring about a substantial improvement in patients' survival rates and overall prognosis. SKIL, known to promote cancer progression, is implicated in cell proliferation, epithelial-mesenchymal transition (EMT), and metastasis, but its specific function in pancreatic cancer remains unclear. Methods We investigated the effects of SKIL on the proliferation, apoptosis, and metastasis of pancreatic cancer cells. Through ChIP-seq, we identified the SKIL downstream target gene and further explored the mechanism by which SKIL regulates the metastasis of pancreatic cancer cells through functional experiments and Western blot. Results A high level of SKIL expression is associated with an unfavorable prognosis in PAAD; it promotes cell migration and EMT. Through ChIP-seq analysis, we identified that SKIL inhibits TSPYL2, a nuclear protein regulating the TGF-β pathway by binding to the TGFB1 promoter. Further studies carried out by us confirmed that SKIL modulates the TGF-β pathway via TSPYL2, facilitating EMT and metastasis in pancreatic cancer cells, independent of Smad4. Conclusions These findings reveal a novel regulatory mechanism involving SKIL, TSPYL2, and the TGF-β pathway, offering new therapeutic targets for PAAD.
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Affiliation(s)
- Chenxi Wang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Weiwei Song
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Yixuan Zhang
- NMPA Key Laboratory for Monitoring and Evaluation of Cosmetics, Shanghai Innovation R&DTesting and Evaluation Technical Service Platform of Cosmetics(22DZ2292100)ShanghaiChina
| | - Hongming Deng
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Zixiang Zhou
- Department of Molecular BiologyPrinceton UniversityPrincetonNew JerseyUSA
| | - Jing Zhu
- College of Nursing and Health InnovationThe University of Texas ArlingtonArlingtonTexasUSA
| | - Xiaobing Wang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
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Li Z, Duan J, Liu Z, Li W, Mai Y, Fu H, Yuan G, Wang J. A triple-mode strategy on JQ1-loaded nanoplatform for superior antitumor therapy in pancreatic cancer. Mater Today Bio 2025; 32:101696. [PMID: 40225138 PMCID: PMC11986615 DOI: 10.1016/j.mtbio.2025.101696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 03/11/2025] [Accepted: 03/20/2025] [Indexed: 04/15/2025] Open
Abstract
Pancreatic cancer's dire prognosis urgently calls for innovative therapeutic strategies. JQ1, a bromodomain 4 inhibitor, exhibits potent anti-tumor activity in preclinical models but faces limitations due to rapid resistance development. Here, we developed a novel multifunctional nanoplatform, JQ1@MSN/FeTA-iRGD, which implemented a triple-mode strategy integrating apoptosis, ferroptosis, and immunogenic cell death for optimized treatment of pancreatic cancer. The particles could precisely target tumors in mice and achieve efficient release of JQ1 and Fe2+ through internalization in the acidic tumor environment. The nanoplatform amplified reactive oxygen species and mitochondrial damage to disrupt the redox homeostasis, thus synergistically escalating apoptosis and ferroptosis for the destruction of tumor cells, circumventing the rapid drug resistance associated with monotherapy. Meanwhile, dying cancer cells released damage-associated molecular patterns, which facilitated immunogenic cell death and triggered antitumor immune responses, guaranteeing the sustained efficacy of the treatment. Moreover, the system exhibited favorable biocompatibility, supporting its feasibility for clinical translation. Our results demonstrated that this novel strategy, combining apoptosis, ferroptosis, and immunogenic cell death, overcame the limitations of monotherapy with JQ1, providing a superior, targeted, and sustainable treatment option for pancreatic cancer.
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Affiliation(s)
- Zhiguo Li
- Guangzhou Key Laboratory of Medical Nanomaterials, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Jinxin Duan
- Guangzhou Key Laboratory of Medical Nanomaterials, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Zhiwen Liu
- School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Weifan Li
- Guangzhou Key Laboratory of Medical Nanomaterials, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Yiyin Mai
- Guangzhou Key Laboratory of Medical Nanomaterials, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Hao Fu
- Guangzhou Key Laboratory of Medical Nanomaterials, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Guotao Yuan
- College of Chemistry and Environmental Engineering, Shenzhen University, 518060, China
- Department of Otolaryngology, Longgang E.N.T. Hospital & Shenzhen Key Laboratory of E.N.T., Shenzhen, 518116, China
| | - Jiawei Wang
- Guangzhou Key Laboratory of Medical Nanomaterials, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
- Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
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Wang M, Bu H, Luo W, Zeng X, Chen G, He Y, Cao D. CA19-9, CEA and PIVKA-Ⅱ as a novel panel of serum markers for diagnosis of pancreatic cancer. Clin Biochem 2025; 137:110902. [PMID: 40024361 DOI: 10.1016/j.clinbiochem.2025.110902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Revised: 02/25/2025] [Accepted: 02/26/2025] [Indexed: 03/04/2025]
Abstract
AIM This retrospective study was aimed to evaluate the diagnostic value of a combination of carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA) and protein induced by vitamin K absence or antagonist-Ⅱ (PIVKA-II) in pancreatic cancer. METHODS Clinical data were collected from 111 pancreatic cancer patients and 158 patients with benign pancreatic diseases (BPD). Serum CA19-9, CEA and PIVKA-II were subjected to receiver operating characteristic curve (ROC) analysis alone and in combination for the diagnosis of pancreatic cancer. RESULTS Serum CA19-9, CEA, and PIVKA-II were higher in pancreatic cancer patients than in BPD patients (P < 0.001). ROC analysis indicated that the cutoff values were 99.390 for CA19-9, 3.065 for CEA, and 42.965 for PIVKA-II, at which the positive rate in pancreatic cancer was 78.38 % for CA19-9, 43.24 % for CEA and 48.65 % for PIVKA-Ⅱ. When serum CA19-9, CEA, and PIVKA-II were used alone, the areas under the curves (AUC), sensitivity and specificity were 0.821, 68.47 % and 89.24 % for CA19-9, 0.763, 61.26 % and 85.44 % for CEA, and 0.681, 45.95 % and 87.34 % for PIVKA-II. When serum CA19-9, CEA, and PIVKA-II were used in combination, the positivity rate was 94.59 % in pancreatic cancer with AUC of 0.903, sensitivity of 81.10 % and specificity of 88.00 %. CONCLUSION PIVKA-II is a potential serum marker of pancreatic cancer and the combination of CA19-9, CEA, and PIVKA-II is a novel panel of serum markers with promising diagnostic value for pancreatic cancer.
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Affiliation(s)
- Meifang Wang
- Science and Technology Innovation Center, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Hongying Bu
- School of Public Health, Hengyang Medical School, University of South China, Hengyang 421001, China
| | - Weijia Luo
- Hunan Engineering Research Center for Early Diagnosis and Treatment of Liver Cancer, Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Xi Zeng
- Hunan Engineering Research Center for Early Diagnosis and Treatment of Liver Cancer, Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Guodong Chen
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, Hunan 421001, China
| | - Yingchun He
- Hunan Provincial Engineering and Technological Research Center for Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Chinese Medicine and Protecting Visual Function, Hunan University of Chinese Medicine, Changsha 410208, China.
| | - Deliang Cao
- Science and Technology Innovation Center, Hunan University of Chinese Medicine, Changsha 410208, China; School of Public Health, Hengyang Medical School, University of South China, Hengyang 421001, China; Hunan Engineering Research Center for Early Diagnosis and Treatment of Liver Cancer, Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
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Fu Y, Chen L, Lv N, Wang J, Yu S, Fang Q, Xin W. miR-135b-5p/PDE3B Axis Regulates Gemcitabine Resistance in Pancreatic Cancer Through Epithelial-Mesenchymal Transition. Mol Carcinog 2025; 64:1119-1130. [PMID: 40170518 DOI: 10.1002/mc.23914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 03/11/2025] [Accepted: 03/18/2025] [Indexed: 04/03/2025]
Abstract
Gemcitabine-based chemotherapy is an effective treatment for pancreatic cancer (PC), but gemcitabine resistance frequently compromises the therapeutic efficacy, resulting in clinical chemotherapeutic failure and a poor prognosis for patients. In this study, we investigated the mechanisms of gemcitabine chemoresistance in PC by examining the roles of microRNAs linked to gemcitabine resistance and their downstream signaling pathways. In vitro experiments were performed to alter miR-135b-5p levels in PC parental and drug-resistant cells to probe its function. miR-135b-5p targets PDE3B was confirmed by using RNA-seq technology to screen for gemcitabine-resistance-associated mRNAs in PC. A series of rescue experiments were performed after cotransfection, demonstrating that PDE3B could reverse miR-135b-5p-mediated chemoresistance and epithelial-mesenchymal transition (EMT). These findings indicate that the miR-135b-5p/PDE3B axis generates resistance by stimulating the EMT signaling pathway, which provides new insights into gemcitabine chemoresistance in PC.
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Affiliation(s)
- Yuxuan Fu
- Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Liangsheng Chen
- Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Neng Lv
- Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Jia Wang
- Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Shuwei Yu
- Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Qilu Fang
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Wenxiu Xin
- Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
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10
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Han YB, Lee S, Lee JO, Jeong SI, Lee KR, Ahn S, Jung K, Lee JC, Yoon YS, Hwang JH, Han HS, Na HY, Kim J. Spatial transcriptomics reveal high T cell and monocyte status as predictive and prognostic markers in pancreatic cancer. J Transl Med 2025; 23:576. [PMID: 40410886 PMCID: PMC12102996 DOI: 10.1186/s12967-025-06599-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 05/09/2025] [Indexed: 05/25/2025] Open
Abstract
BACKGROUND In the present study, we intended to discover predictive or prognostic factors of pancreatic ductal adenocarcinoma (PDAC). We intended to investigate the differences between PDAC cases that are treated with upfront surgery (UFS) and surgery after neoadjuvant FOLFIRINOX chemotherapy (NAT), and cases with good and poor responses to NAT, using digital spatial profiling (DSP) and immunohistochemical (IHC) analysis. METHODS Forty-eight PDAC cases that were surgically resected with or without NAT were included. A tissue microarray was constructed for DSP and IHC. Pathological tumor regression to NAT was graded based on the College of American Pathologists (CAP) system. RESULTS Between the UFS and NAT groups, there were no significant differentially expressed genes in all cell types. In the NAT group, MFAP4 and EGR3 were upregulated in CAP 2 in pan CK- and CD45-negative cells. Gene set enrichment analysis of CD45-positive cells showed that genes related to B or T cell-associated pathways were enriched in CAP 2, which correlated with the IHC; higher CD3-, CD4-, and CD8-positive cell densities in CAP 2. Multivariate analysis revealed age, high monocyte infiltration, and high CD68-positive cell infiltration as independent prognostic factors for overall survival. CONCLUSIONS Increased expression of MFAP4 and EGR3 as well as high CD3-, CD4-, and CD8-positive cell infiltration may be predictive markers of the NAT response in PDAC. Additionally, high monocyte infiltration and high CD68-positive cell infiltration could serve as prognostic markers for PDAC.
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Affiliation(s)
- Yeon Bi Han
- Department of Pathology and Translational Medicine, Seoul National University Bundang Hospital, 82, Fumi-ro 173 Beon-gil, Bundang-gu, Seongnam, 13620, Gyeonggi, Republic of Korea
- Department of Pathology, Seoul National University College of Medicine, 101, Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Sejoon Lee
- Department of Pathology and Translational Medicine, Seoul National University Bundang Hospital, 82, Fumi-ro 173 Beon-gil, Bundang-gu, Seongnam, 13620, Gyeonggi, Republic of Korea
- Precision Medicine Center, Seoul National University Bundang Hospital, Seongnam, 13620, Republic of Korea
| | - Jin-Ok Lee
- Department of Health Science and Technology, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, Republic of Korea
| | - Se In Jeong
- Department of Pathology and Translational Medicine, Seoul National University Bundang Hospital, 82, Fumi-ro 173 Beon-gil, Bundang-gu, Seongnam, 13620, Gyeonggi, Republic of Korea
- Department of Pathology, Seoul National University College of Medicine, 101, Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Ki Rim Lee
- Department of Pathology and Translational Medicine, Seoul National University Bundang Hospital, 82, Fumi-ro 173 Beon-gil, Bundang-gu, Seongnam, 13620, Gyeonggi, Republic of Korea
- Department of Pathology, Seoul National University College of Medicine, 101, Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
- Department of Pathology, Green Cross Laboratories, Yongin, 16924, Republic of Korea
| | - Soomin Ahn
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 03181, Republic of Korea
| | - Kwangrok Jung
- Department of Internal Medicine, Seoul National University Bundang Hospital, 82, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam, 13620, Gyeonggi, Republic of Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
| | - Jong-Chan Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, 82, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam, 13620, Gyeonggi, Republic of Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
| | - Yoo-Seok Yoon
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, 13620, Republic of Korea
| | - Jin-Hyeok Hwang
- Department of Internal Medicine, Seoul National University Bundang Hospital, 82, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam, 13620, Gyeonggi, Republic of Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
| | - Ho-Seong Han
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, 13620, Republic of Korea
| | - Hee Young Na
- Department of Pathology and Translational Medicine, Seoul National University Bundang Hospital, 82, Fumi-ro 173 Beon-gil, Bundang-gu, Seongnam, 13620, Gyeonggi, Republic of Korea.
- Department of Pathology, Seoul National University College of Medicine, 101, Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
| | - Jaihwan Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, 82, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam, 13620, Gyeonggi, Republic of Korea.
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
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Balzano G, Reni M, Di Bartolomeo M, Scorsetti M, Caraceni A, Rivizzigno P, Amorosi A, Ceccarelli G, Scardoni A, Carrara S. An integrated clinical pathway for pancreatic and periampullary tumor management within the Pancreas Unit network in Lombardy, Italy. Dig Liver Dis 2025:S1590-8658(25)00756-X. [PMID: 40413135 DOI: 10.1016/j.dld.2025.04.046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Revised: 04/22/2025] [Accepted: 04/24/2025] [Indexed: 05/27/2025]
Abstract
This study presents a novel clinical pathway framework developed to standardize care protocols across the Pancreas Units network in the Lombardy region, which was established in 2024. The primary goal is to improve the quality of care across hub-and-spoke units by ensuring consistency in diagnosis, treatment, and follow-up. A key feature is the early integration of palliative care, aiming to enhance patient well-being throughout the treatment journey. The framework establishes a comprehensive care continuum, from patient admission to post-treatment follow-up, with local and regional case managers coordinating care and ensuring timely access to services. Their role is essential in maintaining continuity and optimizing treatment. The framework also emphasizes the importance of continuous professional development for healthcare providers and the implementation of a digital platform to enhance care coordination and track treatment outcomes. Additionally, patient rights and ethical considerations are emphasized throughout the care process. This study contributes to the growing body of literature on standardized care pathways in oncology, particularly in the context of regionalized healthcare systems. Future research should focus on evaluating the long-term impacts of this framework on patient outcomes and healthcare system efficiency.
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Affiliation(s)
- Gianpaolo Balzano
- Department of Medicine and Technological Innovation (DIMIT), Insubria University, Via Ravasi, 2, 21100, Varese, Italy.
| | - Michele Reni
- Department of Medical Oncology, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, Vita-Salute University, Via Olgettina 60, 20123, Milan, Italy
| | - Maria Di Bartolomeo
- Gastrointestinal Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Via Giacomo Venezian, 1, 20133, Milan, Italy
| | - Marta Scorsetti
- Department of Radiotherapy and Radiosurgery, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano 20089, Italy; Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy
| | - Augusto Caraceni
- Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Via della Commenda 19 20122 Milan, Italy
| | - Piero Rivizzigno
- Codice Viola, Pancreatic Cancer Advocacy Group, 20855, Lesmo (MB), Italy
| | - Alessandro Amorosi
- Welfare General Directorate, Regione Lombardia, Palazzo Lombardia, Piazza Città di Lombardia, 1, 20124, Milan, Italy
| | - Giovanni Ceccarelli
- S.C. Qualità Rischio Clinico, ASST Grande Ospedale Niguarda, Piazza Ospedale Maggiore, 3, Milano, Italy
| | - Alessandro Scardoni
- Welfare General Directorate, Regione Lombardia, Palazzo Lombardia, Piazza Città di Lombardia, 1, 20124, Milan, Italy
| | - Silvia Carrara
- IRCCS Humanitas Research Hospital - Endoscopic Unit, Department of Gastroenterology, Via Manzoni 56, 20089 Rozzano (Milan), Italy
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12
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Qi J, Fang C, Deng C, Shi F, Yao Q. Mesoporous Magnetic Graphene for Serum Metabolic Profiling in Non-Invasive Early Detection and Diagnosis of Pancreatic Ductal Adenocarcinoma. ACS APPLIED MATERIALS & INTERFACES 2025; 17:29995-30005. [PMID: 40355809 DOI: 10.1021/acsami.5c03176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/15/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal cancer, typically diagnosed at advanced stages due to its asymptomatic onset and challenges in early detection. To address the critical need for the early diagnosis of PDAC, we developed a laser desorption/ionization mass spectrometry (LDI-MS) platform based on mesoporous silica-modified magnetic graphene (MG@mSiO2). MG@mSiO2 exhibited exceptional ultraviolet (UV) absorption, efficient ionization, and minimal background interference, enabling high-resolution profiling of serum metabolic fingerprints (SMFs). Based on the extracted SMFs, we constructed a Random Forest (RF) model to classify PDAC patients, high-risk (HR) individuals, and healthy controls (HC), achieving an accuracy of 97.5% in the independent test set. Additionally, a six-metabolite biomarker panel was identified, showing strong diagnostic potential with sensitivity and accuracy exceeding 89.1% for distinguishing HC from PDAC. When coupled with the serological marker carbohydrate antigen 19-9 (CA19-9), the integrated strategy delivered significantly improved diagnostic performance, achieving high accuracy ranging from 95.3% to 100% in distinguishing HR and PDAC patients from HC. Furthermore, metabolic pathway analysis revealed key pathways associated with PDAC progression, providing mechanistic insights into the disease. This work provides a powerful diagnostic tool for PDAC screening, establishing a foundation for early detection and precision medicine in clinical practice.
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Affiliation(s)
- Jia Qi
- Department of Chemistry, Zhongshan Hospital, Institutes of Biomedical Sciences, Fudan University, Shanghai 200433, China
| | - Caiyun Fang
- Department of Chemistry, Fudan University, Shanghai 200433, China
| | - Chunhui Deng
- Department of Chemistry, Zhongshan Hospital, Institutes of Biomedical Sciences, Fudan University, Shanghai 200433, China
| | - Fangying Shi
- School of Materials Science and Chemical Engineering, Ningbo University, Ningbo 315211, China
| | - Qunyan Yao
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Department of Gastroenterology and Hepatology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen 361015, China
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13
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Huang X, Wen Z, Cai H, Yu D. The role of quercetin in modulating lipid metabolism and enhancing chemotherapy via the STAT3-CPT1B pathway in pancreatic cancer. Biochem Biophys Res Commun 2025; 772:152033. [PMID: 40412371 DOI: 10.1016/j.bbrc.2025.152033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Revised: 05/13/2025] [Accepted: 05/14/2025] [Indexed: 05/27/2025]
Abstract
BACKGROUND Pancreatic cancer is a highly aggressive gastrointestinal tumor with limited treatment options, such as surgery and chemotherapy. Thus, further research into its pathogenesis and new treatments is necessary. METHODS Fluorescence-activated cell sorting was employed to sort pancreatic cancer stem cells (PCSCs). Sphere formation assays and Cell Counting Kit-8 (CCK-8) assays were conducted to assess stemness and proliferation capacity. Quantitative real-time PCR and Western blot analysis were employed to assess gene expression levels. Furthermore, immunofluorescence microscopy and chromatin immunoprecipitation assays were conducted to examine alterations in signaling pathways and gene expression. RESULTS Quercetin and gemcitabine may inhibit PANC-1 cells and PCSCs by affecting energy metabolism. Chromatin immunoprecipitation assays revealed an interaction between STAT3 and CPT1B in PCSCs. Quercetin and gemcitabine might affect energy metabolism by inhibiting STAT3 and CPT1B. Manipulating STAT3 expression (overexpression plasmids and siRNA knockdown) altered CPT1B mRNA and protein expression. Although acetyl-CoA reversed the quercetin- and gemcitabine-induced expression of N-cadherin, DECR1, and ALDH, it had minimal influence on CPT1B and STAT3 levels. CONCLUSION Quercetin inhibits the expression of CPT1B via the STAT3 signaling pathway, affecting lipid metabolism and exerting antitumor effects. Furthermore, the combined administration of quercetin and gemcitabine exhibits enhanced therapeutic efficacy.
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Affiliation(s)
- Xinshi Huang
- Department of Ultrasound, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Ouhai District, Wenzhou, Zhejiang, 325003, PR China
| | - Zhengde Wen
- Departments of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Ouhai District, Wenzhou, Zhejiang, 325003, PR China
| | - Huajie Cai
- Departments of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Ouhai District, Wenzhou, Zhejiang, 325003, PR China
| | - Dinglai Yu
- Departments of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Ouhai District, Wenzhou, Zhejiang, 325003, PR China.
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14
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Brys EA, Gryspeerdt F, Rashidian N, Lerut AV, Dries P, Abreu de Carvalho L, Berrevoet F. Postoperative Refractory Diarrhea After Margin Accentuation of the Superior Mesenteric Artery with Irreversible Electroporation in Pancreaticoduodenectomy. J Clin Med 2025; 14:3568. [PMID: 40429564 DOI: 10.3390/jcm14103568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2025] [Revised: 05/14/2025] [Accepted: 05/19/2025] [Indexed: 05/29/2025] Open
Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) presents a challenge due to its poor prognosis. Irreversible electroporation (IRE) shows promise in improving margin clearance and increasing R0 and R1 indirect resection rates. Although IRE is believed to preserve surrounding tissues, this study aimed to assess postoperative refractory diarrhea as a severe complication and challenge the assumption of consistent tissue preservation. Methods: Patients undergoing pancreaticoduodenectomy (PD) with IRE for superior mesenteric artery (SMA) margin accentuation between May 2022 and April 2024 were included. Primary endpoints were diarrhea-related morbidity and mortality; secondary endpoints included R-status, recurrence, and metastases. IRE electrodes were initially positioned circumferentially around the SMA, but this approach was modified to hemi-circumferential placement and applied in six additional patients. Results: All five patients (median age 70, 80% female) in the initial cohort developed secretory diarrhea lasting a median of 6 months (IQR 5-6.5), with a median frequency of 5 stools/day (IQR 5-6.5). Two patients (40%) died due to diarrhea-associated cachexia. In contrast, among the six patients treated with the modified technique, patients' diarrhea resolved within a median of 8 days (IQR 6-10) without need for opioid or advanced antidiarrheal therapy. Conclusions: Circumferential IRE for SMA margin accentuation may damage the superior mesenteric plexus and induce severe, prolonged diarrhea. Hemi-circumferential application may mitigate this risk. Larger studies are required to validate these findings and optimize the use of IRE in PD.
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Affiliation(s)
- Eline-Alice Brys
- Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium
| | - Filip Gryspeerdt
- Department of General and HPB Surgery and Liver Transplantation, Ghent University Hospital, 9000 Ghent, Belgium
| | - Nikdokht Rashidian
- Department of General and HPB Surgery and Liver Transplantation, Ghent University Hospital, 9000 Ghent, Belgium
| | - An Verena Lerut
- Department of General and HPB Surgery and Liver Transplantation, Ghent University Hospital, 9000 Ghent, Belgium
| | - Pieter Dries
- Department of General and HPB Surgery and Liver Transplantation, Ghent University Hospital, 9000 Ghent, Belgium
| | - Luís Abreu de Carvalho
- Department of General and HPB Surgery and Liver Transplantation, Ghent University Hospital, 9000 Ghent, Belgium
| | - Frederik Berrevoet
- Department of General and HPB Surgery and Liver Transplantation, Ghent University Hospital, 9000 Ghent, Belgium
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15
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Charbonneau J, Noël P, Ouellet JF, Ouellet JFB, Deshaies I, Daigle C, Ouellet É, Brind'Amour A. Diagnostic Value of Diffusion-Weighted MRI for the Detection of Peritoneal and Liver Metastases in High-Risk Pancreatic Ductal Adenocarcinoma: A Prospective Pilot Study. Ann Surg Oncol 2025:10.1245/s10434-025-17319-4. [PMID: 40392457 DOI: 10.1245/s10434-025-17319-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Accepted: 03/30/2025] [Indexed: 05/22/2025]
Abstract
BACKGROUND Metastatic presentation is frequent in patients with pancreatic adenocarcinoma and is not always detected on conventional imaging. This study aimed to evaluate the added value of preoperative diffusion-weighted MRI (DWI-MRI) in patients with high-risk pancreatic adenocarcinoma for the detection of peritoneal metastases. PATIENTS AND METHODS This was a prospective single-center pilot study with an aimed sample size of 40 patients. Eligible patients had pancreatic adenocarcinoma, no evidence of distant metastases on preoperative computed tomography (CT) scan, resectable or borderline resectable tumor, and at least one high-risk feature for peritoneal metastases [tumor size ≥ 3 cm and/or carbohydrate antigen 19-9 (CA19-9) ≥ 400 U/mL]. All patients underwent preoperative DWI-MRI. RESULTS A total of 40 patients were recruited, and 38 patients were included for analysis. Mean tumor size on CT scan was 37.3 mm. Median CA19-9 level was 495 U/mL. DWI-MRI revealed undetected peritoneal metastasis in 5.3% of cases (n = 2), but undetected liver metastases in 34.2% of cases (n = 13). DWI-MRI's sensitivity was 86.7% for liver metastases and 78.9% for overall abdominal metastases. The number needed to treat was 2.9 for the detection of liver metastases, and 2.5 for overall abdominal metastases. Unnecessary surgical exploration was avoided in 39.5% of the cohort. Ultimately, 18 patients were selected for curative-intent surgery, but metastases were found intraoperatively in four additional patients. At 6 months, three additional patients had developed metastatic disease. CONCLUSIONS DWI-MRI revealed few undetected peritoneal metastases, but a significant number of occult liver metastases. Our findings suggest that performing preoperative DWI-MRI in patients with pancreatic adenocarcinoma with high-risk features could be beneficial.
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Affiliation(s)
- Janyssa Charbonneau
- Division of General surgery, Department of Surgery, CHU de Québec - Université Laval, Quebec, QC, Canada
| | - Patricia Noël
- Department of Medical Imaging, CHU de Québec - Université Laval, Quebec, QC, Canada
| | - Jean-François Ouellet
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, CHU de Québec - Université Laval, Quebec, QC, Canada
| | - Jean-François Berthin Ouellet
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, CHU de Québec - Université Laval, Quebec, QC, Canada
| | - Isabelle Deshaies
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, CHU de Québec - Université Laval, Quebec, QC, Canada
| | - Carl Daigle
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, CHU de Québec - Université Laval, Quebec, QC, Canada
| | - Étienne Ouellet
- Department of Medical Imaging, CHU de Québec - Université Laval, Quebec, QC, Canada
| | - Alexandre Brind'Amour
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, CHU de Québec - Université Laval, Quebec, QC, Canada.
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16
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He R, Shen Z, Chen Q, Hu H, Ding X, Zheng Z, Feng Q, Li B. Pancreatic cancer mortality in China from 2004 to 2021: an in-depth analysis of age, gender, and regional disparities. BMC Cancer 2025; 25:891. [PMID: 40389880 PMCID: PMC12087137 DOI: 10.1186/s12885-025-13863-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 03/04/2025] [Indexed: 05/21/2025] Open
Abstract
OBJECTIVE This study aimed to analyze the trends and epidemiological characteristics of pancreatic cancer (PC) mortality in China from 2004 to 2021, focusing on gender, age, and regional disparities. The goal was to provide a comprehensive understanding of PC mortality and identify key risk factors to support future prevention and control strategies. METHODS Using data from the national Disease Surveillance Point (DSP) system, which covers a large and representative sample of the Chinese population, the study examined pancreatic cancer mortality trends across different age groups, sexes, and regions. Statistical analyses, including the independent-sample t-test and age-period-cohort (APC) model, were employed to assess mortality differences and annual percentage changes from 2004 to 2021. RESULTS The study recorded a significant increase in pancreatic cancer mortality, particularly among males and older adults. Mortality was consistently higher in urban areas, but the growth rate in rural areas surpassed that of urban areas. Regional disparities were also observed, with the eastern region showing the highest mortality rates but slower increases compared to the central and western regions. Key risk factors, including aging, diabetes, smoking, and chronic pancreatitis, were identified, with gender-specific differences linked to lifestyle factors such as smoking and alcohol consumption. CONCLUSION Pancreatic cancer mortality in China has shown significant increases over the past 18 years, especially among males, older adults, and rural populations. The findings highlight the urgent need for targeted public health interventions to address gender- and age-specific risks, as well as healthcare access inequalities in less developed regions. Future research should focus on gathering more granular, individual-level data to better understand the complex interplay of risk factors and inform more effective prevention and treatment strategies.
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Affiliation(s)
- Rui He
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Zhengnan Shen
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Qiuping Chen
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Haiyang Hu
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Xin Ding
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Zhenglong Zheng
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Quansheng Feng
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
| | - Baixue Li
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
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17
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Jiang Y, Ji D, Chen W, Zhu Y, Luo M, Zou R, Fu Y, Huang P, Shi Q, Wang D, Song Z. Phosphorylation of USP32 by CDK5 regulates Rap1 stability and therapeutic resistance in pancreatic ductal adenocarcinoma. Oncogene 2025:10.1038/s41388-024-03263-2. [PMID: 40379759 DOI: 10.1038/s41388-024-03263-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 12/03/2024] [Accepted: 12/11/2024] [Indexed: 05/19/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal human cancer. Gemcitabine-based chemotherapy remains the cornerstone for advanced PDAC. However, resistance to chemotherapy greatly limits its clinical therapeutic efficacy. Accordingly, the identification of novel therapeutic targets to overcome chemoresistance and improve prognosis is urgently needed. Screening of deubiquitinase family members, tandem affinity purification, mass spectrometry, and RNA sequencing (RNA-Seq) analysis were performed to predict the interactions and function of the CDK5-USP32-Rap1 axis in PDAC. In vitro and in vivo experiments were performed to elucidate the regulatory mechanism and biological roles of this axis in glycolytic reprogramming and chemoresistance in PDAC. Finally, TCGA database analysis and immunohistochemistry were performed to determine the expression and clinical significance of CDK5, USP32, and Rap1 in PDAC tissues. USP32 was identified as a bona fide deubiquitinase of Rap1. USP32 deubiquitinates and stabilizes Rap1, thereby promoting glycolytic reprogramming and chemoresistance in PDAC cells. Moreover, we unexpectedly found that CDK5-mediated phosphorylation of USP32 is required for its deubiquitinase activity toward Rap1 and drives malignant phenotypes of PDAC. Additionally, these functions can be significantly inhibited by pharmacological inhibition (roscovitine) or genetic ablation of CDK5. Importantly, combining a CDK5 inhibitor with gemcitabine has a synergetic anticancer effect. Indeed, the effectiveness of targeting CDK5 to sensitize PDAC cells to gemcitabine was confirmed in a patient-derived xenograft (PDX) model. CDK5 and USP32 expression is markedly elevated in PDAC samples and positively associated with Rap1 expression. Increased expression of CDK5, USP32, and Rap1 is significantly associated with poorer prognosis in PDAC. We identified the previously unrecognized oncogenic function and clinical importance of the CDK5-USP32-Rap1 axis, providing preclinical evidence for potential new combination strategies for PDAC therapy.
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Affiliation(s)
- Yanxia Jiang
- Department of Endocrinology and Metabolism, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
- Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Dexiang Ji
- Department of Hematology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Wen Chen
- Department of Breast Surgery, Jiangxi Cancer Hospital, the Second Affiliated Hospital of Nanchang Medical College, Jiangxi Clinical Research Center for Cancer, Nanchang, 330029, Jiangxi, China
| | - Yuanzhe Zhu
- Department of Oncology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Ming Luo
- Department of Oncology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Rui Zou
- Department of Oncology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Yilun Fu
- Department of Oncology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Ping Huang
- Department of Oncology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Qing Shi
- Department of Endocrinology and Metabolism, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Dejie Wang
- Department of Gastroenterology, Collaborative Innovation Center of Gastroenterology, Angiocardiopathy and Neurosciences, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China.
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.
| | - Zhiwang Song
- Department of Oncology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China.
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18
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Fang J, Wang M, Gao Y, Qi Y, Hong W, Xiao C. Prediction of overall survival in pancreatic cancer based on a twenty-four-gene risk model associated with lymph node metastasi. Medicine (Baltimore) 2025; 104:e42448. [PMID: 40388767 PMCID: PMC12091656 DOI: 10.1097/md.0000000000042448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Accepted: 04/27/2025] [Indexed: 05/21/2025] Open
Abstract
Pancreatic adenocarcinoma (PAAD) is a leading cause of tumor-related mortality. Identifying potential prognostic risk genes is crucial for predicting the overall survival of PAAD patients. In this study, we constructed and validated a 24-gene risk score. This risk score stratifies PAAD patients into low-risk and high-risk groups. The model demonstrated excellent prognostic accuracy at different follow-up times (1-year AUC: 0.81, 2-year AUC: 0.85, 3-year AUC: 0.92). PAAD patients from 3 GEO datasets were categorized into low-risk and high-risk groups, with survival analysis revealed significant differences in survival rates between the 2 groups (P < .01). Multivariate analysis identified 2 independent risk factors, namely, N stage (HR 2.026, 95% CI 1.139-3.603, P = .016) and the 24-gene risk score (HR 0.239, 95% CI 0.148-0.385, P < .001). The performance of the nomogram in the TCGA database is commendable (AUC for 1-year, 2-year, and 3-year survival rates = 0.76, 0.77, and 0.86, respectively). In essence, our work establishes a 24-gene risk score and nomogram to facilitate clinicians in predicting the prognosis of individual PAAD patients.
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Affiliation(s)
- Junwei Fang
- Department of General Surgery, 900th Hospital of Joint Logistics Support Force of People’s Liberation Army, Fuzhou, China
| | - Meiping Wang
- Department of General Surgery, 900th Hospital of Joint Logistics Support Force of People’s Liberation Army, Fuzhou, China
| | - Yi Gao
- Fujian University of Traditional Chinese, Fuzhou, China
| | - Yafeng Qi
- Department of General Surgery, 900th Hospital of Joint Logistics Support Force of People’s Liberation Army, Fuzhou, China
| | - Weixuan Hong
- Department of General Surgery, 900th Hospital of Joint Logistics Support Force of People’s Liberation Army, Fuzhou, China
| | - Chunhong Xiao
- Department of General Surgery, 900th Hospital of Joint Logistics Support Force of People’s Liberation Army, Fuzhou, China
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19
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Yan B, Fritsche AK, Haußner E, Inamdar TV, Laumen H, Boettcher M, Gericke M, Michl P, Rosendahl J. From Genes to Environment: Elucidating Pancreatic Carcinogenesis Through Genetically Engineered and Risk Factor-Integrated Mouse Models. Cancers (Basel) 2025; 17:1676. [PMID: 40427173 DOI: 10.3390/cancers17101676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2025] [Revised: 05/07/2025] [Accepted: 05/13/2025] [Indexed: 05/29/2025] Open
Abstract
Pancreatic cancer is characterized by late diagnosis, therapy resistance, and poor prognosis, necessitating the exploration of early carcinogenesis and prevention methods. Preclinical mouse models have evolved from cell line-based to human tumor tissue- or organoid-derived xenografts, now to humanized mouse models and genetically engineered mouse models (GEMMs). GEMMs, primarily driven by oncogenic Kras mutations and tumor suppressor gene alterations, offer a realistic platform for investigating pancreatic cancer initiation, progression, and metastasis. The incorporation of inducible somatic mutations and CRISPR-Cas9 screening methods has expanded their utility. To better recapitulate tumor initiation triggered by inflammatory cues, common pancreatic risk factors are being integrated into model designs. This approach aims to decipher the role of environmental factors as secondary or parallel triggers of tumor initiation alongside oncogenic burdens. Emerging models exploring pancreatitis, obesity, diabetes, and other risk factors offer significant translational potential. This review describes current mouse models for studying pancreatic carcinogenesis, their combination with inflammatory factors, and their utility in evaluating pathogenesis, providing guidance for selecting the most suitable models for pancreatic cancer research.
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Affiliation(s)
- Bin Yan
- Department of Internal Medicine IV, Heidelberg University Hospital, 69120 Heidelberg, Germany
| | - Anne-Kristin Fritsche
- Institute of Anatomy and Cell Biology, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany
- Institute of Anatomy, Leipzig University, 04103 Leipzig, Germany
| | - Erik Haußner
- Institute of Molecular Medicine, Section for Molecular Medicine of Signal Transduction, Faculty of Medicine, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany
| | - Tanvi Vikrant Inamdar
- Department of Internal Medicine I, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany
| | - Helmut Laumen
- Department of Internal Medicine I, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany
| | - Michael Boettcher
- Institute of Molecular Medicine, Section for Molecular Medicine of Signal Transduction, Faculty of Medicine, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany
| | - Martin Gericke
- Institute of Anatomy, Leipzig University, 04103 Leipzig, Germany
| | - Patrick Michl
- Department of Internal Medicine IV, Heidelberg University Hospital, 69120 Heidelberg, Germany
| | - Jonas Rosendahl
- Department of Internal Medicine I, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany
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20
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Selvi S, Real CM, Gentiluomo M, Balounova K, Vokacova K, Cumova A, Mohlenikova-Duchonova B, Rizzato C, Halasova E, Vodickova L, Smolkova B, Hemminki K, Campa D, Vodicka P. Genomic instability, DNA damage response and telomere homeostasis in pancreatic cancer. Semin Cancer Biol 2025; 113:59-73. [PMID: 40378535 DOI: 10.1016/j.semcancer.2025.05.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 04/16/2025] [Accepted: 05/04/2025] [Indexed: 05/19/2025]
Abstract
Pancreatic cancer (PC) is becoming one of the most serious health problems at present, but its causes and risk factors are still unclear. One of the drivers in pancreatic carcinogenesis is altered genomic (DNA) integrity with subsequent genomic instability in cancer cells. The latter comprises a) DNA damage response and DNA repair mechanisms, b) DNA replication and mitosis, c) epigenetic regulation, and d) telomere maintenance. In our review we addressed the above aspects in relation to the most abundant and severe form of PC, pancreatic ductal adenocarcinoma (PDAC). In summary, the interactions between the DNA damage response, telomere homeostasis and mitotic regulation are not comprehensively understood at present, including the epigenetic factors entering the trait of genomic stability maintenance. In addition, the complexity of telomere homeostasis in relation to PDAC risk, prognosis and prediction also warrants further investigations.
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Affiliation(s)
- Saba Selvi
- Institute of Experimental Medicine, Czech Academy of Sciences, Videnska 1083, Prague 4 14200, Czech Republic; Department of Genetics and Microbiology, Faculty of Science, Charles University, Prague 12800, Czech Republic
| | - Carmen Macías Real
- Cancer Predisposition and Biomarkers Group, Instituto de Investigacion Sanitaria de Santiago, Santiago de Compostela, Spain
| | | | - Katerina Balounova
- Institute of Experimental Medicine, Czech Academy of Sciences, Videnska 1083, Prague 4 14200, Czech Republic; Department of Physiology, Faculty of Science, Charles University, Prague, Czech Republic
| | - Klara Vokacova
- Institute of Experimental Medicine, Czech Academy of Sciences, Videnska 1083, Prague 4 14200, Czech Republic
| | - Andrea Cumova
- Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, Bratislava 84505, Slovakia
| | | | - Cosmeri Rizzato
- Department of Biology, University of Pisa, Pisa 56123, Italy
| | - Erika Halasova
- Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Mala Hora 4, Martin 03601, Slovakia
| | - Ludmila Vodickova
- Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Mala Hora 4, Martin 03601, Slovakia; Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1655, Pilsen 32300, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, Prague 12800, Czech Republic
| | - Bozena Smolkova
- Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, Bratislava 84505, Slovakia
| | - Kari Hemminki
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1655, Pilsen 32300, Czech Republic; Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, FRG 69120, Germany
| | - Daniele Campa
- Department of Biology, University of Pisa, Pisa 56123, Italy
| | - Pavel Vodicka
- Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Mala Hora 4, Martin 03601, Slovakia; Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1655, Pilsen 32300, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, Prague 12800, Czech Republic.
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21
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Yao XQ, Sabatinos SA, Da Silva E, Taggar A, Ha D, Khan R, Karshafian R, Gräfe J. Therapeutic enhancement effects using a lower energy 2.5 MV photon beam combined with gold nanoparticles on the BxPC-3 pancreatic cancer cell line, in vitro. Phys Med Biol 2025; 70:105017. [PMID: 40328291 DOI: 10.1088/1361-6560/add4b8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Accepted: 05/06/2025] [Indexed: 05/08/2025]
Abstract
Objective. This study investigates the feasibility of using a clinically relevant lower energy 2.5 megavoltage (MV) photon beam in combination with gold nanoparticles (GNPs).Approach.Pancreatic cancer cell line, BxPC-3 impregnated with GNPs were exposedin vitroto 2.5 MV photon beam and compared with orthovoltage 225 kV and clinical 6 MV photon beam. Bare, 50 nm diameter, spherical GNPs were introduced in the cell culture 24 h prior to irradiation at a concentration of either 10μg ml-1or 50μg ml-1. GNP uptake was determined using inductively coupled plasma optical emission spectroscopy. The cells were irradiated with doses between 0 Gy to 8 Gy. Cell survival curves were obtained via clonogenic assay using immediate or delayed plating (24 h) methods 12 d after irradiation. The terminal deoxynucleotidyl transferase dUTP nick end labeling assay was used to evaluate DNA damage at two time points post irradiation, immediate and 24 h for 1 Gy and 6 Gy.Main results. The enhancement factor (EF) in BxPC-3 cells was greatest for cells incubated with 50μg ml-1of GNPs analyzed immediately post irradiation. Cells irradiated with 225 kV showed greatest EF (1.57 ± 0.15), followed by 2.5 MV (1.51 ± 0.04). The lowest EF was seen for 6 MV, immediate plating (1.10 ± 0.04). A significant increase in the number of DNA double strand breaks (DSB) was observed in cells incubated with 50μg ml-1of GNPs irradiated at 6 Gy with 225 kV and 2.5 MV. There was no significant increase in DSBs for the cells irradiated with 6 MV.Significance.These results suggest that the 2.5 MV could be a compromise between an orthovoltage energy beam and a clinical 6 MV beam, showing comparable reduction in cell survival to the 225 kV beam. Future GNP radiation enhancement research may focus on intermediate energy beams.
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Affiliation(s)
- Xiao Qing Yao
- Department of Physics, Toronto Metropolitan University, Toronto, Ontario M5B 2K3, Canada
- Institute for Biomedical Engineering, Science and Technology (iBEST), A Partnership Between Toronto Metropolitan University and St. Michael's Hospital, 209 Victoria Street, Toronto, Ontario M5B 1T8, Canada
| | - Sarah A Sabatinos
- Department of Chemistry & Biology, Toronto Metropolitan University, Toronto M5B 2K3, Canada
| | - Eric Da Silva
- Department of Physics, Toronto Metropolitan University, Toronto, Ontario M5B 2K3, Canada
| | - Amandeep Taggar
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto M4N 3M5, Canada
| | - Diana Ha
- Department of Physics, Toronto Metropolitan University, Toronto, Ontario M5B 2K3, Canada
| | - Rao Khan
- Department of Physics and Astronomy, Howard University, Washington, DC, United States of America
| | - Raffi Karshafian
- Department of Physics, Toronto Metropolitan University, Toronto, Ontario M5B 2K3, Canada
- Institute for Biomedical Engineering, Science and Technology (iBEST), A Partnership Between Toronto Metropolitan University and St. Michael's Hospital, 209 Victoria Street, Toronto, Ontario M5B 1T8, Canada
| | - James Gräfe
- Department of Physics, Toronto Metropolitan University, Toronto, Ontario M5B 2K3, Canada
- Department of Medical Physics, Dr H. Bliss Murphy Cancer Centre, NL Health Services, St. John's, Newfoundland, Canada
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22
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Terzapulo X, Dyussupova A, Ilyas A, Boranova A, Shevchenko Y, Mergenbayeva S, Filchakova O, Gaipov A, Bukasov R. Detection of Cancer Biomarkers: Review of Methods and Applications Reported from Analytical Perspective. Crit Rev Anal Chem 2025:1-46. [PMID: 40367278 DOI: 10.1080/10408347.2025.2497868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/16/2025]
Abstract
One in five deaths in developed countries is related to cancer. The cancer prevalence is likely to grow with aging population. The affordable and accurate early diagnostics of cancer based on detection of cancer biomarkers at low concentration during its early stages is one of the most efficient way to decrease mortality and human suffering from cancer. The data from 201 analytical papers are tabulated in 9 tables, illustrated in 8 figures and used for comparative analysis of methods applied for cancer biomarker detection, including polymerase chain reaction, Loop-mediated isothermal amplification (LAMP), mass spectrometry, enzyme-linked immunosorbent assay, electroanalytical methods, immunoassays, surface enhanced Raman scattering, Fourier Transform Infrared and others in terms of above-mentioned performance parameters. Median and/or average limit of detection (LOD) are calculated and compared between different analytical methods. We also described and compared LOD of the methods used for detection of three frequently detected cancer biomarkers: carcinoembryonic antigen, prostate-specific antigen and alpha-fetoprotein. Among those methods of detection, the reported electrochemical sensors often demonstrate relatively high sensitivity/low LOD while they often have a moderate instrumental cost and fast time to results. The review tabulates, compares and discusses analytical papers, which report LOD of cancer biomarkers and comprehensive quantitative comparison of various analytical methods is made. The discussion of those techniques applied for cancer biomarker detection included brief summary of pro and cons for each of those methods.
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Affiliation(s)
- Xeniya Terzapulo
- Chemistry Department, School of Sciences and Humanities, Nazarbayev University, Astana, Republic of Kazakhstan
| | - Aigerim Dyussupova
- Chemistry Department, School of Sciences and Humanities, Nazarbayev University, Astana, Republic of Kazakhstan
| | - Aisha Ilyas
- Chemistry Department, School of Sciences and Humanities, Nazarbayev University, Astana, Republic of Kazakhstan
| | - Aigerim Boranova
- Chemistry Department, School of Sciences and Humanities, Nazarbayev University, Astana, Republic of Kazakhstan
| | - Yegor Shevchenko
- Chemistry Department, School of Sciences and Humanities, Nazarbayev University, Astana, Republic of Kazakhstan
| | - Saule Mergenbayeva
- Chemistry Department, School of Sciences and Humanities, Nazarbayev University, Astana, Republic of Kazakhstan
| | - Olena Filchakova
- Biology Department, School of Sciences and Humanities, Nazarbayev University, Astana, Republic of Kazakhstan
| | - Abduzhappar Gaipov
- Department of Medicine, Nazarbayev University School of Medicine, Astana, Republic of Kazakhstan
| | - Rostislav Bukasov
- Chemistry Department, School of Sciences and Humanities, Nazarbayev University, Astana, Republic of Kazakhstan
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23
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Zhao H, Du F, Huang J, Guo R, Feng Z, Wang Z, Qiu L. Biomimetic liposomal nanovesicles remodel the tumor immune microenvironment to augment sono-immunotherapy. J Control Release 2025; 383:113830. [PMID: 40355046 DOI: 10.1016/j.jconrel.2025.113830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 05/05/2025] [Accepted: 05/07/2025] [Indexed: 05/14/2025]
Abstract
Sonodynamic therapy (SDT)-mediated immunogenic cell death and immune checkpoint blockade offer new opportunities for tumor treatment. However, challenges including immunosuppression, hypoxic tumor microenvironments, and inadequate drug delivery hinder therapeutic efficacy. Therefore, we developed a multifunctional biomimetic liposome microbubble named H-R@Lip@M, which is coated with melanoma cell membranes, contains perfluoropentane as its core, and is loaded with the sonosensitizer hematoporphyrin monomethyl ether and the immune adjuvant resiquimod. The targeting properties of melanoma cell membranes enable effective accumulation of nanoparticles (NPs) at tumor sites. Equipped with ultrasonic/photoacoustic imaging capabilities, these NPs allow precise control over the release of drugs and oxygen upon ultrasound stimulation. In vitro and in vivo results consistently showed that the NPs enhanced anti-tumor efficacy, halting primary tumor progression and preventing lung metastasis. Moreover, SDT increased reactive oxygen species levels within tumors, preferentially inducing apoptosis while maximizing immunogenic cell death. When combined with PD-L1 blockade, this synergy promotes dendritic cell maturation and alters various immune populations, boosting T-cell infiltration while enhancing M1 macrophage polarization and reducing regulatory T-cell presence. In summary, the proposed combination has the potential to synergistically enhance the efficacy of sono-immunotherapy by remodeling the immunosuppressive microenvironment, providing valuable insights for addressing challenges associated with SDT-based cancer therapy.
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Affiliation(s)
- Hongxin Zhao
- Department of Ultrasound, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Fangxue Du
- Department of Ultrasound, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jianbo Huang
- Department of Ultrasound, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Ruiqian Guo
- Department of Ultrasound, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Ziyan Feng
- Department of Ultrasound, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Ziyao Wang
- Department of Ultrasound, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Li Qiu
- Department of Ultrasound, West China Hospital, Sichuan University, Chengdu 610041, China.
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24
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He Z, Liu F, Lin L, Huang Z, Wang Y. Interplay Between Schwann Cells and Peripheral Cancers: Mechanisms and Therapeutic Targets in Cancer Progression. Glia 2025. [PMID: 40346871 DOI: 10.1002/glia.70032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Revised: 03/19/2025] [Accepted: 05/01/2025] [Indexed: 05/12/2025]
Abstract
Cancer, a leading global health concern, is characterized by uncontrolled proliferation of cells, high invasion into surrounding tissues, and eventual metastasis to distant organs. The complexity of cancer is further amplified by diverse cellular components within the tumor microenvironment (TME), encompassing both cancerous and non-cancerous cells that fuel tumorigenesis and progression. Schwann cells (SCs), the main glial cells of the peripheral nervous system, have emerged as crucial components within the TME in cancer development. Here, we summarize the multifaceted roles of SCs in tumor growth, epithelial-mesenchymal transition, perineural invasion, and chemotherapy resistance. This review focuses on the effects of SCs on eight distinct peripheral cancer types, particularly pancreatic, lung, and colorectal cancers, along with cancer-related pain, one of the most common symptoms that affect quality of life and prognosis in cancer patients. Furthermore, we emphasize the therapeutic potential of SCs by delving into advanced technologies and clinical strategies related to SCs, which make us advocate for further research to elucidate the events and molecular mechanisms underlying the SC-cancer relationship. Translating these insights into clinical applications may offer new hope for improved cancer management and patient outcomes.
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Affiliation(s)
- Ziwan He
- School of Pharmacy, Hangzhou Normal University, Zhejiang, China
| | - Furui Liu
- School of Pharmacy, Hangzhou Normal University, Zhejiang, China
| | - Lin Lin
- School of Pharmacy, Hangzhou Normal University, Zhejiang, China
| | - Zhihui Huang
- School of Pharmacy, Hangzhou Normal University, Zhejiang, China
| | - Yongjie Wang
- School of Pharmacy, Hangzhou Normal University, Zhejiang, China
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25
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Chen L, Li H, Liu J, Wang Y, Zhang S. Hollow Mesoporous Carbon Nanospheres Derived from Metal-Organic Frameworks for Efficient Sono-immunotherapy against Pancreatic Cancer. CYBORG AND BIONIC SYSTEMS 2025; 6:0247. [PMID: 40352815 PMCID: PMC12062583 DOI: 10.34133/cbsystems.0247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2025] [Revised: 01/20/2025] [Accepted: 03/01/2025] [Indexed: 05/14/2025] Open
Abstract
Sono-immunotherapy is expected to effectively enhance treatment efficacy and reduce mortality in patients with pancreatic cancer. Hence, efficient applicable sono-immunotherapy systems are urgently needed for the treatment of this condition. In this study, hollow mesoporous carbon (HMC) nanoparticles were prepared using the sacrificial template method. These nanoparticles had a porphyrin-like structure and could generate singlet oxygen more efficiently than commercial TiO2. Cellular assays showed that HMC killed tumor cells in the presence of ultrasonication, primarily by inducing apoptosis. HMC could also accelerate the release of immune factors by tumor cells, thereby activating dendritic cells and enhancing the efficacy of immunotherapy. Experiments in tumor-bearing mice and in situ pancreatic cancer tests showed that HMC, in combination with the small-molecule inhibitors of programmed cell death ligand 1, could reduce tumor growth via the generation of reactive oxygen species following ultrasonication. HMC could enhance the efficacy of immunotherapy by disrupting the immunosuppressive tumor microenvironment and promoting the accumulation of immune cells. Accordingly, in vivo sono-immunotherapy was achieved, and the growth of transplanted tumors and in situ tumors could be reduced. In conclusion, this study proposes a novel method for the preparation of HMC nanoparticles and demonstrates their potential in tumor treatment. Additionally, owing to their unique structure, these HMC nanoparticles could be used for different combination therapies tailored based on specific clinical requirements.
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Affiliation(s)
- Libin Chen
- Liaoning Cancer Hospital & Institute, Cancer Hospital of Dalian University of Technology,
Cancer Hospital of China Medical University, Shenyang 110042, China
- Department of Ultrasound Medicine,
The First Affiliated Hospital of Ningbo University, Ningbo 315010, China
| | - Haiwei Li
- Liaoning Cancer Hospital & Institute, Cancer Hospital of Dalian University of Technology,
Cancer Hospital of China Medical University, Shenyang 110042, China
| | - Jing Liu
- Department of Radiology,
The First Hospital of China Medical University, Shenyang 110001, China
| | - Yunzhong Wang
- Department of Ultrasound Medicine,
The First Affiliated Hospital of Ningbo University, Ningbo 315010, China
| | - Shengmin Zhang
- Department of Ultrasound Medicine,
The First Affiliated Hospital of Ningbo University, Ningbo 315010, China
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Yonemura H, Kuwatani M, Nakajima K, Masamune A, Ogawa M, Sakamoto N. Treatment of Pancreatic Cancer Using Near-Infrared Photoimmunotherapy Targeting Cancer-Associated Fibroblasts in Combination with Anticancer Chemotherapeutic Drug. Cancers (Basel) 2025; 17:1584. [PMID: 40361512 PMCID: PMC12071749 DOI: 10.3390/cancers17091584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2025] [Revised: 04/26/2025] [Accepted: 05/03/2025] [Indexed: 05/15/2025] Open
Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC), which has a poor prognosis, involves an overabundance of fibroblasts and extracellular matrix. Cancer-associated fibroblasts (CAFs) are critical for providing structural support by secreting soluble factors and extracellular matrix proteins into the stroma. We assessed the potential of near-infrared photoimmunotherapy (NIR-PIT) targeting CAFs in PDAC. Methods: PDAC cells (Capan-1 and SUIT-2) and CAFs (hPSC-5) were used. Anti-human fibroblast activation protein (FAP)/podoplanin (PDPN) antibodies were used to bind to CAFs and conjugates with the specific photosensitizer IRDye®700DX (IR700) to investigate the effects of NIR-PIT. Thereafter, BALB/c Slc-nu/nu mice were transplanted with Capan-1 and/or CAFs and treated with gemcitabine (GEM) with or without NIR-PIT. Results: The binding rate of anti-FAP antibody-AlexaFluor®488 conjugate to hPSC-5 cells was high, whereas that of the anti-PDPN antibody-conjugate was not. The incubation of anti-FAP antibody-IR700 conjugate (αFAP-IR700) with hPSC-5 cells for 3 h led to maximal fluorescence on the surface of hPSC-5 cells. When NIR-PIT with αFAP-IR700 was performed in the co-culture group of Capan-1 and hPSC-5 cells, the proliferative capacity of Capan-1 cells decreased to the same level as that when Capan-1 cells were cultured alone (p < 0.05). In vivo, compared with the GEM group, the NIR-PIT with the GEM group showed a significant reduction in the tumor volume (day 28: 79 vs. 382 mm3, p < 0.05). Tumor volumes in the NIR-PIT group were not reduced compared with those in the control group. Conclusions: Combining NIR-PIT with conventional chemotherapy to target CAFs may enhance the anticancer effects on PDAC.
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Affiliation(s)
- Hiroki Yonemura
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, North 15, West 7, Kita-ku, Sapporo 060-8648, Hokkaido, Japan; (H.Y.); (N.S.)
| | - Masaki Kuwatani
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, North 15, West 7, Kita-ku, Sapporo 060-8648, Hokkaido, Japan; (H.Y.); (N.S.)
| | - Kohei Nakajima
- Laboratory of Bioanalysis and Molecular Imaging, Graduate School of Pharmaceutical Sciences, Hokkaido University, North 12, West 6, Kita-ku, Sapporo 060-0812, Hokkaido, Japan; (K.N.); (M.O.)
| | - Atsushi Masamune
- Division of Gastroenterology, Tohoku University Hospital, Seiryocho1-1, Aoba-ku, Sendai 980-8574, Miyagi, Japan;
| | - Mikako Ogawa
- Laboratory of Bioanalysis and Molecular Imaging, Graduate School of Pharmaceutical Sciences, Hokkaido University, North 12, West 6, Kita-ku, Sapporo 060-0812, Hokkaido, Japan; (K.N.); (M.O.)
- Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, North 21, West 10, Kita-ku, Sapporo 001-0021, Hokkaido, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, North 15, West 7, Kita-ku, Sapporo 060-8648, Hokkaido, Japan; (H.Y.); (N.S.)
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Ge Y, Zhu X, Zhang Z, Zhu H, Wang T, Cui J, Zeng H, Wu X, Zhang Z. RGD peptide/dextran sulfate-based nanocarriers loaded with triptolide for double-targeted apoptosis of both tumor cells and M2-like TAMs in pancreatic cancer therapy. Int J Biol Macromol 2025; 311:144032. [PMID: 40345287 DOI: 10.1016/j.ijbiomac.2025.144032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 04/08/2025] [Accepted: 05/06/2025] [Indexed: 05/11/2025]
Abstract
Triptolide (TP) is a promising anti-tumor candidate derived from the herb Tripterygium wilfordii, but its poor water solubility and multi-organ toxicity limit its application. Here, we developed novel nanoparticles (TP-SP@NPs) modified with dextran sulfate and RGD peptide for double-targeted delivery of TP to both tumor cells and pro-tumor macrophages in pancreatic cancer treatment. TP-SP@NPs exhibited suitable particle size (about 98 nm), good stability and controlled release performance. TP-SP@NPs showed high cellular uptake in Pan02 cells and M2 macrophages through αvβ3 integrin-RGD interaction and SR-A-DS interaction, effectively inhibiting tumor growth by triggering apoptosis of these cells. In Pan02 tumor-bearing mice, TP-SP@NPs specifically accumulated at the tumor site and efficiently decreased the number of M2 macrophages, thereby exerting better curative effect on pancreatic cancer and lower systemic toxicity as compared with TP. As a result, TP-SP@NPs had achieved selective anti-tumor effect, good biosafety and great promise in clinical application.
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Affiliation(s)
- Yaning Ge
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, Henan Province 450046, PR China
| | - Xin Zhu
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, Henan Province 450046, PR China
| | - Zhengxian Zhang
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, Henan Province 450046, PR China
| | - Huanhuan Zhu
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, Henan Province 450046, PR China
| | - Tianqi Wang
- Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Henan Province 450046, PR China
| | - Jingru Cui
- Academy of Chinese Medicine Sciences, Henan University of Chinese Medicine, Zhengzhou, Henan Province 450046, PR China
| | - Huahui Zeng
- Academy of Chinese Medicine Sciences, Henan University of Chinese Medicine, Zhengzhou, Henan Province 450046, PR China; Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Henan Province 450046, PR China.
| | - Xiangxiang Wu
- Academy of Chinese Medicine Sciences, Henan University of Chinese Medicine, Zhengzhou, Henan Province 450046, PR China; Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Henan Province 450046, PR China.
| | - Zhenqiang Zhang
- Academy of Chinese Medicine Sciences, Henan University of Chinese Medicine, Zhengzhou, Henan Province 450046, PR China; Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Henan Province 450046, PR China.
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Hammouz RY, Baryła I, Styczeń-Binkowska E, Bednarek AK. Twenty-five years of WWOX insight in cancer: a treasure trove of knowledge. Funct Integr Genomics 2025; 25:100. [PMID: 40327201 PMCID: PMC12055895 DOI: 10.1007/s10142-025-01601-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 04/01/2025] [Accepted: 04/12/2025] [Indexed: 05/07/2025]
Abstract
More than two decades ago, MD Anderson Cancer group discovered, characterised, and identified the WW domain-containing oxidoreductase (WWOX) as a genes of interest mapping to the chromosomal region 16q23.3-24.2. This was pioneering research since WWOX is a critical tumour suppressor gene implicated in various cancers, involving interactions with numerous signalling pathways and molecular mechanisms. Notably, it inhibits the Wnt/β-catenin pathway, which is often activated in tumours. This inhibition helps prevent tumour formation by regulating cell proliferation and promoting apoptosis. Restoration of WWOX expression in cancer cell lines has been shown to reduce tumour growth and increased sensitivity to treatments. In addition to its role in tumour suppression, WWOX has been found to interact with proteins involved in critical signalling pathways such as TGF-β. Recent advancements allowed to reveal its interactions with key proteins and microRNAs that regulate cellular adhesion, invasion, and motility. Proteomic studies have shown that WWOX directly interacts with signalling molecules like Dishevelled and SMAD3, further underscoring its role in antagonizing metastasis. Challenges remain in translating this knowledge into clinical applications. For instance, the mechanisms underlying WWOX loss in tumours and its role across diverse cancer types require further investigation. Overall, WWOX serves as a vital player in maintaining cellular stability and preventing cancer progression through its multifaceted functions. Here, we include an updated molecular function of WWOX in cancers to possibly contribute to the potential use of WWOX expression as a biomarker regarding prognosis and response to the treatment. CLINICAL TRIAL NUMBER: Not applicable.
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Affiliation(s)
- Raneem Y Hammouz
- Department of Molecular Carcinogenesis, Medical University of Lodz, Żeligowskiego 7/9, Lodz, 90-752, Poland
| | - Izabela Baryła
- Department of Molecular Carcinogenesis, Medical University of Lodz, Żeligowskiego 7/9, Lodz, 90-752, Poland
| | - Ewa Styczeń-Binkowska
- Department of Molecular Carcinogenesis, Medical University of Lodz, Żeligowskiego 7/9, Lodz, 90-752, Poland
| | - Andrzej K Bednarek
- Department of Molecular Carcinogenesis, Medical University of Lodz, Żeligowskiego 7/9, Lodz, 90-752, Poland.
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Chen C, Wang J, Zhu X, Zhang S, Yuan X, Hu J, Liu C, Liu L, Zhang Z, Li J. Lactylation as a metabolic epigenetic modification: Mechanistic insights and regulatory pathways from cells to organs and diseases. Metabolism 2025; 169:156289. [PMID: 40324589 DOI: 10.1016/j.metabol.2025.156289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2025] [Revised: 04/20/2025] [Accepted: 04/30/2025] [Indexed: 05/07/2025]
Abstract
In recent years, lactylation, a novel post-translational modification, has demonstrated a unique role in bridging cellular metabolism and epigenetic regulation. This modification exerts a dual-edged effect in both cancer and non-cancer diseases by dynamically integrating the supply of metabolic substrates and the activity of modifying enzymes: on one hand, it promotes tissue homeostasis and repair through the activation of repair genes; on the other, it exacerbates pathological progression by driving malignant phenotypes. In the field of oncology, lactylation regulates key processes such as metabolic reprogramming, immune evasion, and therapeutic resistance, thereby shaping the heterogeneity of the tumor microenvironment. In non-cancerous diseases, including neurodegeneration and cardiovascular disorders, its aberrant activation can lead to mitochondrial dysfunction, fibrosis, and chronic inflammation. Existing studies have revealed a dynamic regulatory network formed by the cooperation of modifying and demodifying enzymes, and have identified mechanisms such as subcellular localization and RNA metabolism intervention that influence disease progression. Nevertheless, several challenges remain in the field. This article comprehensively summarizes the disease-specific regulatory mechanisms of lactylation, with the aim of providing a theoretical foundation for its targeted therapeutic application.
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Affiliation(s)
- Cong Chen
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medicine Sciences, Beijing 100053, China
| | - Jie Wang
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medicine Sciences, Beijing 100053, China.
| | - Xueying Zhu
- Department of Anatomy, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Shan Zhang
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Xiandun Yuan
- Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing 100096, China
| | - Jun Hu
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medicine Sciences, Beijing 100053, China
| | - Chao Liu
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medicine Sciences, Beijing 100053, China
| | - Lanchun Liu
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medicine Sciences, Beijing 100053, China
| | - Zhenpeng Zhang
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medicine Sciences, Beijing 100053, China.
| | - Jun Li
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medicine Sciences, Beijing 100053, China.
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30
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Liu PJ, Zhou ZP, Wang GY, Xu S, Wang W, Chen X, Tan XD, Liu ZH, Zhao ZM, Gao YX, Zhang XP, Liu R. New-onset diabetes worsens prognosis of patients with pancreatic ductal adenocarcinoma after R0 resection: A multicenter study. Hepatobiliary Pancreat Dis Int 2025:S1499-3872(25)00088-8. [PMID: 40374469 DOI: 10.1016/j.hbpd.2025.04.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 04/03/2025] [Indexed: 05/17/2025]
Abstract
BACKGROUND The risk of pancreatic ductal adenocarcinoma (PDAC) is increased in patients with diabetes mellitus (DM), particularly in new-onset diabetes (NOD). This study aimed to analyze the effect of NOD on the outcomes of patients with PDAC after R0 resection. METHODS PDAC patients from six centers in China undergoing R0 resection from 2015 to 2022 were included. Patients were categorized as long-term diabetes (LTD), NOD, or non-diabetes mellitus (non-DM) based on the timing of diagnosis relative to pancreatic resection. We compared the effects of diabetes status on perioperative and oncological outcomes of PDAC. RESULTS Of 1211 patients, 602 (49.7%), 127 (10.5%), and 482 (39.8%) were in the non-DM, LTD, and NOD groups, respectively. Patients with NOD suffered from higher rates of fatty pancreas and postoperative pancreatic fistula (POPF) (both P < 0.05). When compared with the non-DM group, the NOD group had worse median overall survival (OS) (24.6 vs. 29.4 months, P < 0.001) and recurrence-free survival (RFS) (13.3 vs. 15.8 months, P < 0.001); and the LTD group also had worse median OS (25.2 vs. 29.4 months, P = 0.041) and RFS (13.8 vs. 15.8 months, P = 0.007) compared with non-DM group. However, there were no significant differences in survival between the NOD and the LTD groups. Multivariate analysis indicated that NOD, LTD, largest tumor size, and poor tumor differentiation were independently associated with worse OS and RFS (all P < 0.05). CONCLUSIONS Patients with PDAC undergoing R0 resection experienced a higher probability of POPF in the presence of concurrent NOD. Long-term survival prognosis was worse in NOD or LTD patients than in non-DM patients.
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Affiliation(s)
- Peng-Jiong Liu
- Faculty of Hepato-Biliary-Pancreatic Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Zhi-Peng Zhou
- Faculty of Hepato-Biliary-Pancreatic Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Guan-Yu Wang
- Faculty of Hepato-Biliary-Pancreatic Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Shuai Xu
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China
| | - Wei Wang
- Department of General Surgery, the First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, China
| | - Xiong Chen
- Department of Hepatobiliary Surgery, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830001, China
| | - Xiao-Dong Tan
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Zhong-Hua Liu
- Department of Hepatobiliary Surgery, Chifeng Municipal Hospital, Chifeng 024050, China
| | - Zhi-Ming Zhao
- Faculty of Hepato-Biliary-Pancreatic Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Yuan-Xing Gao
- Faculty of Hepato-Biliary-Pancreatic Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Xiu-Ping Zhang
- Faculty of Hepato-Biliary-Pancreatic Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China.
| | - Rong Liu
- Faculty of Hepato-Biliary-Pancreatic Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China.
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Xing X, Yin SQ, Li XQ, Li H, Ma HT, Tulamaiti A, Xiao SY, Liu YT, Zhang H, Zhang Z, Huo YM, Yang XM, Yang Y, Zhang XL. B4GALT5 inhibits CD8 + T-cell response by downregulating MHC-I level through ERAD pathway in PDAC. J Immunother Cancer 2025; 13:e010908. [PMID: 40316305 PMCID: PMC12049881 DOI: 10.1136/jitc-2024-010908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 04/17/2025] [Indexed: 05/04/2025] Open
Abstract
BACKGROUND Immune evasion is a crucial event in the progression of pancreatic ductal adenocarcinoma (PDAC). The identification of new immunotherapeutic targets may provide a promising platform for advancing PDAC treatment. This study aims to investigate the role of beta-1,4-galactosyltransferase-5 (B4GALT5) in immune evasion by pancreatic cancer cells and evaluate its potential as an immunotherapeutic target. METHODS We conducted a comprehensive analysis using RNA sequencing data and tissue microarrays from patients with PDAC to investigate the association between B4GALT5 expression and patient prognosis. Using animal models, we further explored the impact of B4GALT5 on the quantity and activity of tumor-infiltrating CD8+ T cells. RNA sequencing and co-immunoprecipitation were used to explore the mechanism by which B4GALT5 regulates major histocompatibility complex (MHC-I) levels. RESULTS Our study demonstrates that high expression of B4GALT5 in tumor cells is significantly associated with poor prognosis in patients with PDAC and reduced cytotoxic activity of tumor-infiltrating CD8+ T cells. Specifically, B4GALT5 suppresses MHC-I expression in tumor cells through the endoplasmic reticulum-associated degradation pathway, enabling them to evade immune surveillance by CD8+ T cells. CONCLUSIONS B4GALT5 impairs CD8+ T-cell recognition of tumor cells by regulating MHC-I levels, thereby promoting immune evasion. This makes B4GALT5 a highly promising immunotherapeutic target for improving the poor prognosis of patients with PDAC.
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Affiliation(s)
- Xin Xing
- Shanghai Fengxian District Central Hospital, School of Medicine, Anhui University of Science and Technology, Shanghai, China
- Shanghai University of Medicine and Health Sciences Affiliated Sixth People's Hospital South Campus, Shanghai, China
| | - Shi-Qi Yin
- Shanghai Fengxian District Central Hospital, School of Medicine, Anhui University of Science and Technology, Shanghai, China
| | - Xia-Qing Li
- Shanghai Fengxian District Central Hospital, School of Medicine, Anhui University of Science and Technology, Shanghai, China
| | - Hui Li
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hong-Tai Ma
- Shanghai Fengxian District Central Hospital, School of Medicine, Anhui University of Science and Technology, Shanghai, China
| | - Aziguli Tulamaiti
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Shu-Yu Xiao
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yu-Tong Liu
- The First Hospital of Jilin University, Changchun, Jilin, China
| | - Hao Zhang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zhigang Zhang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yan-Miao Huo
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiao-Mei Yang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yan Yang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xue-Li Zhang
- Shanghai University of Medicine and Health Sciences Affiliated Sixth People's Hospital South Campus, Shanghai, China
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Lin Q, Guan S, Peng M, Zhang K, Zhang H, Mo T, Yu H. Comprehensive analysis of SQOR involvement in ferroptosis resistance of pancreatic ductal adenocarcinoma in hypoxic environments. Front Immunol 2025; 16:1513589. [PMID: 40375994 PMCID: PMC12078260 DOI: 10.3389/fimmu.2025.1513589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Accepted: 04/07/2025] [Indexed: 05/18/2025] Open
Abstract
Introduction Pancreatic ductal adenocarcinoma (PDAC) exhibits higher hypoxia level than most solid tumors, and the presence of intratumoral hypoxia is associated with a poor prognosis. However, the identification of hypoxia levels based on pathological images, and the mechanisms regulating ferroptosis resistance, remain to be elucidated. The objective of this study was to construct a deep learning model to evaluate the hypoxia characteristics of PDAC and to explore the role of Sulfide quinone oxidoreductase (SQOR) in hypoxia-mediated ferroptosis resistance. Methods Multi-omics data were integrated to analyze the correlation between hypoxia score of PDAC, SQOR expression and prognosis, and ferroptosis resistance level. A deep learning model of Whole Slide Images (WSIs) were constructed to predict the hypoxia level of patients. In vitro hypoxia cell models, SQOR knockdown experiments and nude mouse xenograft models were used to verify the regulatory function of SQOR on ferroptosis. Results PDAC exhibited significantly higher hypoxia levels than normal tissues, correlating with reduced overall survival in patients. In slide level, our deep learning model can effectively identify PDAC hypoxia levels with good performance. SQOR was upregulated in tumor tissues and positively associated with both hypoxia score and ferroptosis resistance. SQOR promotes the malignant progression of PDAC in hypoxic environment by enhancing the resistance of tumor cells to ferroptosis. SQOR knockdown resulted in decreased cell viability, decreased migration ability and increased MDA level under hypoxic Ersatin induced conditions. Furthermore, SQOR inhibitor in combination with ferroptosis inducer has the potential to inhibit tumor growth in vivo in a synergistic manner. Discussion This study has established a hypoxia detection model of PDAC based on WSIs, providing a new tool for clinical evaluation. The study revealed a new mechanism of SQOR mediating ferroptosis resistance under hypoxia and provided a basis for targeted therapy.
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Affiliation(s)
- Quan Lin
- Department of Hepatobiliary Surgery, Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Shiwei Guan
- Department of Hepatobiliary Surgery, Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Minghui Peng
- Department of Hepatobiliary Surgery, Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Kailun Zhang
- Department of Hepatobiliary Surgery, Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Hewei Zhang
- Department of Hepatobiliary Surgery, Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Taoming Mo
- Department of Pathology, Medical School of Nantong University, Nantong, Jiangsu, China
| | - Haibo Yu
- Department of Hepatobiliary Surgery, Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, Wenzhou, Zhejiang, China
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Liu W, Li J, Yuan X, Chen C, Shen Y, Zhang X, Yu J, Zhu M, Fang X, Liu F, Wang T, Wang L, Fan J, Jiang H, Lu J, Shao C, Bian Y. A Novel Deep Learning-based Pathomics Score for Prognostic Stratification in Pancreatic Ductal Adenocarcinoma. Pancreas 2025; 54:e430-e441. [PMID: 40314741 DOI: 10.1097/mpa.0000000000002463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 12/27/2024] [Indexed: 05/03/2025]
Abstract
BACKGROUND AND OBJECTIVES Accurate survival prediction for pancreatic ductal adenocarcinoma (PDAC) is crucial for personalized treatment strategies. This study aims to construct a novel pathomics indicator using hematoxylin and eosin-stained whole slide images and deep learning to enhance PDAC prognosis prediction. METHODS A retrospective, 2-center study analyzed 864 PDAC patients diagnosed between January 2015 and March 2022. Using weakly supervised and multiple instance learning, pathologic features predicting 2-year survival were extracted. Pathomics features, including probability histograms and TF-IDF, were selected through random survival forests. Survival analysis was conducted using Kaplan-Meier curves, log-rank tests, and Cox regression, with AUROC and C-index used to assess model discrimination. RESULTS The study cohort comprised 489 patients for training, 211 for validation, and 164 in the neoadjuvant therapy (NAT) group. A pathomics score was developed using 7 features, dividing patients into high-risk and low-risk groups based on the median score of 131.11. Significant survival differences were observed between groups (P<0.0001). The pathomics score was a robust independent prognostic factor [Training: hazard ratio (HR)=3.90; Validation: HR=3.49; NAT: HR=4.82; all P<0.001]. Subgroup analyses revealed higher survival rates for early-stage low-risk patients and NAT responders compared to high-risk counterparts (both P<0.05 and P<0.0001). The pathomics model surpassed clinical models in predicting 1-, 2-, and 3-year survival. CONCLUSIONS The pathomics score serves as a cost-effective and precise prognostic tool, functioning as an independent prognostic indicator that enables precise stratification and enhances the prediction of prognosis when combined with traditional pathologic features. This advancement has the potential to significantly impact PDAC treatment planning and improve patient outcomes.
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Affiliation(s)
- Wenbin Liu
- Department of Radiology, Changhai Hospital
| | - Jing Li
- Department of Radiology, Changhai Hospital
| | | | | | | | | | - Jieyu Yu
- Department of Radiology, Changhai Hospital
| | | | - Xu Fang
- Department of Radiology, Changhai Hospital
| | - Fang Liu
- Department of Radiology, Changhai Hospital
| | | | - Li Wang
- Department of Radiology, Changhai Hospital
| | - Jie Fan
- Department of Pathology, Huashan Hospital
| | - Hui Jiang
- Department of Pathology, Changhai Hospital, Shanghai, China
| | | | | | - Yun Bian
- Department of Radiology, Changhai Hospital
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Wang Y, Bian Z, Xu L, Du G, Qi Z, Zhang Y, Long J, Li W. The scRNA-sequencing landscape of pancreatic ductal adenocarcinoma revealed distinct cell populations associated with tumor initiation and progression. Genes Dis 2025; 12:101323. [PMID: 40092486 PMCID: PMC11907457 DOI: 10.1016/j.gendis.2024.101323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 04/09/2024] [Accepted: 04/21/2024] [Indexed: 03/19/2025] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) stands as a formidable malignancy characterized by its profound lethality. The comprehensive analysis of the transcriptional landscape holds immense significance in understanding PDAC development and exploring novel treatment strategies. However, due to the firm consistency of pancreatic cancer samples, the dissociation of single cells and subsequent sequencing can be challenging. Here, we performed single-cell RNA sequencing (scRNA-seq) on 8 PDAC patients with different lymph node metastasis status. We first identified the crucial role of MMP1 in the transition from normal pancreatic cells to cancer cells. The knockdown of MMP1 in pancreatic cancer cell lines decreased the expression of ductal markers such as SOX9 while the overexpression of MMP1 in hTERT-HPNE increased the expression of ductal markers, suggesting its function of maintaining ductal identity. Secondly, we found a S100A2 + tumor subset which fueled lymph node metastasis in PDAC. The knockdown of S100A2 significantly reduced the motility of pancreatic cancer cell lines in both wound healing and transwell migration assays. While overexpression of S100A2 led to increased migratory capability. Moreover, overexpression of S100A2 in KPC1199, a mouse pancreatic cancer cell line, caused a larger tumor burden in a hemi-spleen injection model of liver metastasis. In addition, epithelial-mesenchymal transition-related genes were decreased by S100A2 knockdown revealed by bulk RNA sequencing. We also identified several pivotal contributors to the pro-tumor microenvironment, notably OMD + fibroblast and CCL2 + macrophage. As a result, our study provides valuable insights for early detection of PDAC and promising therapeutic targets for combatting lymph node metastasis.
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Affiliation(s)
- Ying Wang
- Department of Interventional Radiology, Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Zhouliang Bian
- Department of Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201900, China
- Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China
| | - Lichao Xu
- Department of Interventional Radiology, Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Guangye Du
- Department of Pathology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201900, China
| | - Zihao Qi
- Department of Pancreatic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
- Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Yanjie Zhang
- Department of Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201900, China
- Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China
| | - Jiang Long
- Department of Pancreatic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
- Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Wentao Li
- Department of Interventional Radiology, Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
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Bos MD, Meyer NH, Wijma AG, Khatib-Chahidi K, van den Broek E, Ho CS, Meerdink M, Klaase JM, Bockhorn M, Hoogwater FJ, Nijkamp MW. Preoperative Anemia as a Prognostic Risk Factor for Inferior Oncological Survival Following Resection for Pancreatic Ductal Adenocarcinoma. Pancreas 2025; 54:e397-e406. [PMID: 39854689 PMCID: PMC12052068 DOI: 10.1097/mpa.0000000000002448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 11/13/2024] [Indexed: 01/26/2025]
Abstract
OBJECTIVES A significant proportion of patients undergoing surgery for pancreatic ductal adenocarcinoma (PDAC) are anemic at the time of resection. In these patients, blood transfusions are omitted because of their potential negative impact on oncological outcomes. The present study aimed to determine the prognostic value of preoperative anemia in resected PDAC patients, irrespective of blood transfusion status. MATERIALS AND METHODS This retrospective 2-center cohort study included patients who underwent resection for PDAC between 2013 and 2022. The prognostic role of preoperative anemia was investigated using Cox proportional-hazard regression analysis. A subgroup analysis excluded PDAC patients who received a perioperative blood transfusion. RESULTS Among 280 included PDAC patients, 110 (39%) were found to have preoperative anemia. Preoperative anemia was associated with increased use of blood transfusions, with 44 patients (16%) requiring transfusion perioperatively. In the whole cohort, preoperative anemia was an independent predictor of lower disease-free survival (hazard ratio [HR] = 1.518; 95% confidence interval [CI] = 1.103-2.090, P = 0.011), but not overall survival. However, when patients who received a perioperative blood transfusion were excluded, preoperative anemia was independently associated with both lower disease-free survival (HR = 1.636; 95% CI = 1.113-2.404, P = 0.012) and overall survival (HR = 1.484; 95% CI = 1.036-2.127, P = 0.031). CONCLUSIONS Preoperative anemia was identified as an independent risk factor for inferior oncological survival after resection for PDAC. These results support the need for increased awareness regarding the potential adverse effects of preoperative anemia on oncological outcomes in PDAC.
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Affiliation(s)
- Mylena D. Bos
- Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - N. Helge Meyer
- Department of Human Medicine, University Hospital of General and Visceral Surgery, University of Oldenburg and Klinikum Oldenburg, Oldenburg, Germany
| | - Allard G. Wijma
- Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Karl Khatib-Chahidi
- Department of Human Medicine, University Hospital of General and Visceral Surgery, University of Oldenburg and Klinikum Oldenburg, Oldenburg, Germany
| | - Evert van den Broek
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Cassandra S.L. Ho
- Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
- Department of Human Medicine, University Hospital of General and Visceral Surgery, University of Oldenburg and Klinikum Oldenburg, Oldenburg, Germany
| | - Mark Meerdink
- Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Joost M. Klaase
- Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Maximilian Bockhorn
- Department of Human Medicine, University Hospital of General and Visceral Surgery, University of Oldenburg and Klinikum Oldenburg, Oldenburg, Germany
| | - Frederik J.H. Hoogwater
- Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Maarten W. Nijkamp
- Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
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Wu S, Xu W, Shan X, Sun L, Liu S, Sun X, Li S, Hou X, Bo X, Peng C, Huang B, Xu H, Yue W. Targeting Splenic Myeloid Cells with Nanobiologics to Prevent Postablative Pancreatic Cancer Recurrence via Inducing Antitumor Peripheral Trained Immunity. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2413562. [PMID: 40289661 DOI: 10.1002/advs.202413562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 03/27/2025] [Indexed: 04/30/2025]
Abstract
Minimally invasive irreversible electroporation ablation shows promise for pancreatic cancer (PCa), but the high recurrence and metastasis rates pose a therapeutic challenge for loco-regional ablation treatment. Immunotherapy holds promise for preventing tumor recurrence, however, its efficacy against PCa remains limited. Here, using a preclinical model of PCa, it is identified that tumor development dramatically restructures the splenic immune landscape characterized by increased frequency of myeloid cells. Further, nanobiologics with high affinity for splenic myeloid cells using erythrocyte membrane fused with apoA1-modified liposomes are presented. Biocompatible CaCO3 nanoparticles are incorporated to serve as a release reservoir of immunomodulatory therapeutics (muramyl dipeptide, MDP). The nanobiologics, MDCa@RBC-Alipo, induce antitumor-trained immunity by epigenetically and metabolically rewiring splenic myeloid cells, thereby overcoming the immunosuppressive tumor microenvironment in residual PCa following irreversible electroporation ablation. This approach enhances the therapeutic efficacy of aPD-L1 and significantly inhibits tumor recurrence and hemorrhagic ascites development. The trafficking of MDP directly to the spleen highlights a previously uncharacterized pathway for inducing peripheral trained immunity, thereby presenting a novel therapeutic approach for locally advanced PCa treatment.
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Affiliation(s)
- Shengbo Wu
- Ultrasound Department, Zhejiang Hospital, No. 1229 Gudun Road, Xihu District, Hangzhou, Zhejiang Province, 310013, P. R. China
- Department of Medical Ultrasound, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, P. R. China
- Shanghai Engineering Research Center of Ultrasound Diagnosis and Treatment, National Clinical Research Center for Interventional Medicine, Shanghai, 200072, P. R. China
| | - Weichen Xu
- Department of Medical Ultrasound, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, P. R. China
- Shanghai Engineering Research Center of Ultrasound Diagnosis and Treatment, National Clinical Research Center for Interventional Medicine, Shanghai, 200072, P. R. China
| | - Xuexia Shan
- Department of Medical Ultrasound, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, P. R. China
- Shanghai Engineering Research Center of Ultrasound Diagnosis and Treatment, National Clinical Research Center for Interventional Medicine, Shanghai, 200072, P. R. China
| | - Liping Sun
- Department of Medical Ultrasound, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, P. R. China
- Shanghai Engineering Research Center of Ultrasound Diagnosis and Treatment, National Clinical Research Center for Interventional Medicine, Shanghai, 200072, P. R. China
| | - Shuo Liu
- Department of Medical Ultrasound, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, P. R. China
- Shanghai Engineering Research Center of Ultrasound Diagnosis and Treatment, National Clinical Research Center for Interventional Medicine, Shanghai, 200072, P. R. China
| | - Xixi Sun
- Ultrasound Department, Zhejiang Hospital, No. 1229 Gudun Road, Xihu District, Hangzhou, Zhejiang Province, 310013, P. R. China
| | - Shaoyue Li
- Department of Medical Ultrasound, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, P. R. China
- Shanghai Engineering Research Center of Ultrasound Diagnosis and Treatment, National Clinical Research Center for Interventional Medicine, Shanghai, 200072, P. R. China
| | - Xiaodong Hou
- Department of Medical Ultrasound, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, P. R. China
- Shanghai Engineering Research Center of Ultrasound Diagnosis and Treatment, National Clinical Research Center for Interventional Medicine, Shanghai, 200072, P. R. China
| | - Xiaowan Bo
- Department of Medical Ultrasound, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, P. R. China
- Shanghai Engineering Research Center of Ultrasound Diagnosis and Treatment, National Clinical Research Center for Interventional Medicine, Shanghai, 200072, P. R. China
| | - Chengzhong Peng
- Department of Medical Ultrasound, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, P. R. China
- Shanghai Engineering Research Center of Ultrasound Diagnosis and Treatment, National Clinical Research Center for Interventional Medicine, Shanghai, 200072, P. R. China
| | - Bin Huang
- Ultrasound Department, Zhejiang Hospital, No. 1229 Gudun Road, Xihu District, Hangzhou, Zhejiang Province, 310013, P. R. China
| | - Huixiong Xu
- Department of Ultrasound, Zhongshan Hospital, Institute of Ultrasound in Medicine and Engineering, Fudan University, Shanghai, 200032, P. R. China
| | - Wenwen Yue
- Department of Medical Ultrasound, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, P. R. China
- Shanghai Engineering Research Center of Ultrasound Diagnosis and Treatment, National Clinical Research Center for Interventional Medicine, Shanghai, 200072, P. R. China
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Xu Z, Sun B, Wang W, Fan Y, Su J, Sun J, Gu X. Research progress on m6A and drug resistance in gastrointestinal tumors. Front Pharmacol 2025; 16:1565738. [PMID: 40356985 PMCID: PMC12066682 DOI: 10.3389/fphar.2025.1565738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Accepted: 04/21/2025] [Indexed: 05/15/2025] Open
Abstract
Gastrointestinal (GI) tumors represent a significant global health burden and are among the leading causes of cancer-related mortality worldwide. their drug resistance is one of the major challenges in cancer therapy. In recent years, epigenetic modifications, especially N6-methyladenosine (m6A) RNA modifications, have become a hot research topic. m6A modification plays an important role in gene expression and cancer progression by regulating RNA splicing, translation, stability, and degradation, which are regulated by "writers," "erasers" and "readers." In GI tumors, resistance to chemotherapy, targeted therapy, and immunotherapy is closely associated with m6A RNA modification. Therefore, the molecular mechanism of m6A modification and its targeted drug development provide new therapeutic strategies for overcoming drug resistance and therapeutic efficacy in GI tumors. In this review, the biological functions of m6A were explored, the specific resistance mechanisms of m6A in different types of GI tumors were explored, new ideas and targets for future treatment resistance were identified, and the limitations of this field were highlighted.
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Affiliation(s)
| | | | | | | | | | - Jiachun Sun
- Henan Key Laboratory of Cancer Epigenetics, Cancer Institute, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China
| | - Xinyu Gu
- Henan Key Laboratory of Cancer Epigenetics, Cancer Institute, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China
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Li L, Li J, Yan A, Xiang W, Gao W, Zhu H. Temporal trends in cross-country inequalities of early-onset pancreatic cancer: a comprehensive analysis for the global burden of disease study 2021. Sci Rep 2025; 15:14835. [PMID: 40295659 PMCID: PMC12037719 DOI: 10.1038/s41598-025-93892-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Accepted: 03/10/2025] [Indexed: 04/30/2025] Open
Abstract
By 2040, pancreatic cancer is expected to become the second leading cause of cancer-related deaths in the U.S., with early-onset pancreatic cancer (EOPC) cases rising among adolescents and young adults. This study uses the global burden of disease (GBD) 2021 dataset to examine global, regional, and national EOPC trends and predicts the burden through 2050. The analysis covers EOPC burden from 1990 to 2021, focusing on age-standardized prevalence rate (ASPR), incidence rate (ASIR), mortality rate (ASMR), and disability-adjusted life years rate (ASDR). Annual percentage change (APC) and average annual percentage change (AAPC) were calculated via joinpoint regression. Clustering and frontier analysis based on the sociodemographic index (SDI) assessed the link between development levels and health outcomes. We used WHO-recommended health equity methods to quantify EOPC burden disparities and applied a Bayesian age-period-cohort (BAPC) model to project trends. In 2021, EOPC cases rose to 42,254, a 73% increase from 1990, while deaths reached 26,996, up 57%. Although ASIR, ASMR, and ASDR declined, ASPR rose (EAPC = 0.1). Central and Eastern Europe had the highest EOPC burden, with the fastest growth in Australasia (EAPC = 2.78) and Western Sub-Saharan Africa (EAPC = 2.25). Males had about double the burden of females, though female prevalence increased. The widening gap in health burden between low- and high-SDI regions is especially concerning. While EOPC currently affects high-SDI countries the most, there is a clear trend over time showing a gradual shift of EOPC burden towards low-SDI countries. By 2050, ASIR, ASPR, ASMR, and ASDR are projected to stabilize, with cases increasing until 2036, then decreasing. High-SDI countries bear a disproportionately high EOPC burden, with significant diagnostic and management challenges, particularly in Central and Eastern Europe. Rising global EOPC prevalence highlights the need to identify burden differences and risk factors across countries to develop targeted prevention and control strategies.
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Affiliation(s)
- Luohong Li
- Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, People's Republic of China
- State Key Laboratory of Systems Medicine for Cancer, Department of Obstetrics and Gynecology, Shanghai Cancer Institute, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Jiahao Li
- Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, People's Republic of China
| | - An Yan
- Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, People's Republic of China
| | - Wei Xiang
- Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, People's Republic of China
| | - Wenzhe Gao
- Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, People's Republic of China.
| | - Hongwei Zhu
- Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, People's Republic of China.
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Liu S, Su J, Zhao H, Bai R, Zeng L, Xue C, Deng S, Liu S, Chen Z, Xu Z, Zhou Y, Zhao S, Wu X, Peng X, Zhang J, Huang X, Zheng J, Zhao C, Zheng L. Identification of novel plasma proteins as promising noninvasive biomarker for early diagnosis and surveillance of pancreatic ductal adenocarcinoma. J Gastroenterol 2025:10.1007/s00535-025-02252-w. [PMID: 40285860 DOI: 10.1007/s00535-025-02252-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Accepted: 04/09/2025] [Indexed: 04/29/2025]
Abstract
BACKGROUND Although cancer antigen 19-9 (CA 19-9) is the only FDA-approved biomarker for pancreatic ductal adenocarcinoma (PDAC), its diagnostic effectiveness is limited, as it may not be elevated in 15-25% of patients. This study aims to explore novel plasma proteins associated with PDAC as potential biomarkers for early diagnosis and clinical surveillance. METHODS Novel plasma protein biomarkers potentially causally associated with PDAC were identified using Mendelian randomization (MR). These biomarkers were validated in a multicenter study encompassing 230 tissue and 1,011 plasma samples to establish a diagnostic model for PDAC. Furthermore, their pre- and post-operative levels were compared to evaluate their potential as clinical surveillance biomarkers. RESULTS Genetically predicted expression of seven proteins potentially causally associated with an increased risk of PDAC. In a multicenter, large-scale study, Keratin 5 (KRT5) and Versican (VCAN) were identified as promising biomarkers for PDAC, with an area under the curve (AUC) of 0.90, and a combined panel including CA 19-9 achieved an AUC of 0.95. Additionally, plasma KRT5 and VCAN demonstrated superior diagnostic performance for early-stage PDAC with CA 19-9 levels below 37 U/mL (Stage I, AUC 0.85; Stage II, AUC 0.85). The specificity of plasma KRT5 and VCAN for PDAC was further validated by comparing their expression levels across various digestive cancers. Moreover, a significant decrease in plasma KRT5 and VCAN levels was observed post-surgery (P < 0.05), supporting their potential as biomarkers for clinical surveillance of PDAC. CONCLUSIONS Plasma KRT5 and VCAN proteins may serve as promising valuable biomarkers for the early diagnosis and clinical surveillance of PDAC.
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Affiliation(s)
- Shuang Liu
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Jiachun Su
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Hongzhe Zhao
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Ruihong Bai
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Lingxing Zeng
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Chunling Xue
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Shuang Deng
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Shaoqiu Liu
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Ziming Chen
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Zilan Xu
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yifan Zhou
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Sihan Zhao
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Xiaoyu Wu
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Xinyi Peng
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Jialiang Zhang
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Xudong Huang
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Jian Zheng
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
- Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
| | - Chongyu Zhao
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Army Medical University, Chongqing, China
| | - Lu Zheng
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Army Medical University, Chongqing, China
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Vella R, Giardino A, Pizzocaro E, Frigerio I, Bannone E, Vieni S, Butturini G. Unconventional Treatments for Pancreatic Cancer: A Systematic Review. Cancers (Basel) 2025; 17:1437. [PMID: 40361364 PMCID: PMC12071172 DOI: 10.3390/cancers17091437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2025] [Revised: 04/21/2025] [Accepted: 04/23/2025] [Indexed: 05/15/2025] Open
Abstract
OBJECTIVE This study aims to review the existing literature on the efficacy and safety of unconventional treatments among pancreatic cancer patients, including the use of natural products, dietary supplements, probiotics, whole medical systems, and body-based therapies. METHODS An electronic, systematic, and comprehensive literature review was conducted searching for studies up to November 2024 following the PRISMA 2020 guidelines. Randomized controlled trials and prospective and retrospective studies assessing the efficacy and safety of unconventional treatments for pancreatic cancer were considered eligible. Data on overall survival, quality of life, and treatment tolerability were extracted. RESULTS A total of 21 studies, providing data from 3095 patients, met the inclusion criteria. Various types of unconventional treatments are used in pancreatic cancer patients, including Chinese herbal medicine (CHM), mistletoe extract (ME), curcumin, and electroacupuncture. Among these, the use of CHM and curcumin concomitant with standard therapy was associated with survival and quality-of-life benefits. Electroacupuncture reduced pancreatic cancer pain intensity in a cost-effective manner. The data on ME are mixed and of insufficient quality for drawing definitive conclusions. CONCLUSIONS Some unconventional treatments showed potential benefits in improving overall survival and quality of life in pancreatic cancer patients within an integrative oncology setting. Further high-quality studies are needed to provide robust, rigorous, and ethical evidence to support their integration into future guidelines, ensuring a holistic approach to cancer treatment.
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Affiliation(s)
- Roberta Vella
- HPB Surgery, Pederzoli Hospital, Peschiera del Garda, 37019 Verona, Italy; (R.V.); (A.G.); (I.F.); (E.B.); (G.B.)
- Department of Precision Medicine in Medical, Surgical, and Critical Care, (Me.Pre.C.C.), University of Palermo, 90133 Palermo, Italy;
| | - Alessandro Giardino
- HPB Surgery, Pederzoli Hospital, Peschiera del Garda, 37019 Verona, Italy; (R.V.); (A.G.); (I.F.); (E.B.); (G.B.)
| | - Erica Pizzocaro
- HPB Surgery, Pederzoli Hospital, Peschiera del Garda, 37019 Verona, Italy; (R.V.); (A.G.); (I.F.); (E.B.); (G.B.)
- PhD School of Applied Medical-Surgical Sciences, University Tor Vergata, 00133 Rome, Italy
| | - Isabella Frigerio
- HPB Surgery, Pederzoli Hospital, Peschiera del Garda, 37019 Verona, Italy; (R.V.); (A.G.); (I.F.); (E.B.); (G.B.)
- Collegium Medicum, SAN University, 90-012 Lodz, Poland
| | - Elisa Bannone
- HPB Surgery, Pederzoli Hospital, Peschiera del Garda, 37019 Verona, Italy; (R.V.); (A.G.); (I.F.); (E.B.); (G.B.)
| | - Salvatore Vieni
- Department of Precision Medicine in Medical, Surgical, and Critical Care, (Me.Pre.C.C.), University of Palermo, 90133 Palermo, Italy;
| | - Giovanni Butturini
- HPB Surgery, Pederzoli Hospital, Peschiera del Garda, 37019 Verona, Italy; (R.V.); (A.G.); (I.F.); (E.B.); (G.B.)
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Song TL, Zhang F, Zhang C, Cheng HJ, Maswikiti EP, Ji CY, Chen H, Tang FT, Guo WZ, Zhai WL, Li YM. Development and validation of a nomogram for a prognostic model for resected pancreatic ductal adenocarcinoma. Hepatobiliary Pancreat Dis Int 2025:S1499-3872(25)00062-1. [PMID: 40348634 DOI: 10.1016/j.hbpd.2025.04.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 04/18/2025] [Indexed: 05/14/2025]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor. Surgical resection is the most promising therapeutic strategy for PDAC, and how to improve the survival rate remains a vital key point. This study aimed to establish and validate a nomogram for predicting the prognosis of resected PDAC. METHODS A total of 174 patients with PDAC who underwent surgical resection at Lanzhou University Second Hospital and the First Affiliated Hospital of Zhengzhou University from January 2012 to July 2022 were enrolled. The clinicopathological characteristics and survival data were analyzed by R software (version 4.1.3). Univariate and multivariate Cox regression analyses were used to analyze the effects of clinicopathological characteristics on overall survival (OS). RESULTS Multivariate Cox regression showed that carbohydrate antigen 19-9 (CA19-9) ≥ 476 U/mL, carbohydrate antigen 125 (CA125) ≥ 32 U/mL, fasting blood glucose (FBG) < 6.86 mmol/L, aspartate aminotransferase (AST) ≥ 107 U/L, positive surgical margin, and more than 4 cycles of postoperative chemotherapy were independent prognostic factors for OS. Patients were divided into the high-risk and low-risk groups based on the median risk score calculated by multivariate Cox regression analysis. Kaplan-Meier survival curves revealed that the 5-year survival rates of the high-risk and low-risk groups in the training cohort were 5.79% and 24.3%, respectively, and those in the validation cohort were 0 and 19.0%, respectively (P < 0.05). Receiver operating characteristic (ROC) curve analysis revealed that area under the ROC curve (AUC) of the risk score in the training set and the validation set were 0.855 and 0.838, respectively. The C-indexes of the nomogram in the training set and validation set were 0.788 (95% CI: 0.745-0.831) and 0.773 (95% CI: 0.718-0.828), respectively. CONCLUSIONS We developed a nomogram that predicts OS in patients with resected PDAC, and the validation results showed that the nomogram model had a strong predictive ability. Particularly, FBG < 6.86 mmol/L and more than 4 cycles of postoperative chemotherapy can predict better OS of PDAC after surgery.
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Affiliation(s)
- Tian-Liang Song
- Department of Oncology Surgery, Lanzhou University Second Hospital, Lanzhou 730030, China; Gansu Province Key Laboratory of Environmental Oncology, Lanzhou 730030, China
| | - Fan Zhang
- Department of Oncology Surgery, Lanzhou University Second Hospital, Lanzhou 730030, China; Gansu Province Key Laboratory of Environmental Oncology, Lanzhou 730030, China
| | - Chong Zhang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Hui-Juan Cheng
- Gansu Province Key Laboratory of Environmental Oncology, Lanzhou 730030, China
| | | | - Cheng-Yang Ji
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Hao Chen
- Department of Oncology Surgery, Lanzhou University Second Hospital, Lanzhou 730030, China; Gansu Province Key Laboratory of Environmental Oncology, Lanzhou 730030, China
| | - Fu-Tian Tang
- Gansu Province Key Laboratory of Environmental Oncology, Lanzhou 730030, China
| | - Wen-Zhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Wen-Long Zhai
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
| | - Yu-Min Li
- Gansu Province Key Laboratory of Environmental Oncology, Lanzhou 730030, China; Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730030, China.
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Awale S, Maneenet J, Phan ND, Nguyen HH, Fujii T, Ihmels H, Soost D, Tajuddeen N, Feineis D, Bringmann G. Toyaburgine, a Synthetic N-Biphenyl-Dihydroisoquinoline Inspired by Related N, C-Coupled Naphthylisoquinoline Alkaloids, with High In Vivo Efficacy in Preclinical Pancreatic Cancer Models. ACS Chem Biol 2025; 20:917-929. [PMID: 40048237 DOI: 10.1021/acschembio.4c00870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/19/2025]
Abstract
Pancreatic cancer is a highly aggressive and lethal malignancy, with a 5-year survival rate below 10%. Traditional chemotherapy, including gemcitabine, has limited efficacy due to chemoresistance and a unique tumor microenvironment characterized by hypovascularity and nutrient deprivation. This study reports on the discovery of a new N-biphenyl-dihydroisoquinoline, named toyaburgine (4), inspired by naturally occurring N,C-coupled naphthylisoquinoline alkaloids. Developed through systematic structural optimization, toyaburgine is a potent anticancer agent, showing promise for pancreatic cancer treatment. It exhibits strong antiausterity activity with low nanomolar PC50 values, effectively inhibiting pancreatic cancer cell viability under nutrient-deprived conditions. In vitro, 4 causes significant morphological changes and cancer cell death in MIA PaCa-2 cells while also inhibiting cell migration and colony formation, which indicates its antimetastatic potential. Mechanistically, toyaburgine disrupts the PI3K/Akt/mTOR pathway, essential for pancreatic cancer cell survival in a stressful microenvironment, and inhibits MIA PaCa-2 spheroid formation. In vivo, toyaburgine, alone or combined with gemcitabine, shows effective tumor suppression in subcutaneous xenograft and clinically relevant orthotopic models, where it also reduces cachexia. These results highlight the potential of toyaburgine as a new therapeutic drug for pancreatic cancer. Its combination with gemcitabine presents a promising treatment approach by targeting both proliferating and gemcitabine-resistant cancer cells.
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Affiliation(s)
- Suresh Awale
- Natural Drug Discovery Laboratory, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
| | - Juthamart Maneenet
- Natural Drug Discovery Laboratory, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
| | - Nguyen Duy Phan
- Natural Drug Discovery Laboratory, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
- Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan
| | - Hung Hong Nguyen
- Natural Drug Discovery Laboratory, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
- Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan
| | - Tsutomu Fujii
- Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan
| | - Heiko Ihmels
- Department of Chemistry-Biology, and Center of Micro- and Nanochemistry and (Bio)Technology (Cμ), University of Siegen, Adolf-Reichwein-Straße 2, 57068 Siegen, Germany
| | - Denisa Soost
- Department of Chemistry-Biology, and Center of Micro- and Nanochemistry and (Bio)Technology (Cμ), University of Siegen, Adolf-Reichwein-Straße 2, 57068 Siegen, Germany
| | - Nasir Tajuddeen
- Department of Chemistry-Biology, and Center of Micro- and Nanochemistry and (Bio)Technology (Cμ), University of Siegen, Adolf-Reichwein-Straße 2, 57068 Siegen, Germany
- Department of Chemistry, Ahmadu Bello University, 810107 Zaria, Nigeria
| | - Doris Feineis
- Institute of Organic Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany
| | - Gerhard Bringmann
- Institute of Organic Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany
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Cho SY, Eun HS, Kim J, Ko YD, Rou WS, Joo JS. The Solute Carrier Superfamily as Therapeutic Targets in Pancreatic Ductal Adenocarcinoma. Genes (Basel) 2025; 16:463. [PMID: 40282424 PMCID: PMC12027052 DOI: 10.3390/genes16040463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2025] [Revised: 04/10/2025] [Accepted: 04/16/2025] [Indexed: 04/29/2025] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC), a challenging and malignant cancer, primarily originates from the exocrine cells of the pancreas. The superfamily of solute carrier (SLC) transporters, consisting of more than 450 proteins divided into 65 families, is integral to various cellular processes and represents a promising target in precision oncology. As therapeutic targets, SLC transporters are explored through an integrative analysis. MATERIALS AND METHODS The expression profiles of SLCs were systematically analyzed using mRNA data from The Cancer Genome Atlas (TCGA) and protein data from the Human Protein Atlas (HPA). Survival analysis was examined to evaluate the prognostic significance of SLC transporters for overall survival (OS) and disease-specific survival (DSS). Genetic alterations were examined using cBioPortal, while structural studies were performed with AlphaFold and AlphaMissense to predict functional impacts. Furthermore, Gene Set Enrichment Analysis (GSEA) was carried out to identify oncogenic pathways linked to SLC transporter expression. RESULTS SLC transporters were significantly upregulated in tumors relative to normal tissues. Higher expression levels of SLC39A10 (HR = 1.89, p = 0.0026), SLC22B5 (HR = 1.84, p = 0.0042), SLC55A2 (HR = 2.15, p = 0.00023), and SLC30A6 (HR = 1.90, p = 0.003) were strongly associated with unfavorable OS, highlighting their connection to poor prognosis in PDAC. GSEA highlighted that these four transporters are significantly involved in key oncogenic pathways, such as epithelial-mesenchymal transition (EMT), TNF-α signaling, and angiogenesis. CONCLUSIONS The study identifies four SLCs as therapeutic targets in PDAC, highlighting their crucial role in essential metabolic pathways. These findings lay the groundwork for developing next-generation metabolic anti-cancer treatment to improve survival for PDAC patients.
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Affiliation(s)
- Sang Yeon Cho
- Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, Republic of Korea;
- CHOMEDICINE Inc., TIPS Town, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Hyuk Soo Eun
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon 35015, Republic of Korea
- Department of Internal Medicine, Chungnam National University Hospital, Daejeon 35015, Republic of Korea
| | - Jaejeung Kim
- Department of Computer Science and Engineering, Chungnam National University, Daejeon 34134, Republic of Korea;
| | - Yun Dam Ko
- Seoul Teunteun Rehabilitation Clinic, Jeungpyeong-gun, Chungcheongbuk-do 27937, Republic of Korea
| | - Woo Sun Rou
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon 35015, Republic of Korea
- Department of Internal Medicine, Chungnam National University Sejong Hospital, Sejong 30099, Republic of Korea
| | - Jong Seok Joo
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon 35015, Republic of Korea
- Department of Internal Medicine, Chungnam National University Sejong Hospital, Sejong 30099, Republic of Korea
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Sun MH, Shen HZ, Jin HB, Yang JF, Zhang XF. Efficacy and safety of early pancreatic duct stenting for unresectable pancreatic cancer: A randomized controlled trial. World J Gastrointest Oncol 2025; 17:103311. [PMID: 40235863 PMCID: PMC11995310 DOI: 10.4251/wjgo.v17.i4.103311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 01/01/2025] [Accepted: 02/10/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Palliative care for unresectable pancreatic cancer (PC) focuses mainly on the symptoms of the disease, including abdominal pain, obstructive jaundice, and malnutrition. Biliary stent placement using endoscopic retrograde cholangiopancreatography (ERCP) to relieve biliary obstruction has become an internationally recognized treatment. Although a few studies have evaluated the efficacy of endoscopic pancreatic duct stenting in advanced PC, no consensus exists on the use of endoscopic treatment to relieve pain and improve nutritional status. AIM To evaluate the efficacy and safety of early pancreatic duct stenting in patients with unresectable PC. METHODS Patients with unresectable PC were recruited. The participants were randomized into two groups: The double-stent group underwent ERCP with a fully-covered self-expandable metallic biliary stent (FCSEMS) and a pancreatic duct stent, while the single-stent group underwent ERCP with an FCSEMS only. Abdominal pain, nutritional status, and incidence of adverse events were compared between the two groups using the SPSS software. RESULTS Seventy-eight patients with unresectable PC were included in the analysis (40 and 38 in the double- and single-stent groups, respectively). The median pain scores of patients in the double-stent group were lower than those in the single-stent group at 1 (0 vs 2.5, P = 0.002), 2 (0 vs 3, P < 0.001), 3 (0 vs 4, P < 0.001), and 6 months (0 vs 4, P < 0.001) after ERCP. Total serum protein levels in patients in the double-stent group were higher than those in the single-stent group (66.6 ± 8.4 g/L vs 60.4 ± 4.0 g/L, P = 0.046) 6 months postoperatively. The body mass index (BMI) of patients in both groups decreased at six months. However, the BMI in the single-stent group was higher than that in the double-stent group (P < 0.001). CONCLUSION Early pancreatic duct stenting reduces abdominal pain and improves nutritional status in patients with unresectable PC without reducing the technical success rate or increasing the incidence of adverse events.
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Affiliation(s)
- Min-Hui Sun
- Department of Gastroenterology, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou 310000, Zhejiang Province, China
- Department of Gastroenterology, The Fourth Clinical Medical College of Zhejiang Chinese Medicine University, Hangzhou 310000, Zhejiang Province, China
| | - Hong-Zhang Shen
- Department of Gastroenterology, The Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou Digestive Disease Research Institute, Key Laboratory of Pancreatobiliary Disease of Zhejiang Integrated Chinese and Western Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Hang-Bin Jin
- Department of Gastroenterology, The Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou Digestive Disease Research Institute, Key Laboratory of Pancreatobiliary Disease of Zhejiang Integrated Chinese and Western Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Jian-Feng Yang
- Department of Gastroenterology, The Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou Digestive Disease Research Institute, Key Laboratory of Pancreatobiliary Disease of Zhejiang Integrated Chinese and Western Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Xiao-Feng Zhang
- Department of Gastroenterology, The Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou Digestive Disease Research Institute, Key Laboratory of Pancreatobiliary Disease of Zhejiang Integrated Chinese and Western Medicine, Hangzhou 310000, Zhejiang Province, China
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Liu Y, Lao X, Wong MC, Song M, Zhao Y, Ma Y, Bai Q, Hao J. Intelligent Point-of-Care Biosensing Platform Based on Luminescent Nanoparticles and Microfluidic Biochip with Machine Vision Algorithm Analysis. NANO-MICRO LETTERS 2025; 17:215. [PMID: 40227357 PMCID: PMC11996743 DOI: 10.1007/s40820-025-01745-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Accepted: 03/24/2025] [Indexed: 04/15/2025]
Abstract
Realizing the point-of-care tumor markers biodetection with good convenience and high sensitivity possesses great significance for prompting cancer monitoring and screening in biomedical study field. Herein, the quantum dots luminescence and microfluidic biochip with machine vision algorithm-based intelligent biosensing platform have been designed and manufactured for point-of-care tumor markers diagnostics. The employed quantum dots with excellent photoluminescent performance are modified with specific antibody as the optical labeling agents for the designed sandwich structure immunoassay. The corresponding biosensing investigations of the designed biodetection platform illustrate several advantages involving high sensitivity (~ 0.021 ng mL-1), outstanding accessibility, and great integrability. Moreover, related test results of human-sourced artificial saliva samples demonstrate better detection capabilities compared with commercially utilized rapid test strips. Combining these infusive abilities, our elaborate biosensing platform is expected to exhibit potential applications for the future point-of-care tumor markers diagnostic area.
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Affiliation(s)
- Yuan Liu
- Department of Applied Physics, The Hong Kong Polytechnic University, Kowloon, 999077, Hong Kong, People's Republic of China
| | - Xinyue Lao
- Department of Applied Physics, The Hong Kong Polytechnic University, Kowloon, 999077, Hong Kong, People's Republic of China
| | - Man-Chung Wong
- Department of Applied Physics, The Hong Kong Polytechnic University, Kowloon, 999077, Hong Kong, People's Republic of China
| | - Menglin Song
- Department of Applied Physics, The Hong Kong Polytechnic University, Kowloon, 999077, Hong Kong, People's Republic of China
| | - Yifei Zhao
- Department of Applied Physics, The Hong Kong Polytechnic University, Kowloon, 999077, Hong Kong, People's Republic of China
| | - Yingjin Ma
- Department of Applied Physics, The Hong Kong Polytechnic University, Kowloon, 999077, Hong Kong, People's Republic of China
| | - Qianqian Bai
- Department of Applied Physics, The Hong Kong Polytechnic University, Kowloon, 999077, Hong Kong, People's Republic of China
| | - Jianhua Hao
- Department of Applied Physics, The Hong Kong Polytechnic University, Kowloon, 999077, Hong Kong, People's Republic of China.
- Research Centre for Nanoscience and Nanotechnology, The Hong Kong Polytechnic University, Kowloon, 999077, Hong Kong, People's Republic of China.
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Fan Z, Xiao Y, Du Y, Zhang Y, Zhou W. Pancreatic cancer subtyping - the keystone of precision treatment. Front Immunol 2025; 16:1563725. [PMID: 40264765 PMCID: PMC12011869 DOI: 10.3389/fimmu.2025.1563725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Accepted: 03/17/2025] [Indexed: 04/24/2025] Open
Abstract
In recent years, the incidence and mortality rates of pancreatic cancer have been rising, posing a severe threat to human health. Tumor heterogeneity remains a critical barrier to advancing diagnosis and treatment efforts. The lack of specific early symptoms, limited early diagnostic methods, high biological complexity, and restricted therapeutic options contribute to the poor outcomes and prognosis of pancreatic cancer. Therefore, there is an urgent need to explore the different subtypes in-depth and develop personalized therapeutic strategies tailored to each subtype. Increasing evidence highlights the pivotal role of molecular subtyping in treating pancreatic cancer. This review focuses on recent advancements in classifying molecular subtypes and therapeutic approaches, discussed from the perspectives of gene mutations, genomics, transcriptomics, proteomics, metabolomics, and immunomics.
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Affiliation(s)
- Zeyang Fan
- The Second Clinical Medical School, Lanzhou University,
Lanzhou, China
| | - Yao Xiao
- The Second Clinical Medical School, Lanzhou University,
Lanzhou, China
| | - Yan Du
- The Second Clinical Medical School, Lanzhou University,
Lanzhou, China
| | - Yan Zhang
- The Second Clinical Medical School, Lanzhou University,
Lanzhou, China
| | - Wence Zhou
- Department of General Surgery , The Second Hospital of Lanzhou University & The Second Clinical Medical School, Lanzhou University, Lanzhou, China
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Ren J, Su T, Ding J, Chen F, Mo J, Li J, Wang Z, Han L, Wu Z, Wu S. Chlorophyllin exerts synergistic anti-tumor effect with gemcitabine in pancreatic cancer by inducing cuproptosis. Mol Med 2025; 31:126. [PMID: 40186145 PMCID: PMC11969790 DOI: 10.1186/s10020-025-01180-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 03/24/2025] [Indexed: 04/07/2025] Open
Abstract
Pancreatic cancer (PC) has high lethality due to multiple reasons, and its limited response to conventional chemotherapy like gemcitabine (GEM) is a non-negligible one. Therefore, our study introduces Chlorophyllin (CHL) as an effective therapeutic candidate to enhance the therapeutic efficacy of GEM. Our results demonstrate that the combination of CHL and GEM exhibits a significant synergistic anti-tumor effect by targeting multiple oncogenic processes in PC, including inhibiting cell proliferation, invasion, and migration, as well as inducing cell apoptosis. Further investigations of mechanism have revealed that CHL induces cuproptosis in PC cells through a multifaceted process, involving depleting cellular intracellular glutathione (GSH), increasing reactive oxygen species (ROS) levels, and subsequently upregulating the HSP70 protein in response to heightened oxidative stress. Additionally, CHL releases free Cu2+, binds to the Ferredoxin 1 (FDX1) protein, and ultimately leads to the oligomerization of Dihydrolipoamide S-Acetyltransferase (DLAT) proteins to amplify the copper toxicity within PC cells. Moreover, in vivo experiments have demonstrated that the combination of CHL and GEM effectively inhibits the growth of subcutaneously transplanted tumors while maintaining a favorable biosafety profile. In conclusion, our study identifies CHL as a potent enhancer of GEM's anti-tumor effects in PC through the induction of cuproptosis, thus providing a novel therapeutic avenue for patients with PC.
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Affiliation(s)
- Jiaqiang Ren
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Tong Su
- School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China
| | - Jiachun Ding
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Fan Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Jiantao Mo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Jie Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Zheng Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Liang Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Zheng Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
| | - Shuai Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
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Guo Z, Huang J, Lu ZJ, Shi Y, David CJ, Chen M. Targeting TUT1 Depletes Tri-snRNP Pools to Suppress Splicing and Inhibit Pancreatic Cancer Cell Survival. Cancer Res 2025; 85:1270-1286. [PMID: 39854320 DOI: 10.1158/0008-5472.can-24-2563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 11/30/2024] [Accepted: 01/17/2025] [Indexed: 01/26/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive and lacks effective therapeutic options. Cancer cells frequently become more dependent on splicing factors than normal cells due to increased rates of transcription. Terminal uridylyltransferase 1 (TUT1) is a specific terminal uridylyltransferase for U6 small nuclear RNA (snRNA), which plays a catalytic role in the spliceosome. In this study, we found that TUT1 was required for the survival of PDAC cells but not for normal pancreatic cells. In PDAC cells, the uridylylation activity of TUT1 promoted U4/U6.U5 tri-small nuclear ribonucleoprotein particles (snRNP) assembly by facilitating the binding of LSM proteins to U6 snRNA and subsequent tri-snRNP assembly. PDAC cells required higher amounts of U4/U6.U5 tri-snRNP to efficiently splice pre-mRNA with weak splice sites to support the high transcriptional output. Depletion of TUT1 in PDAC cells resulted in inefficient splicing of exons in a group of highly expressed RNAs containing weak splice sites, thereby resulting in the collapse of an mRNA processing circuit and consequently dysregulating splicing required by PDAC cells. Overall, this study unveiled an interesting function of TUT1 in regulating splicing by modulating U4/U6.U5 tri-snRNP levels and demonstrated a distinct mechanism underlying splicing addiction in pancreatic cancer cells. Significance: The higher amounts of U6 snRNA in tri-snRNP pools in pancreatic cancer cells compared with normal cells confers sensitivity to TUT1 inhibition, which mimics tri-snRNP inhibition and causes pancreatic cancer cell senescence.
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Affiliation(s)
- Ziwei Guo
- State Key Laboratory of Molecular Oncology, SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, School of Basic Medical Sciences, Tsinghua University, Beijing, China
| | - Junran Huang
- State Key Laboratory of Molecular Oncology, SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, School of Basic Medical Sciences, Tsinghua University, Beijing, China
| | - Zhi J Lu
- MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, China
| | - Yongsheng Shi
- Department of Microbiology and Molecular Genetics, School of Medicine, University of California at Irvine, Irvine, California
| | - Charles J David
- State Key Laboratory of Molecular Oncology, SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, School of Basic Medical Sciences, Tsinghua University, Beijing, China
- Peking University-Tsinghua Center for Life Sciences, Beijing, China
| | - Mo Chen
- State Key Laboratory of Molecular Oncology, SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, School of Basic Medical Sciences, Tsinghua University, Beijing, China
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Zhou K, Liu Y, Tang C, Zhu H. Pancreatic Cancer: Pathogenesis and Clinical Studies. MedComm (Beijing) 2025; 6:e70162. [PMID: 40182139 PMCID: PMC11965705 DOI: 10.1002/mco2.70162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 03/08/2025] [Accepted: 03/12/2025] [Indexed: 04/05/2025] Open
Abstract
Pancreatic cancer (PC) is a highly lethal malignancy, with pancreatic ductal adenocarcinoma (PDAC) being the most common and aggressive subtype, characterized by late diagnosis, aggressive progression, and resistance to conventional therapies. Despite advances in understanding its pathogenesis, including the identification of common genetic mutations (e.g., KRAS, TP53, CDKN2A, SMAD4) and dysregulated signaling pathways (e.g., KRAS-MAPK, PI3K-AKT, and TGF-β pathways), effective therapeutic strategies remain limited. Current treatment modalities including chemotherapy, targeted therapy, immunotherapy, radiotherapy, and emerging therapies such as antibody-drug conjugates (ADCs), chimeric antigen receptor T (CAR-T) cells, oncolytic viruses (OVs), cancer vaccines, and bispecific antibodies (BsAbs), face significant challenges. This review comprehensively summarizes these treatment approaches, emphasizing their mechanisms, limitations, and potential solutions, to overcome these bottlenecks. By integrating recent advancements and outlining critical challenges, this review aims to provide insights into future directions and guide the development of more effective treatment strategies for PC, with a specific focus on PDAC. Our work underscores the urgency of addressing the unmet needs in PDAC therapy and highlights promising areas for innovation in this field.
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Affiliation(s)
- Kexun Zhou
- Department of Medical OncologyCancer CenterWest China HospitalSichuan UniversityChengduChina
| | - Yingping Liu
- Department of RadiotherapyCancer HospitalChinese Academy of Medical SciencesBeijingChina
| | - Chuanyun Tang
- The First Clinical Medical College of Nanchang UniversityNanchang UniversityNanchangChina
| | - Hong Zhu
- Department of Medical OncologyCancer CenterWest China HospitalSichuan UniversityChengduChina
- Division of Abdominal Tumor Multimodality TreatmentCancer CenterWest China HospitalSichuan UniversityChengduChina
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Yang Z, Tang Y, Wu X, Wang J, Yao W. MicroRNA-130b Suppresses Malignant Behaviours and Inhibits the Activation of the PI3K/Akt Signaling Pathway by Targeting MET in Pancreatic Cancer. Biochem Genet 2025; 63:1660-1685. [PMID: 38607540 PMCID: PMC11929638 DOI: 10.1007/s10528-024-10696-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 01/10/2024] [Indexed: 04/13/2024]
Abstract
There has been interested in the microRNAs' roles in pancreatic cancer (PC) cell biology, particularly in regulating pathways related to tumorigenesis. The study aimed to explore the hub miRNAs in PC and underlying mechanisms by bioinformatics and fundamental experiments. RNA datasets collected from the Gene Expression Omnibus were analysed to find out differentially expressed RNAs (DERNAs). The miRNA-mRNA and protein-protein interaction (PPI) networks were built. The clinicopathological features and expressions of hub miRNAs and hub mRNAs were explored. Dual-luciferase reporter gene assay was performed to assess the interaction between microRNA and target gene. RT-qPCR and western blot were employed to explore RNA expression. The roles of RNA were detected by CCK-8 test, wound healing, transwell, and flow cytometry experiment. We verified 40 DEmiRNAs and 1613 DEmRNAs, then detected a total of 69 final functional mRNAs (FmRNAs) and 23 DEmiRNAs. In the miRNA-mRNA networks, microRNA-130b (miR-130b) was the hub RNA with highest degrees. Clinical analysis revealed that miR-130b was considerably lower expressed in cancerous tissues than in healthy ones, and patients with higher-expressed miR-130b had a better prognosis. Mechanically, miR-130b directly targeted MET in PC cells. Cell functional experiments verified that miR-130b suppressed cell proliferation, migration, promoted apoptosis, and inhibited the PI3K/Akt pathway by targeting MET in PC cells. Our findings illustrated the specific molecular mechanism of miR-130b regulating PC progress. The miR-130b/MET axis may be an alternative target in the therapeutic intervention of PC and provide an opportunity to deepen our understanding of the pathogenesis of PC.
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Affiliation(s)
- Zilin Yang
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yuming Tang
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Xuejiao Wu
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Jiancheng Wang
- Department of General Surgery, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Weiyan Yao
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
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