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.

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.

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.

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.

Pancreatic neuroendocrine carcinoma (PNEC) is a rare, aggressive malignancy with limited therapeutic options and a dismal prognosis, particularly in young patients. Approximately 85% of PNEC cases eventually progress to metastatic cancer. Despite advances in oncology, optimal management strategies for metastatic PNEC remain undefined, especially in chemotherapy-ineligible cases.

An 18-year-old male patient, reporting anorexia with associated weight loss (15 kg weight loss over 3 months) and significant abdominal distension.

The results of whole abdominal computed tomography, histopathology, immunohistochemistry, and laboratory examination were consistent with pancreatic neuroendocrine carcinoma with liver metastasis.

Due to the family refusal of chemotherapy, and immunohistochemistry revealed programmed death-1 ligand positivity. The patient received penpulimab (anti-programmed death-1) combined with anlotinib capsules and then changed to penpulimab combined with sorafenib capsules after progression.

Initial therapy achieved 13 months of progression-free survival, demonstrating durable disease control. Subsequent progression highlighted challenges of acquired resistance, with no severe treatment-related toxicity. The patient was still alive at the time of follow-up in July 2024.

Pancreatic neuroendocrine cancer is rare. There are various treatment options available. However, the best treatment plan still needs further exploration. This case underscores that programmed death-1 ligand + PNEC may respond to immunotherapy/antiangiogenic combinations, offering alternatives for chemotherapy-ineligible patients. In addition, young patients with aggressive PNEC represent an understudied population, necessitating tailored strategies.

Clinical outcomes remain unsatisfactory in patients with pancreatic cancer (PAC). In this study, through single-cell sequencing, we identified eight cell subpopulations in the tumor microenvironment (TME). Redimensional clustering of epithelial cells, myeloid cells, and cancer-associated fibroblasts (CAFs) revealed heterogeneity in the TME of PAC. Intercellular communication analysis showed strong direct interactions between matrix CAFs, inflammatory CAFs, and epithelial cells. Additionally, we found that the SPP1-associated pathway was activated in monocytes, whereas the vascular endothelial growth factor-associated pathway was activated in epithelial cells. These results improve the understanding of the TME of pancreatic cancer and provide a foundation for further studies on intratumoral heterogeneity. In addition, differentially expressed gene secretory leukocyte protease inhibitor (SLPI) was identified in pancreatic cancer, and functional experiments showed that SLPI had a strong impact on cell viability and apoptosis, which offers a potential therapy target for pancreatic cancer.

Pancreatic cancer is among the most lethal malignancies, with the lowest survival rates. The use of image-guided radiotherapy has shown significant potential in enhancing surgical outcomes for pancreatic cancer. However, accurate segmentation of pancreatic tumors prior to radiotherapy remains a challenge due to the small size, irregular shape, and indistinct boundaries of the pancreas and tumor in monomodal imaging. Furthermore, the availability of multimodal images that meet the requirements for precise pancreatic segmentation is highly limited, leading to the datasets that fail to provide comprehensive knowledge for effective image representation in pancreatic tumor segmentation.

This study aims to develop a method for accurately segmenting pancreatic tumors under very harsh data conditions, in which the currently available datasets are fragmented with the issues, such as limited sample sizes, inconsistent lesion matching, and incomplete modalities.

We propose a knowledge relay framework that leverages synergistic generation and transfer learning strategies. The relay comprises three batons: pancreatic PET image generation, coarse detection, and fine segmentation. Multimodal images, including CT, MR, and PET from three separate datasets, are integrated within this framework. The knowledge contained in each dataset is sequentially transferred and aggregated through the batons by the strategies of transfer learning and fine-tuning. Additionally, we introduce a mask-constrained CycleGAN and an inter-attention UNet within this framework to enhance the extraction and utilization of knowledge for accurate pancreatic tumor segmentation.

The proposed knowledge relay framework achieves the state-of-the-art performance in pancreatic tumor segmentation on PET/MR images. On the images collected from 19 subjects, our method attained a DSC $\text{DSC}$ of 80.06%, SEN $\text{SEN}$ of 83.39%, SPE $\text{SPE}$ of 99.81%, ASD $\text{ASD}$ of 4.87 mm $\text{mm}$ , and95 HD $95 \text{HD}$ of 12.69 mm $\text{mm}$ .

The results of comparison and ablation experiments validate the effectiveness of the proposed knowledge relay framework in extracting and integrating knowledge from fragmented datasets under constrained conditions. The comprehensive and enriched knowledge significantly enhances the accuracy of pancreatic tumor segmentation.

Radiation therapy (RT) for locally advanced pancreatic cancer (LAPC) continues to be controversial. Advances in both systemic therapy and RT techniques have changed the landscape of LAPC management in recent years. Clinical outcomes of ablative RT have been encouraging, and randomized clinical trials may clarify the role of RT for LAPC. We present a contemporary critical review of key aspects regarding optimal patient selection, radiation dose escalation techniques, novel radiosensitizers and radioprotectors, and treatment response assessment for LAPC.

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.

Cyclophilin-B (CypB) is overexpressed in pancreatic cancer, thus, the potential screening of CypB in biofluids and tissue samples may boost the identification of early-stage pancreatic cancer. A novel strategy of CypB detection utilizing the molecularly imprinted polymer platform, comprising higher binding affinity exhibiting cavities against the CypB protein was developed. Specifically, a nanocatalyst consisting of Pt single atom (Ptsa)-doped selenium disulfide (SeS2)/Ti3CNTx MXene nanocomposite is designed. The sluggish diffusion of Ptsa caused by the highest migration energy barrier of 6.39 eV unveils exceptionally high stability (2.89 ×1088 d (300 K) and 1.053 × 1024 d (750 K)) with (SeS2)/Ti3CNTx surface. The Ptsa boosted charge transfer kinetics paves the improved performance of the CypB sensor, while SeS2/Ti3CNTx supports the stable current density overall. The system establishes a dynamic linear range from 0.12 to 250 nm of CypB detection which correlates with the physiological existence of the CypB in human biofluids and tissues and the excellent detection limit of 80 pm. The liquid chromatography integrated mass spectrometer investigation warranted the significant enhancement of CypB associates with the progression of pancreatic cancer.

The perioperative period is characterized by psychological stress and inflammatory reactions that can contribute to disease recurrence or metastatic spread. These reactions are mediated particularly by catecholamines and prostaglandins. The PROSPER trial aimed to evaluate whether a perioperative drug repurposing with a non-selective betablocker (propranolol) and a COX-2 inhibitor (etodolac) is feasible and safe in the setting of pancreatic cancer surgery.

Patients undergoing partial pancreatoduodenectomy for pancreatic cancer were randomized to perioperative treatment with propranolol and etodolac or placebo. Main safety endpoint was the rate of serious adverse events (SAE) and the main feasibility endpoint was adherence. Overall and disease-free survival (DFS) as well as recurrences were assessed as efficacy parameters and the trial was accompanied by a translational study.

The trial was prematurely closed due to slow recruitment. 26 patients were randomized, but 6 never started trial medication. Finally, 9 patients received the trial medication and 11 patients placebo. There were 6 SAE in the treatment vs. 14 in the placebo group. Adherence was lower in the treatment group, but without statistically significance. Median DFS was 16.36 months (95%-CI 1.18 - not reached) in verum vs. 11.25 (95%-CI 2.2 - 17.25) in placebo group. The rate of distant recurrences was 11.1% in verum vs. 54.5% in placebo group.

There were no safety concerns, but the trial intervention was not feasible given slow recruitment and limited adherence. However, the translational study and preliminary efficacy data revealed some promising findings, warranting further investigation.

DRKS00014054.

Pancreatic cancer is characterised by its highly aggressive nature and extremely poor prognosis, with a uniquely complex tumour immune microenvironment that manifests as a prototypical "immune desert." This immune-desert phenotype primarily arises from the inherently low immunogenicity of the tumour, the formation of a dense fibrotic stroma, severe deficiency in immune cell infiltration, and profound immunosuppressive effects of the metabolic landscape. Specifically, dysregulated tryptophan metabolism, such as indoleamine 2,3-dioxygenase (IDO)-mediated catabolism, and excessive lactate accumulation contribute to impaired T-cell functionality. Collectively, these factors severely limit the efficacy of current immunotherapy strategies, particularly those based on immune checkpoint inhibitors, which have demonstrated significantly lower clinical response rates in pancreatic cancer than in other malignancies. In response to these therapeutic challenges, this review explores integrated treatment strategies that combine metabolic reprogramming, tumour microenvironment remodelling, and next-generation immune checkpoint blockades, such as LAG-3, TIM-3, and VISTA. These emerging approaches hold substantial promise for clinical application. For example, targeting key metabolic pathways, including glycolysis (Warburg effect) and glutamine metabolism, may help restore T-cell activity by alleviating metabolic stress within the tumour milieu. Additionally, localised administration of immune stimulators such as interleukin-12 (IL-12) and CD40 agonists may enhance immune cell infiltration and promote tumour-specific immune activation. Future research should prioritise large-scale, multicentre clinical trials to validate the therapeutic efficacy of these innovative strategies, aiming to achieve meaningful breakthroughs in pancreatic cancer immunotherapy and significantly improve long-term survival and clinical outcomes in affected patients.

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.

The application of magnetite nanoparticles (MagNPs) for photothermal therapy (MagNP-PTT) has recently expanded to cancer treatment. This study introduces MagNP-PTT in a tumor-on-a-chip model to target highly aggressive pancreatic ductal adenocarcinoma (PDAC). A tumor-on-chip system was developed using PANC-1 PDAC cells embedded in a collagen type I extracellular matrix and cultured for 1 week to form tumor spheroids. This platform offers a framework for applying PTT in a model system that aims to mimic the native tumor microenvironment. MagNPs efficiently penetrate the tumor spheroids, achieving controlled heating via near-infrared (NIR) light. By adjusting nanoparticle concentration and laser power, temperature increments of 2 °C between 38-48 °C were established. Temperatures above 44 °C significantly increased cell death, while lower temperatures allowed partial recovery. Beyond inducing cancer cell death, MagNP-PTT altered the extracellular matrix and triggered a slight epithelial-mesenchymal transition marked by increased vimentin expression. These findings highlight MagNP-PTT as a dual-action therapy, targeting both tumor cells and their microenvironment, offering an alternative approach for overcoming stromal barriers in pancreatic cancer treatment.

Pancreatic ductal adenocarcinoma (PDAC) is accompanied by endocrine dysfunction, particularly involving dysregulation of the insulin and insulin-like growth factor (IGF) signaling pathways. Clinical manifestations such as hyperglycemia and insulin resistance are common and have been linked to aberrant expression of insulin-like growth factor-binding proteins (IGFBPs). However, the specific roles and mechanisms of IGFBP family genes in PDAC remain unclear.

We conducted a multi-dimensional integrative analysis using publicly available PDAC cohorts, stratifying patients based on IGFBP gene expression profiles. A prognostic model was constructed to classify patients into risk groups. To explore the biological mechanisms underlying IGFBP involvement in PDAC, we further incorporated single-cell transcriptomic sequencing and spatial transcriptomic data to investigate the relationship between IGFBP expression and the tumor immune microenvironment.

Our prognostic model effectively stratified PDAC patients into distinct risk categories with significant survival differences. High-risk patients demonstrated specific IGFBP expression patterns associated with aggressive tumor biology. Single-cell and spatial transcriptomic analyses revealed that IGFBP family genes modulate immune cell infiltration and spatial immune heterogeneity within the tumor microenvironment.

This study identified the IGFBP family genes as key modulators of PDAC progression and immune landscape remodeling. These findings supported the potential of IGFBP family genes as prognostic biomarkers and therapeutic targets, offering new insights into PDAC biology and opportunities for personalized treatment strategies.

The tumor microenvironment (TME) plays a crucial role in cancer development and spreading being considered as "the dark side of the tumor". Within this term tumor cells, immune components, supporting cells, extracellular matrix and a myriad of bioactive molecules that synergistically promote tumor development and therapeutic resistance, are included. Recent findings revealed the profound impacts of TME on cancer development, serving as physical support, critical mediator and biodynamic matrix in cancer evolution, immune modulation, and treatment outcomes. TME targeting strategies built on vasculature, immune checkpoints, and immuno-cell therapies, have paved the way for revolutionary clinical interventions. On this basis, the relevance of pre-clinical and clinical investigations has rapidly become fundamental for implementing novel therapeutical strategies breaking cell-cell and cell -mediators' interactions between TME components and tumor cells. This review summarizes the key players in the breast and pancreatic TME, elucidating the intricate interactions among cancer cells and their essential role for cancer progression and therapeutic resistance. Different tumors such breast and pancreatic cancer have both different and similar stroma features, that might affect therapeutic strategies. Therefore, this review aims to comprehensively evaluate recent findings for refining breast and pancreatic cancer therapies and improve patient prognoses by exploiting the TME's complexity in the next future.

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.

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.

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).

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.

The efficacy of neoadjuvant chemoradiotherapy for resectable pancreatic ductal adenocarcinoma (R-PDAC) remains unclear. This study was designed to evaluate neoadjuvant chemoradiotherapy by using intensity-modulated radiotherapy (NAC-IMRT) for R-PDAC compared with upfront surgery (UpS).

Among 198 patients with R-PDAC who were indicated for resection between 2013 and 2021, 130 were included in this study after excluding patients who underwent neoadjuvant chemotherapy and did not meet the NAC-IMRT criteria (Eligible set). NAC-IMRT was planned for 58 patients, and UpS was planned for 72 patients. Additionally, in 105 patients who could undergo the planned treatment (As-treated set), the surgical, pathological, and oncological outcomes were evaluated.

In the Eligible set, median overall survival (OS) was 50.5 months with NAC-IMRT and 34.7 months with UpS and progression-free survival was 20.4 months with NAC-IMRT and 13.9 months with UpS. In the As-treated set, OS was longer in the NAC-IMRT group (66.7 months vs. 34.7 months, p = 0.007). On multivariate analysis, NAC-IMRT was identified as an independent factor for better OS (hazard ratio 0.617, 95% confidence interval 0.382-0.995, p = 0.047, in the Eligible set). The incidence of postoperative complications did not show a difference between the two groups, and NAC-IMRT suppressed local tumor invasion, including lymphatic, venous, perineural invasion, and lymph node metastases.

NAC-IMRT may offer superior survival outcomes and manageable toxicity in R-PDAC patients compared with upfront surgery. This study supports the efficacy and safety of NAC-IMRT and recommends its consideration in R-PDAC treatment protocols.

Pancreatic surgery is a complex and challenging field, with patients facing a high risk of postoperative complications. In recent years, indocyanine green (ICG) has gained prominence as a valuable tool used in various aspects of pancreatic surgery. ICG is a fluorescent dye that offers real-time imaging capabilities that enhance the surgeon's ability to accurately localize tumors and critical anatomical structures, thereby improving surgical precision and potentially reducing operative time and complications. One of the most significant advantages of ICG is its ability to provide enhanced visualization of the biliary tract and vascular structures, which is particularly beneficial in complex pancreatic resections, in which the anatomy can be highly variable and challenging to navigate. Furthermore, ICG can be instrumental in ensuring the adequate perfusion of anastomoses, thereby reducing the risk of postoperative leaks and associated morbidity. This comprehensive review aims to provide an in-depth analysis of the current applications, advantages, and limitations of ICG in pancreatic surgery.

Low sensitivity, photobleaching, high-power excitation and long acquisition times constrain the utility of afterglow luminescence. Here we report the design and imaging performance of nanoparticles made of electron-rich trianthracene derivatives that, on excitation by room light at ultralow power (58 μW cm-2), emit afterglow luminescence at ~500 times those of commonly used organic afterglow nanoparticles. The nanoparticles' ultrabright afterglow allowed for deep-tissue imaging (up to 6 cm), for ultrafast afterglow imaging (at short acquisition times down to 0.01 s) of naturally behaving mice with negligible photobleaching, even after re-excitation for over 15 cycles, and for the accurate visualization of subcutaneous and orthotopic tumours and of plaque in carotid arteries. We also show that an afterglow nanoparticle that is activated only in the presence of granzyme B allowed for the tracking of granzyme-B activity in the context of therapeutic monitoring. The high sensitivity and negligible photobleaching of the organic afterglow nanoparticles offer advantages for real-time in vivo monitoring of physiopathological processes.

Pancreatic cancer is a lethal invasive tumor with one of the worst prognosis. Accurate and reliable segmentation for pancreas and pancreatic cancer on computerized tomography (CT) images is vital in clinical diagnosis and treatment. Although certain deep learning-based techniques have been tentatively applied to this task, current performance of pancreatic cancer segmentation is far from meeting the clinical needs due to the tiny size, irregular shape and extremely uncertain boundary of the cancer. Besides, most of the existing studies are established on the black-box models which only learn the annotation distribution instead of the logical thinking and diagnostic experience of high-level medical experts, the latter is more credible and interpretable. To alleviate the above issues, we propose a novel Segment-Like-A-Doctor (SLAD) framework to learn the reliable clinical thinking and experience for pancreas and pancreatic cancer segmentation on CT images. Specifically, SLAD aims to simulate the essential logical thinking and experience of doctors in the progressive diagnostic stages of pancreatic cancer: organ, lesion and boundary stage. Firstly, in the organ stage, an Anatomy-aware Masked AutoEncoder (AMAE) is introduced to model the doctors' overall cognition for the anatomical distribution of abdominal organs on CT images by self-supervised pretraining. Secondly, in the lesion stage, a Causality-driven Graph Reasoning Module (CGRM) is designed to learn the global judgment of doctors for lesion detection by exploring topological feature difference between the causal lesion and the non-causal organ. Finally, in the boundary stage, a Diffusion-based Discrepancy Calibration Module (DDCM) is developed to fit the refined understanding of doctors for uncertain boundary of pancreatic cancer by inferring the ambiguous segmentation discrepancy based on the trustworthy lesion core. Experimental results on three independent datasets demonstrate that our approach boosts pancreatic cancer segmentation accuracy by 4%-9% compared with the state-of-the-art methods. Additionally, the tumor-vascular involvement analysis is also conducted to verify the superiority of our method in clinical applications. Our source codes will be publicly available at https://github.com/ZouLiwen-1999/SLAD.

Pancreatic ductal adenocarcinoma (PDAC) is among the cancer types with poorest prognosis and survival rates primarily due to resistance to standard-of-care therapies, including gemcitabine (GEM) and olaparib. Particularly, wild-type (wt)BRCA tumours, the most prevalent in PDAC, are more resistant to DNA-targeting agents like olaparib, restraining their clinical application. Recently, we disclosed a monoterpene indole alkaloid derivative (BBIT20) as a new inhibitor of homologous recombination (HR) DNA repair with anticancer activity in breast and ovarian cancer. Since inhibition of DNA repair enhances the sensitivity of cancer cells to chemotherapy, we aimed to investigate the anticancer potential of BBIT20 against PDAC, particularly carrying wtBRCA.

In vitro and in vivo PDAC models, particularly human cell lines (including GEM-resistant PDAC cells), patient-derived organoids and xenograft mice of PDAC were used to evaluate the anticancer potential of BBIT20, alone and in combination with GEM or olaparib. Disruption of the BRCA1-BARD1 interaction by BBIT20 was assessed by co-immunoprecipitation, immunofluorescence and yeast two-hybrid assay.

The potent antiproliferative activity of BBIT20, superior to olaparib, was demonstrated in PDAC cells regardless of BRCA status, by inducing cell cycle arrest, apoptosis, and DNA damage, while downregulating HR. The disruption of DNA double-strand breaks repair by BBIT20 was further reinforced by non-homologous end joining (NHEJ) suppression. The inhibition of BRCA1-BARD1 heterodimer by BBIT20 was demonstrated in PDAC cells and confirmed in a yeast two-hybrid assay. In GEM-resistant PDAC cells, BBIT20 showed potent antiproliferative, anti-migratory and anti-invasive activity, overcoming GEM resistance by inhibiting the multidrug resistance P-glycoprotein, upregulating the intracellular GEM-transporter ENT1, and downregulating GEM resistance-related microRNA-20a and GEM metabolism enzymes as RRM1/2. Furthermore, BBIT20 did not induce resistance in PDAC cells. It inhibited the growth of patient-derived PDAC organoids, by inducing apoptosis, repressing HR, and potentiating olaparib and GEM cytotoxicity. The enhancement of olaparib antitumor activity by BBIT20 was confirmed in xenograft mice of PDAC. Notably, it hindered tumour growth and liver metastasis formation, improving survival of orthotopic xenograft mice of PDAC. Furthermore, its potential as a stroma-targeting agent, reducing fibrotic extracellular matrix and overcoming desmoplasia, associated with an enhancement of immune cell response by depleting PD-L1 expression in tumour tissues, renders BBIT20 even more appealing for combination therapy, particularly with immunotherapy.

These findings underscore the great potential of BBIT20 as a novel multifaceted anticancer drug candidate for PDAC treatment.

Pancreatic cancer is a malignancy with a poor prognosis and high mortality. Survival outcomes remain very poor despite significant advances in molecular diagnostics and therapeutics in clinical practice. Surgical resection is the only potentially curative treatment, but the tumor is often diagnosed at an advanced stage, and most cancers recur after surgery. Treatments other than surgery, including chemotherapy and immunotherapy, still offer disappointing results. Multidisciplinary treatment approaches through appropriate carriers have provided new solutions for improving the prognosis of pancreatic cancer. Herein, we reported an in situ formed thermo-responsive hybrid hydrogel loaded with gemcitabine and manganese dioxide nanoparticles, which exhibited good injectability, high photothermal hyperthermia, and biocompatibility, leading to efficient multidisciplinary treatment of pancreatic cancer in combination with chemotherapy and photothermal therapy (PTT). The hybrid hydrogel could be heated to 51 °C under 808 nm laser irradiation in five minutes. In situ intratumoral injection results suggested that the hybrid hydrogel exhibited high photothermal efficiency in killing rabbit pancreatic tumors. In vivo results indicated that the multidisciplinary treatment almost completely eliminated subcutaneous tumors in mice within 14 days. This development offers an efficient multidisciplinary treatment for pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a prevalent cancer with a high mortality rate. This study aims to identify and validate biomarkers for early PDAC diagnosis. We employed the GEO2R online tool to screen differentially expressed genes (DEGs), construct protein interaction networks, and perform functional enrichment analysis, survival prognosis analysis, and expression level validation. We identified 260 DEGs, comprising 165 upregulated genes and 95 downregulated genes. Following functional enrichment and survival analysis, we selected plasminogen activator urokinase (PLAU) for the RNA and protein level verification and preliminary cell phenotype analysis. We found that PLAU knockdown inhibits the proliferation and survival of pancreatic cancer cells. Therefore, PLAU may serve as a potential biomarker, offering new strategies for understanding PDAC's pathological mechanisms.

Pancreatic cancer is one of the most aggressive malignancies with poor prognostic outcomes, necessitating the exploration of novel biomarkers and therapeutic targets for early detection and effective treatment. Small extracellular vesicles (sEVs) secreted by cells, have gained considerable attention in cancer research due to their role in intercellular communication and their potential as non-invasive biomarkers. This review focuses on the role of sEVs in the progression of pancreatic cancer and their application as biomarkers. We delve into the biogenesis, composition, and functional implications of sEVs in pancreatic tumor biology, emphasizing their involvement in processes such as tumor growth, metastasis, immune modulation, and chemotherapy resistance. In addition, we discuss the challenges in isolating and characterizing sEVs. The review also highlights recent advances in the utilization of sEV-derived biomarkers for the early diagnosis, prognosis, and monitoring of pancreatic cancer. By synthesizing the latest findings, we aim to underscore the significance of sEVs in pancreatic cancer and their potential to revolutionize patient management through improved diagnostics and targeted therapies.

Endoscopic ultrasound-guided tissue acquisition (EUS-TA) for focal liver lesions has gained attention as an alternative to percutaneous biopsy. Although the outcomes of EUS-TA for focal liver lesions have been reported to be favorable, no studies have focused on small focal liver lesions (≤2 cm). The aim of this study was to evaluate the outcomes of EUS-TA for small focal liver lesions (≤2 cm).

The details of EUS-TA performed for focal liver lesions between 2016 and 2022 were retrospectively reviewed. The outcomes were compared between cases involving ≤2 cm lesions and those involving >2 cm lesions. The primary outcomes were diagnostic ability and adverse events.

EUS-TA for focal liver lesions was performed in 109 cases. Of the 109 cases, 32 (29.3%) involved ≤2 cm lesions and 77 (70.6%) involved >2 cm lesions. Right lobe lesions and transduodenal puncture were significantly fewer in the ≤2 cm group. There were no significant differences in needle gauge, needle type, or number of punctures between the groups. The sensitivity, specificity, and accuracy rates were 96.8%, 100%, and 96.8%, respectively, in the ≤2 cm group and 97.4%, 100%, and 97.4%, respectively, in the >2 cm group, with no significant differences between the groups. There was no difference in adverse events between the groups (0% in the ≤2 cm group and 2.3% in the >2 cm group).

EUS-TA for small focal liver lesions measuring ≤2 cm has favorable outcomes, which are similar to those for lesions measuring >2 cm.

This review addresses oxidative stress and redox signaling in the pancreas under healthy physiological conditions as well as in acute pancreatitis, chronic pancreatitis, pancreatic cancer, and diabetes. Physiological redox homeodynamics is maintained mainly by NRF2/KEAP1, NF-κB, protein tyrosine phosphatases, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α), and normal autophagy. Depletion of reduced glutathione (GSH) in the pancreas is a hallmark of acute pancreatitis and is initially accompanied by disulfide stress, which is characterized by protein cysteinylation without increased glutathione oxidation. A cross talk between oxidative stress, MAPKs, and NF-κB amplifies the inflammatory cascade, with PP2A and PGC1α as key redox regulatory nodes. In acute pancreatitis, nitration of cystathionine-β synthase causes blockade of the transsulfuration pathway leading to increased homocysteine levels, whereas p53 triggers necroptosis in the pancreas through downregulation of sulfiredoxin, PGC1α, and peroxiredoxin 3. Chronic pancreatitis exhibits oxidative distress mediated by NADPH oxidase 1 and/or CYP2E1, which promotes cell death, fibrosis, and inflammation. Oxidative stress cooperates with mutant KRAS to initiate and promote pancreatic adenocarcinoma. Mutant KRAS increases mitochondrial reactive oxygen species (ROS), which trigger acinar-to-ductal metaplasia and progression to pancreatic intraepithelial neoplasia (PanIN). ROS are maintained at a sufficient level to promote cell proliferation, while avoiding cell death or senescence through formation of NADPH and GSH and activation of NRF2, HIF-1/2α, and CREB. Redox signaling also plays a fundamental role in differentiation, proliferation, and insulin secretion of β-cells. However, ROS overproduction promotes β-cell dysfunction and apoptosis in type 1 and type 2 diabetes.

Acute pancreatitis (AP) is a common disease of acute abdominal pain, the incidence of which is increasing annually, but its pathogenesis remains incompletely understood.

Gene expression profiles of AP were obtained from the Gene Expression Omnibus (GEO) database. R software was used to identify differentially expressed genes (DEGs) and perform functional analysis. The diagnostic value of HLA-DR-related genes was assessed by receiver operating characteristic (ROC) curves. Monocyte infiltration abundance in AP and normal groups was analyzed by Cibersort method, and the correlation between HLA-DR-related genes and monocyte abundance was analyzed. The modules highly correlated with HLA-DR-related genes were clarified by WGCNA modeling, and the core genes regulating HLA-DR were obtained by using LASSO regression. Finally, potential drugs targeting the above genes were analyzed by Enrichr database.

A Total of 3 HLA-DR-related genes (HLA-DRA, HLA-DRB1, and HLA-DRB5) were identified, which were negatively correlated with the severity of AP and had excellent disease diagnostic value (AUC = 0.761, 0.761, and 0.718), were were positively correlated with monocyte abundance. We identified 110 genes that positively regulate HLA-DR and 130 genes that negatively regulate HLA-DR. LASSO regression identified UCP2, GK, and SAMHD1 as the core nodes of the regulated genes. Compared with the normal group, UCP2 and SAMHD1 were reduced in AP, and the opposite was true for GK, and SAMHD1 had better sensitivity and specificity in diagnosing AP. Drug sensitivity analysis predicted 12 drugs acting on HLA-DRA, HLA-DRB1, and HLA-DRB5 and 8 drugs acting on UCP2, GK, and SAMHD1.

We identified 3 HLA-DR-related genes (HLA-DRA, HLA-DRB1, and HLA-DRB5) and 3 coregulatory nodes (UCP2, GK, and SAMHD1), which were associated with AP severity and monocyte abundance. Based on these genes, we predicted 20 potential therapeutic agents for AP.

Disulfidptosis is a newly discovered formation of programmed cell death. However, the significance of disulfidptosis in pancreatic adenocarcinoma remains unclear. Our investigation aims to elucidate the significance of disulfidptosis in pancreatic ductal adenocarcinoma by integrating diverse datasets, including bulk RNA sequencing data, microarray profiles, single-cell transcriptome profiles, spatial transcriptome data, and biospecimens. Utilizing various bioinformatics tools, we screened disulfidptosis-related genes based on single-cell RNA sequencing profiles, subsequently validating them through enrichment analysis. An 8-gene disulfidptosis-related prognostic signature was established by constructing massive LASSO-Cox regression models and validated by multiple external PDAC cohorts. Evaluation methods, such as Kaplan-Meier curves, ROC curves, time-dependent ROC curves, and decision curve analysis, were employed to assess the prognostic signature's reliability. High disulfidptosis-related scores were associated with a poorer prognosis and diminished sensitivity to immune checkpoint blockade. Further investigation uncovered that the potential components of elevated DPS involve malignant tumor hallmarks, extensive interactions between myCAFs and tumor cells, and the exclusion of immune cells. Cell-cell communication analysis highlighted myCAFs' role in signaling, potentially influencing tumor cells towards increased malignancy through collagen, laminin, and FN1 signaling networks. Spatial transcriptome analysis confirmed the crosstalk between myCAFs and tumor cells. Biospecimens including 20 pairs of PDAC samples and adjacent normal tissues further demonstrated the robustness of DPS and its correlation with CAF markers. In conclusion, our study introduces a novel disulfidptosis-related signature with high efficacy in patient risk stratification, which has the ability to predict the sensitivity to immune checkpoint blockade.

The pancreas tumor microbiota may influence tumor microenvironment and influence survival in early-stage pancreatic ductal adenocarcinoma (PDAC); however, current studies are limited and small. We investigated the relationship of tumor microbiota to survival in 201 surgically resected patients with localized PDAC (Stages I-II), from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) cohorts. We characterized the tumor microbiome using RNA-sequencing data. We examined the association of the tumor microbiome with overall survival (OS), via meta-analysis with the Cox PH model. A microbial risk score (MRS) was calculated from the OS-associated microbiota. We further explored whether the OS-associated microbiota is related to host tumor immune infiltration. PDAC tumor microbiome α- and β-diversities were not associated with OS; however, 11 bacterial species, including species of Gammaproteobacteria, confirmed by extensive resampling, were significantly associated with OS (all Q < 0.05). The MRS summarizing these bacteria was related to a threefold change in OS (hazard ratio = 2.96 per standard deviation change in the MRS, 95% confidence interval = 2.26-3.86). This result was consistent across the two cohorts and in stratified analyses by adjuvant therapy (chemotherapy/radiation). Identified microbiota and the MRS also exhibited association with memory B cells and naïve CD4+ T cells, which may be related to the immune landscape through BCR and TCR signaling pathways. Our study shows that a unique tumor microbiome structure, potentially affecting the tumor immune microenvironment, is associated with poorer survival in resected early-stage PDAC. These findings suggest that microbial mechanisms may be involved in PDAC survival, potentially informing PDAC prognosis and guiding personalized treatment strategies.IMPORTANCEMuch of the available data on the PDAC tumor microbiome and survival are derived from relatively small and heterogeneous studies, including those involving patients with advanced stages of pancreatic cancer. There is a critical knowledge gap in terms of the tumor microbiome and survival in early-stage patients treated by surgical resection; we expect that advancements in survival may initially be best achieved in these patients who are treated with curative intent.

Tryptophan (Trp) is an essential amino acid that must be acquired exclusively through dietary intake. The metabolism of tryptophan plays a critical role in maintaining immune homeostasis and tolerance, as well as in preventing excessive inflammatory responses. Tryptophan-2,3-dioxygenase (TDO2) is a tetrameric heme protein and serves as one of the pivotal rate-limiting enzymes in the first step of tryptophan metabolism. Dysregulation of TDO2 expression has been observed in various digestive system diseases, encompassing those related to the oral cavity, esophagus, liver, stomach, pancreas, and colon and rectum. Digestive system diseases are the most common clinical diseases, with complex clinical manifestations and interrelated symptoms, and have become a research hotspot in the field of medicine. Studies have demonstrated that aberrant TDO2 expression is closely associated with various clinical manifestations and disease outcomes in patients with digestive system disorders. Consequently, TDO2 has garnered increasing recognition as a promising therapeutic target for digestive system diseases in recent years, attracting growing attention. This article provides a brief overview of the role of TDO2 in the tryptophan pathway, emphasizing its significant involvement in diseases of the digestive system. Strategies targeting TDO2 through specific inhibitors suggest considerable promise in enhancing therapeutic outcomes for digestive diseases. Thus, this review concludes by discussing recent advancements in the development of TDO2 inhibitors. We believe that targeted inhibition of TDO2 combined with immunotherapy, the screening of a large number of natural products, and the assistance of artificial intelligence in drug design will be important directions for developing more effective TDO2 inhibitors and improving treatment outcomes in the future.

In pancreatic cancer (PC), vascular endothelial growth factor (VEGF) and its primary receptor, vascular endothelial growth factor receptor (VEGFR)-2, are central drivers of angiogenesis and metastasis, with their overexpression strongly associated with poor prognosis. In some PC patients, VEGF levels correlate with disease stage, tumor burden, and survival outcomes. However, therapies targeting VEGF and VEGFR-2, including tyrosine kinase inhibitors (TKIs) and monoclonal antibodies, have demonstrated limited efficacy, partly due to the emergence of resistance mechanisms. Resistance appears to stem from the activation of alternative vascularization pathways. This review explores the multifaceted roles of VEGFRs in pancreatic cancer, including VEGFR-1 and VEGFR-3. Potential strategies to improve VEGFR-targeting therapies, such as combination treatments, the development of more selective inhibitors, and the use of biomarkers, are discussed as promising approaches to enhance treatment efficacy and outcomes.

Randomized trials and meta-analyses have indicated longer survival with neoadjuvant than with adjuvant therapy in patients with resectable or borderline resectable (R/BR) pancreatic adenocarcinoma. Despite the efficacy of chemotherapy, the role of radiation therapy as an adjuvant or neoadjuvant treatment for patients with R/BR pancreatic adenocarcinoma remains unclear. In this systematic review and meta-analysis, we compared the benefits of additional chemoradiation therapy (CRT) to neoadjuvant chemotherapy (NAC) with NAC alone for R/BR pancreatic adenocarcinoma.

A systematic literature search was conducted on Embase, Web of Science, PubMed, Cochrane, and Google Scholar. Median overall survival (OS) was the primary endpoint. Secondary endpoints included disease-free survival (DFS), resection rate, and R0 resection rate.

This review and meta-analysis included 31 prospective studies, of which 9 were randomized trials. In these studies, 658 patients from 14 study arms received NAC alone and 912 patients from 19 study arms received both NAC and CRT (NAC-CRT). The pooled median OS was 25.55 months (95% CI, 21.59-30.24 months) for NAC alone and 17.55 months (95% CI, 16.47-18.70 months; P < .0001) for NAC-CRT. The pooled R0 resection rate was higher with NAC-CRT (83.43%) than with NAC (69.97%; P < .0001). No significant difference was observed in DFS or resection rate between the 2 groups. In patients who received 5 or more cycles of initial chemotherapy, NAC-CRT was associated with longer OS than NAC (23.30 vs 21.85 months; P = .856).

NAC provides significantly longer OS than NAC-CRT to R/BR pancreatic adenocarcinoma. NAC-CRT is associated with a significantly improved R0 resection rate. This positive local effect of CRT can be translated to extended survival when 5 cycles or more of NAC are prescribed.

Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive type of pancreatic cancer, with a five-year survival rate below 8%. Its high mortality is largely due to late diagnosis, metastatic potential, and resistance to therapy. Epithelial-mesenchymal transition (EMT) plays a key role in metastasis, enabling cancer cells to become mobile. Partial EMT, where cells maintain both epithelial and mesenchymal traits, is more frequent in tumors than complete EMT and contributes to cancer progression. The long non-coding RNA MIR31 host gene (MIR31HG) has recently emerged as a critical factor in PDAC oncogenesis. This study aimed to investigate MIR31HG's role in partial EMT and its association with the basal-like PDAC subtype.

We analyzed the relationship between MIR31HG expression, partial EMT, and the basal-like subtype of PDAC by integrating data from public databases. We reanalyzed public data from PDAC patient-derived organoids to assess MIR31HG expression and gene signatures under hypoxic and normoxic conditions. RNA sequencing and bioinformatics analyses, including gene set enrichment analysis (GSEA), were used to investigate differentially expressed genes and pathway enrichments. EMT, partial EMT, and hypoxia scores were calculated based on the expression levels of specific gene sets.

We observed that MIR31HG overexpression strongly correlates with higher partial EMT scores and the stabilization of the epithelial phenotype in PDAC. MIR31HG is highly expressed in the basal-like subtype of PDAC, which exhibits partial EMT traits. Hypoxia, a hallmark of basal-like PDAC, was shown to significantly induce MIR31HG expression, thereby promoting the basal-like phenotype and partial EMT. In patient-derived organoids, hypoxic conditions increased MIR31HG expression and enhanced basal-like and partial EMT gene signatures, while normoxia reduced these expressions. These findings suggest that hypoxia-induced MIR31HG expression plays a crucial role in driving the aggressive basal-like subtype of PDAC.

Our results indicate that MIR31HG is crucial in regulating PDAC progression, particularly in the aggressive basal-like subtype associated with hypoxia and partial EMT. Targeting the MIR31HG-mediated network may offer a novel therapeutic approach to combat hypoxia-driven PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest diseases, despite advancements in elucidating tumor biology and developing novel therapeutics. Importantly, lipids, such as phospholipids, are crucial for the survival and proliferation of tumor cells. However, the impact of chemotherapeutic drugs on phospholipid metabolism in PDAC remains poorly understood. Gemcitabine (a nucleoside analogue) is a first-line drug in PDAC treatment, but its clinical effectiveness is limited by multiple factors. Herein, we employed matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) and proteomics approaches to investigate gemcitabine-induced lipid metabolism alterations in mouse pancreatic tumors following gemcitabine treatment (n = 3, control tumors; n = 3, gemcitabine-treated tumors). From MALDI MSI experiments, we observed elevated levels of several phosphatidylcholines (PCs), PC(30:0), PC(32:3), PC(34:2), PC(36:1), and PC(36:2), in gemcitabine-treated tumor tissues compared to the control. In addition, proteomics data revealed the differential abundance of several phospholipid-binding proteins in response to gemcitabine treatments. Furthermore, several endoplasmic reticulum stress-related proteins exhibited high expression in gemcitabine-treated tumor tissues. Altogether, our MALDI MSI and proteomics data provide important insights into alterations in PC metabolism in pancreatic tumors in response to gemcitabine treatment. Importantly, targeting the altered PC metabolism during gemcitabine therapy might help combat pancreatic cancer.

A 71-year-old woman diagnosed with unresectable locally advanced pancreatic cancer was initially treated with gemcitabine and nab-paclitaxel as first-line therapy. The tumor exhibited no significant progression; however, after 12 cycles, the patient developed drug-induced interstitial pneumonia, leading to the discontinuation of gemcitabine and nab-paclitaxel therapy. Following recovery from pneumonia, S-1 therapy was initiated as second-line treatment. During S-1 therapy, she was hospitalized because of impaired consciousness and was subsequently diagnosed with hyperammonemia induced by S-1. Although rarely reported, S-1-induced hyperammonemia is potentially a significant adverse effect. Here, we herein report the case of a patient with pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is recognized as one of the most formidable cancers, largely due to its distinct microenvironment characterized predominantly by extensive desmoplastic stroma. In this study, we synthesized three novel water-soluble fullerene-based nanomaterials targeting EGFR protein.

The direct amination of fullerene carbon atoms, was followed by conjugation with a modified derivative of the EGFR inhibitor-erlotinib, resulting in the formation of novel water-soluble fullerene derivatives.

Further investigation into PAN02 and AsPC-1 cell lines revealed that these fullerene nanomaterials could induce cell cycle arrest in the G0/G1 phase, corroborated by alterations in the expression levels of the p27 and cyclin E1 proteins. Additionally, mechanisms of cell death were identified as autophagy for C60BUT and C70BUT-ERL, and apoptosis for Gd@C82EDA-ERL nanomaterials.

Crucially, the study uncovered the efficacy of synthesized aminofullerenes in inhibiting the EGFR signaling pathway. The further toxicological studies of Gd@C82EDA-ERL fullerene on Drosophila melanogaster, underscored its potential for theranostic applications.

Autophagy and the Warburg effect are two common pathways in pancreatic ductal adenocarcinoma (PDAC). To date, the reciprocal effects of these pathways have not yet been elucidated. Therefore, this study was designed to investigate the relationship between these factors in vitro and may provide therapeutic targets in the future. The Mia-Paca-2 and AsPc-1 cell lines were cultured under normal conditions. To achieve autophagy, starvation was induced by Hank's balanced salt solution (HBSS), whereas autophagy was inhibited by 3-methyladenine (3-MA). The Warburg effect is mimicked by lactic acid, and the Warburg effect is inhibited by oxamate, the main inhibitor of lactate dehydrogenase. Cell viability was checked through the MTT assay method. Autophagy was checked via evaluation of Beclin-1 via western blotting. The amount of lactic acid was also measured with a lactate dehydrogenase (LDH) assay kit. The cells were incubated with different concentrations of 3-MA, lactic acid and oxamate. The viability of AsPc-1 cells decreased, and the IC50 values were 1195 µM, 23.06 mM and 8.617 mM for 3-MA, lactic acid and oxamate, respectively. Similarly, the IC50 values of Mia-Paca-2 were 873.9 µM, 35.9 mM and 26.74 mM for 3-MA, lactic acid and oxamate, respectively. Our data revealed that starvation increased the expression of the autophagy-related protein Beclin-1 (P value < 0.05); however, 3-MA significantly reduced its expression (P value < 0.05). In addition, lactic acid alone did not affect the expression level of Beclin-1 (P value > 0.05), but oxamate treatment increased its expression (P value < 0.05). We also showed that starvation reduced lactic acid levels, but an autophagy inhibitor, 3MA, significantly increased lactic acid production (P value < 0.05). Our findings showed that lactic acid alone has no significant effect on autophagy and that oxamate induces autophagy, possibly because of caloric restriction. On the other hand, autophagy inhibits lactic acid production, whereas the inhibition of autophagy leads to increased lactic acid production.

Pancreatic ductal adenocarcinoma stands out as an exceptionally fatal cancer owing to the complexities associated with its treatment and diagnosis, leading to a notably low five-year survival rate. This study offers a detailed exploration of epidemiological trends in pancreatic cancer and key molecular drivers, such as mutations in CDKN2A, KRAS, SMAD4, and TP53, along with the influence of cancer-associated fibroblasts (CAFs) on disease progression. In particular, we focused on the pivotal roles of signaling pathways such as the transforming growth factor-β and Wnt/β-catenin pathways in the development of pancreatic cancer and investigated their application in emerging therapeutic strategies. This study provides new scientific perspectives on pancreatic cancer treatment, especially in the development of precision medicine and targeted therapeutic strategies, and demonstrates the importance of signaling pathway research in the development of effective therapeutic regimens. Future studies should explore the subtypes of CAFs and their specific roles in the tumor microenvironment to devise more effective therapeutic methods.

Cancer immunotherapy has reshaped the landscape of cancer treatment over the past decades. Genetic manipulation of T cells to express synthetic receptors, known as chimeric antigen receptors (CAR), has led to the creation of tremendous commercial and therapeutic success for the treatment of certain hematologic malignancies. However, since the engagement of CAR-T cells with their respective antigens is solely what triggers their cytotoxic reactions against target cells, the slightest changes to the availability and/or structure of the target antigen often result in the incapacitation of CAR-T cells to enforce tumoricidal responses. This results in the resistance of tumor cells to a particular CAR-T cell therapy that requires meticulous heeding to sustain remissions in cancer patients. In this review, we highlight the antigen-dependent resistance mechanisms by which tumor cells dodge being recognized and targeted by CAR-T cells. Moreover, since substituting the target antigen is the most potent strategy for overcoming antigen-dependent disease relapse, we tend to highlight the current status of some target antigens that might be considered suitable alternatives to the currently available antigens in various cancers. We also propose target antigens whose targeting might reduce the off-tumor adverse events of CAR-T cells in certain malignancies.

α-Hederin is a pentacyclic triterpenoid saponin extracted from Pulsatilla chinensis, which is known to suppress cancer cell proliferation. However, the role of this compound in pancreatic cancer cells remains unclear. The aim of this study was to reveal the docking molecular and the regulatory mechanism of α-hederin in pancreatic cancer. Here, we cultured Capan-1 and BxPC-3 cells and treated with different doses of α-hederin. Cell proliferation, migration, and apoptosis were detected using CCK8, EdU, Transwell, wound healing assay, and flow cytometer apoptosis assay. The in vivo experiment using subcutaneous tumor and caudal vein metastasis model to evaluate the inhibit effect of α-hederin Capan-1 cell tumor growth and metastasis. Proteomics were used to reveal the regulatory mechanism. The result shows that α-hederin treatment inhibits cell proliferation and invasion in concentration dependence way in both vivo and in vitro. The result shows that the IC50 for both Capan-1 and BxPC-3 were 32.5 Mµ and 15 Mµ, respectively. Flow cytometer apoptosis assay shows that α-hederin treatment promotion cell apoptosis in both Capan-1 and BxPC-3 cells. Proteomics and immunofluorescence detection confirmed that α-hederin treatment downregulated lactate dehydrogenase A (LDHA) expression and inhibited glycolysis. Molecular docking of α-hederin and LDHA proteins further confirmed that LDHA is a target of α-hederin. Taken together, this study confirms that α-hederin inhibits pancreatic cancer cell proliferation and invasion by inhibiting LDHA-mediated glycolysis. LDHA may be a direct target of α-hederin in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a malignant form of cancer with the worst survival rate and an extremely low rate of response to treatments. The development and molecular characterization of pancreatic cancer cell lines (PCCLs) are essential for studying the biology of highly aggressive pancreatic adenocarcinoma.

We applied whole exome sequencing (WES) and RNA-seq to identify molecular characteristics of 26 newly established PCCLs. Eighteen clinically relevant anti-cancer drugs were used to assess highly heterogeneous drug responses across the 26 cell lines.

We confirmed that common driver mutations of PDAC were well retained in our cell lines through WES analysis. Transcriptomic analysis identified two representative clusters that correlated with responses to certain drugs. By using Moffitt's classification method, the two clusters, C1 and C2, showed comparable expression patterns to "Basal-like" and "Classical" types, respectively. Drug screening results showed varying responses among different cell lines. In our cohort, C2 displayed greater sensitivity to anti-cancer drugs compared to C1. Furthermore, drugs targeting similar molecular pathways exhibited corresponding reactions among cell lines.

Our results underscored that transcriptomic features of pancreatic cancer correlate with drug sensitivity rather than with the effects of targeted drugs. Cell lines are useful in vitro model systems for studying the molecular mechanisms of PDAC.