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Ye W, An D, Ou WB. SMARCA4: Promises and challenges in the treatment of cancers. Cancer Lett 2025; 625:217811. [PMID: 40398707 DOI: 10.1016/j.canlet.2025.217811] [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: 03/16/2025] [Revised: 05/09/2025] [Accepted: 05/18/2025] [Indexed: 05/23/2025]
Abstract
The SWI/SNF (switch/sucrose non-fermentable) related BAF (BRG1/BRM-related factor) chromatin remodeling complex subunit ATPase 4 (SMARCA4) is a gene with a high mutation frequency in the SWI/SNF complex. It plays a role as an ATP-dependent catalytic subunit, participates in remodeling chromatin structure and regulation of gene expression, and is closely related to the poor prognosis of malignant tumors. It is imperative to conduct a comprehensive investigation into the distinctive biological functions and mechanisms by which SMARCA4 contributes to cancer development and to devise targeted therapeutic strategies. Despite numerous studies associating SMARCA4 with the regulation of essential genes, ferroptosis, autophagy, lipid metabolism, and oxidative stress, the precise mechanisms of SMARCA4 in tumors remain unclear. Patients with SMARCA4 mutations exhibit a poor prognosis and demonstrate limited responsiveness to surgery, targeted therapies, immunotherapy, and chemotherapies. Thus, SMARCA4 emerges as a promising biomarker and therapeutic target. However, the development of more effective precision therapy tools remains an urgent unmet need. The unique molecular characteristics of SMARCA4 pose significant challenges for targeted drug development. Notably, the discovery of inhibitors targeting SMARCA4 synthetic lethal partners and associated pathways has marked a breakthrough in this field. Monotherapies directed against SMARCA4 face several limitations, including drug resistance, suboptimal objective response rates, and dose-limiting toxicities. Consequently, the exploration of combinatorial therapeutic strategies for SMARCA4 deficiency populations represents a critical direction for future clinical translation.
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Affiliation(s)
- Wei Ye
- Department of Biopharmaceutics, Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, Zhejiang Sci-Tech University, Hangzhou, Zhejiang, China
| | - Ding An
- Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, Zhejiang, China
| | - Wen-Bin Ou
- Department of Biopharmaceutics, Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, Zhejiang Sci-Tech University, Hangzhou, Zhejiang, China; Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, Zhejiang, China.
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2
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Baldassarre G, L de la Serna I, Vallette FM. Death-ision: the link between cellular resilience and cancer resistance to treatments. Mol Cancer 2025; 24:144. [PMID: 40375296 PMCID: PMC12080166 DOI: 10.1186/s12943-025-02339-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Accepted: 04/22/2025] [Indexed: 05/18/2025] Open
Abstract
One of the key challenges in defeating advanced tumors is the ability of cancer cells to evade the selective pressure imposed by chemotherapy, targeted therapies, immunotherapy and cellular therapies. Both genetic and epigenetic alterations contribute to the development of resistance, allowing cancer cells to survive initially effective treatments. In this narration, we explore how genetic and epigenetic regulatory mechanisms influence the state of tumor cells and their responsiveness to different therapeutic strategies. We further propose that an altered balance between cell growth and cell death is a fundamental driver of drug resistance. Cell death programs exist in various forms, shaped by cell type, triggering factors, and microenvironmental conditions. These processes are governed by temporal and spatial constraints and appear to be more heterogeneous than previously understood. To capture the intricate interplay between death-inducing signals and survival mechanisms, we introduce the concept of Death-ision. This framework highlights the dynamic nature of cell death regulation, determining whether specific cancer cell clones evade or succumb to therapy. Building on this understanding offers promising strategies to counteract resistant clones and enhance therapeutic efficacy. For instance, combining DNMT inhibitors with immune checkpoint blockade may counteract YAP1-driven resistance or the use of transcriptional CDK inhibitors could prevent or overcome chemotherapy resistance. Death-ision aims to provide a deeper understanding of the diversity and evolution of cell death programs, not only at diagnosis but also throughout disease progression and treatment adaptation.
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Affiliation(s)
- Gustavo Baldassarre
- Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, National Cancer Institute, Aviano, 33081, Italy.
| | - Ivana L de la Serna
- Department of Cell and Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.
| | - François M Vallette
- Centre de Recherche en Cancérologie et Immunologie Intégrées Nantes Angers (CRCI2 NA), INSERM UMR1307/CNRS UMR 6075/Nantes Université/Univ. Angers. Nantes, 44007, Nantes, France.
- Institut de Cancérologie de L'Ouest (ICO), 44085, Saint-Herblain, France.
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3
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Dawalibi A, Bakir M, Mohammad KS. The genetic architecture of bone metastases: unveiling the role of epigenetic and genetic modifications in drug resistance. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2025; 8:19. [PMID: 40342734 PMCID: PMC12059479 DOI: 10.20517/cdr.2025.28] [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: 02/05/2025] [Revised: 03/26/2025] [Accepted: 04/17/2025] [Indexed: 05/11/2025]
Abstract
Bone metastases represent frequent and severe complications in various cancers, notably impacting prognosis and quality of life. This review article delves into the genetic and epigenetic mechanisms underpinning drug resistance in bone metastases, a key challenge in effective cancer treatment. The development of drug resistance in cancer can manifest as either intrinsic or acquired, with genetic heterogeneity playing a pivotal role. Intrinsic resistance is often due to pre-existing mutations, while acquired resistance evolves through genetic and epigenetic alterations during treatment. These alterations include mutations in driver genes like TP53 and RB1, epigenetic modifications such as DNA methylation and histone changes, and pathway alterations, notably involving RANK-RANKL signaling and the PI3K/AKT/mTOR cascade. Recent studies underline the significance of the tumor microenvironment in fostering drug resistance, with components such as cancer-associated fibroblasts and hypoxia playing crucial roles. The interactions between metastatic cancer cells and the bone microenvironment facilitate survival and the proliferation of drug-resistant clones. This review highlights the necessity of understanding these complex interactions to develop targeted therapies that can overcome resistance and improve treatment outcomes. Current therapeutic strategies and future directions are discussed, emphasizing the integration of genomic profiling and targeted interventions in managing bone metastases. The evolving landscape of genetic research, including the application of next-generation sequencing and CRISPR technology, offers promising avenues for novel and more effective therapeutic strategies. This comprehensive exploration aims to provide insights into the molecular intricacies of drug resistance in bone metastases, paving the way for improved clinical management and patient care.
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Affiliation(s)
- Ahmad Dawalibi
- Department of Anatomy, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Mohamad Bakir
- Department of Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Khalid S. Mohammad
- Department of Anatomy, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
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4
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Lu D, Zheng Y, Yi X, Hao J, Zeng X, Han L, Li Z, Jiao S, Jiang B, Ai J, Peng J. Identifying potential risk genes for clear cell renal cell carcinoma with deep reinforcement learning. Nat Commun 2025; 16:3591. [PMID: 40234405 PMCID: PMC12000451 DOI: 10.1038/s41467-025-58439-5] [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: 05/13/2024] [Accepted: 03/18/2025] [Indexed: 04/17/2025] Open
Abstract
Clear cell renal cell carcinoma (ccRCC) is the most prevalent type of renal cell carcinoma. However, our understanding of ccRCC risk genes remains limited. This gap in knowledge poses challenges to the effective diagnosis and treatment of ccRCC. To address this problem, we propose a deep reinforcement learning-based computational approach named RL-GenRisk to identify ccRCC risk genes. Distinct from traditional supervised models, RL-GenRisk frames the identification of ccRCC risk genes as a Markov Decision Process, combining the graph convolutional network and Deep Q-Network for risk gene identification. Moreover, a well-designed data-driven reward is proposed for mitigating the limitation of scant known risk genes. The evaluation demonstrates that RL-GenRisk outperforms existing methods in ccRCC risk gene identification. Additionally, RL-GenRisk identifies eight potential ccRCC risk genes. We successfully validated epidermal growth factor receptor (EGFR) and piccolo presynaptic cytomatrix protein (PCLO), corroborated through independent datasets and biological experimentation. This approach may also be used for other diseases in the future.
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Affiliation(s)
- Dazhi Lu
- AI for Science Interdisciplinary Research Center, School of Computer Science, Northwestern Polytechnical University, Xi'an, China
| | - Yan Zheng
- College of Intelligence and Computing, Tianjin University, Tianjin, China
| | - Xianyanling Yi
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Jianye Hao
- College of Intelligence and Computing, Tianjin University, Tianjin, China.
| | - Xi Zeng
- AI for Science Interdisciplinary Research Center, School of Computer Science, Northwestern Polytechnical University, Xi'an, China
| | - Lu Han
- AI for Science Interdisciplinary Research Center, School of Computer Science, Northwestern Polytechnical University, Xi'an, China
| | - Zhigang Li
- College of Intelligence and Computing, Tianjin University, Tianjin, China
| | - Shaoqing Jiao
- School of Software, Northwestern Polytechnical University, Xi'an, China
| | - Bei Jiang
- Tianjin Second People's Hospital, Tianjin, China
| | - Jianzhong Ai
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.
| | - Jiajie Peng
- AI for Science Interdisciplinary Research Center, School of Computer Science, Northwestern Polytechnical University, Xi'an, China.
- Key Laboratory of Big Data Storage and Management, Northwestern Polytechnical University, Ministry of Industry and Information Technology, Xi'an, China.
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5
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Guo Z, Wang P, Han Y, Jiang S, Yang X, Cao S. SMARCA2 protein: Structure, function and perspectives of drug design. Eur J Med Chem 2025; 286:117319. [PMID: 39879937 DOI: 10.1016/j.ejmech.2025.117319] [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: 11/29/2024] [Revised: 01/21/2025] [Accepted: 01/21/2025] [Indexed: 01/31/2025]
Abstract
SMARCA2 is an ATPase that regulates chromatin structure via ATP pathways, controlling cell division and differentiation. SMARCA2's bromodomain and ATPase domain, crucial for chromatin remodeling and cell regulation, are therapeutic targets in cancer treatment. This review explores the role of SMARCA2 in cancer development by studying its protein structure and physiological functions. It further discusses the roles and distinctions of SMARCA2 and its related family proteins in cancer. Additionally, this article categorizes known SMARCA2 inhibitors into four classes based on their basic structure and examines their structure-activity relationships (SAR). This review outlines the structural mechanisms of SMARCA2 inhibitors, highlighting interactions with specific amino acids. By analyzing the SAR of inhibitors, we propose a tailored inhibitor model for the bromodomain of SMARCA2, emphasizing α, γ-H-bond donors/acceptors, and β-rigid structures as crucial for effective binding. This research provides guidance for the design and optimization of future drugs targeting the SMARCA2 protein.
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Affiliation(s)
- Zhaolin Guo
- Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan, 430205, P. R. China
| | - Peng Wang
- Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan, 430205, P. R. China
| | - Yuxuan Han
- Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan, 430205, P. R. China
| | - Sisi Jiang
- Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan, 430205, P. R. China
| | - Xinyu Yang
- Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan, 430205, P. R. China
| | - Shuang Cao
- Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan, 430205, P. R. China.
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Ruan DY, Huang WW, Li Y, Zhao Y, Shi Y, Jia Y, Cang S, Zhang W, Shi J, Chen J, Lin J, Liu Y, Xu J, Ouyang W, Fang J, Zhuang W, Liu C, Bu Q, Li M, Meng X, Sun M, Yang N, Dong X, Pan Y, Li X, Qu X, Zhang T, Yuan X, Hu S, Guo W, Li Y, Li S, Liu D, Song F, Tan L, Yu Y, Yu X, Zang A, Sun C, Zhang Q, Zou K, Dan M, Xu RH, Zhao H. Safety, pharmacokinetics and efficacy of HA121-28 in patients with advanced solid tumors and RET fusion-positive non-small-cell lung cancer: a multicenter, open-label, single-arm phase 1/2 trial. Signal Transduct Target Ther 2025; 10:62. [PMID: 40016191 PMCID: PMC11868595 DOI: 10.1038/s41392-025-02155-5] [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: 09/13/2024] [Revised: 12/20/2024] [Accepted: 01/22/2025] [Indexed: 03/01/2025] Open
Abstract
HA121-28, a promising multikinase inhibitor, mainly targets rearranged during transfection (RET) fusions and selectively targets vascular endothelial growth factor receptor-2, endothelial growth factor receptor, and fibroblast growth factor receptor 1-3. The safety, pharmacokinetics, and efficacy of HA121-28 were assessed in advanced solid tumors (phase 1, ClinicalTrials.gov NCT03994484) and advanced RET fusion-positive non-small-cell lung cancer (RET-TKI naive NSCLC, phase 2, ClinicalTrials.gov NCT05117658). HA121-28 was administered orally in doses range from 25 to 800 mg under the 21-day on/7-day off scheme for a 28-day cycle in phase 1 trial. The recommended dose identified in phase 1 (450 mg) was administered for patients during phase 2. The primary endpoints were the maximum tolerated dose (MTD) in phase 1 and the objective response rate (ORR) in phase 2. 162 patients were enrolled in phase 1 and 48 in phase 2. A total of 600 mg once daily was set as MTD. Across 100-800 mg, the exposure of HA121-28 increased in a dose-dependent manner. Consistent between both trials, diarrhea, rash, and prolonged QTc interval, were the most reported treatment-emergent adverse events. 40.0% (phase 1) and 62.5% (phase 2) patients experienced grade ≥3 treatment-related adverse events, respectively. The overall ORR was 26.8% and the median progression-free survival (PFS) was 5.5 months among 97 NSCLC patients with advanced RET fusion receiving a dose at ≥450 mg once daily. HA121-28 showed encouraging efficacy in advanced RET fusion NSCLC and its toxicity was tolerable in most patients. Nevertheless, cardiotoxicity is a notable concern that warrants careful attention.
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Affiliation(s)
- Dan-Yun Ruan
- Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Wen-Wen Huang
- Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Yongsheng Li
- Department of Phase 1 Ward, Chongqing University Cancer Hospital, Chongqing Cancer Hospital, Chongqing, People's Republic of China
| | - Yanqiu Zhao
- Department of Respiratory Medicine, Henan Cancer Hospital, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Yehui Shi
- Department of Breast Oncology, Tianjin Medical University Cancer Institute & Hospital, Tianjin, People's Republic of China
| | - Yuming Jia
- Department of Oncology, The second people's hospital of Yibin, Yibin, Sichuan, People's Republic of China
| | - Shundong Cang
- Department of Medical Oncology, Phase 1 Clinical Research Unit, Department of Medical Oncology, Henan Provincial People's Hospital, Zhengzhou, Hannan, People's Republic of China
| | - Wei Zhang
- Department of Medical Oncology, Phase 1 Clinical Research Unit, Department of Medical Oncology, Henan Provincial People's Hospital, Zhengzhou, Hannan, People's Republic of China
| | - Jianhua Shi
- Department of the Second General Medicine, Linyi Cancer Hospital, Linyi, Shandong, People's Republic of China
| | - Jun Chen
- Department of Pulmonary Oncology, Tianjin Medical University General Hospital, Tianjin, People's Republic of China
| | - Jie Lin
- Department of Oncology, The Second Affiliated hospital of Kunming Medical University, Kunming, Yunnan, People's Republic of China
| | - Yunpeng Liu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Jianming Xu
- Department of Medical Oncology, The Fifth Medical Center, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Weiwei Ouyang
- The Phase1 Clinical Center, The Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, Guizhou, People's Republic of China
| | - Jian Fang
- Department of the Second Thoracic Oncology, Beijing Cancer Hospital, Beijing, People's Republic of China
| | - Wu Zhuang
- Department of Respiratory Oncology, Fujian Cancer Hospital, Fuzhou, Fujian, People's Republic of China
| | - Caigang Liu
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Qing Bu
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Manxiang Li
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, People's Republic of China
| | - Xiangjiao Meng
- Department of the Fourth Thoracic Radiotherapy Ward, Shandong Cancer Hospital & Institute, Jinan, Shandong, People's Republic of China
| | - Meili Sun
- Department of Oncology, General Hospital Affiliated Shandong First Medical University, Jinan, Shandong, People's Republic of China
| | - Nong Yang
- Department of Pulmonary and Gastrointestinal Medicine, Hunan Cancer Hospital, Changsha, Hunan, People's Republic of China
| | - Xiaorong Dong
- Department of Cancer Center, Wuhan Union Hospital of China, Wuhan, Hubei, People's Republic of China
| | - Yueyin Pan
- Department of Oncology Chemotherapy, The First Affiliated Hospital of USTC, Hefei, Anhui, People's Republic of China
| | - Xingya Li
- Department of the Second Oncology Ward, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Xiujuan Qu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Tongmei Zhang
- General Department, Beijing Chest Hospital, Beijing, People's Republic of China
| | - Xianglin Yuan
- Department of Oncology, Tongji Hospital, Tongji Medical College of HUST, Wuhan, Hubei, People's Republic of China
| | - Sheng Hu
- Department of Oncology, Hubei Cancer Hospital, Wuhan, Hubei, People's Republic of China
| | - Wei Guo
- Respiratory Department, Shanxi Cancer Hospital, Taiyuan, Shanxi, People's Republic of China
| | - Yalun Li
- Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Shengqing Li
- Respiratory Department, Huashan Hospital Fudan University, Shanghai, People's Republic of China
| | - Dongying Liu
- Department of Breast Oncology, Tianjin Medical University Cancer Institute & Hospital, Tianjin, People's Republic of China
| | - Feixue Song
- Department of Medical Oncology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu, People's Republic of China
| | - Liping Tan
- Department of Respiratory Oncology, Guangxi Medical University Cancer Hospital & Guangxi Cancer Institute, Nanning, Guangxi, People's Republic of China
| | - Yan Yu
- Department of the Third Respiratory Medicine, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, People's Republic of China
| | - Xinmin Yu
- Department of Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, People's Republic of China
| | - Aimin Zang
- Department of Medical Oncology, Affiliated Hospital of Hebei University, Baoding, Hebei, People's Republic of China
| | - Chang Sun
- CSPC ZhongQi Pharmaceutical Technology (Shijiazhuang) Co., Ltd., Shijiazhuang, Hebei, People's Republic of China
| | - Qian Zhang
- CSPC ZhongQi Pharmaceutical Technology (Shijiazhuang) Co., Ltd., Shijiazhuang, Hebei, People's Republic of China
| | - Kai Zou
- CSPC ZhongQi Pharmaceutical Technology (Shijiazhuang) Co., Ltd., Shijiazhuang, Hebei, People's Republic of China
| | - Mo Dan
- CSPC ZhongQi Pharmaceutical Technology (Shijiazhuang) Co., Ltd., Shijiazhuang, Hebei, People's Republic of China
| | - Rui-Hua Xu
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, People's Republic of China.
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, People's Republic of China.
| | - Hongyun Zhao
- Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, People's Republic of China.
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Wang B, You H, Ye D, Yi Y, Liu Y, Qing B, Wang C, Liu J, Zhang J, Wang N, Wan P, Shen L, Xu Z. A retrospective study of the efficacy and safety of immune checkpoint inhibitors combined with chemotherapy for the treatment of SMARCA4-deficient thoracic tumors. Transl Lung Cancer Res 2024; 13:3460-3472. [PMID: 39830761 PMCID: PMC11736595 DOI: 10.21037/tlcr-24-691] [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: 08/08/2024] [Accepted: 11/26/2024] [Indexed: 01/22/2025]
Abstract
Background Thoracic tumors characterized by a deficiency in SMARCA4 are highly aggressive and linked to a poor prognosis. This retrospective study explores the efficacy and safety of immune checkpoint inhibitors (ICIs) in combination with chemotherapy for SMARCA4-deficient undifferentiated tumors (SMARCA4-dUT) and SMARCA4-deficient non-small cell lung cancer (SMARCA4-dNSCLC). Methods A cohort of 59 individuals was analyzed, including 35 patients with SMARCA4-dUT and 24 with SMARCA4-dNSCLC. Results Clinical characteristics as gender, age, smoking status, and metastatic sites did not significantly vary between SMARCA4-dUT and SMARCA4-dNSCLC. Nonsense and frameshift mutations in the SMARCA4 gene can result in the loss of its protein expression. Following a median follow-up of 7.6 months, the median progression-free survival (mPFS) notably increased with ICIs-based combination therapy compared to chemotherapy, the mPFS was 12.60 vs. 4.03 months in the SMARCA4-dUT subgroup (P=0.007) and not reached vs. 3.42 months in the SMARCA4-dNSCLC subgroup (P=0.03). In stage IV patients, the risk of disease progression and death decreased with ICIs-based combination therapy vs. chemotherapy [ICIs-based therapy vs. chemotherapy: hazard ratio (HR) =0.076; 95% confidence interval (CI): 0.009-0.624]. The most prevalent grade 3 or higher adverse events (AEs) in both groups were hematologic decreases, consistent with typical chemotherapy AEs. No treatment-related AEs led to patient fatalities. Conclusions The combination of ICIs and chemotherapy is more effective than chemotherapy for patients with advanced SMARCA4-deficient thoracic tumors (SMARCA4-dTT), and the safety is manageable.
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Affiliation(s)
- Bin Wang
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Third Military Medical University (Army Medical University), Chongqing, China
- Chongqing Key Laboratory of Precision Medicine and Prevention of Major Respiratory Diseases, Chongqing, China
| | - Heng You
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Third Military Medical University (Army Medical University), Chongqing, China
- Chongqing Key Laboratory of Precision Medicine and Prevention of Major Respiratory Diseases, Chongqing, China
- The Disease Prevention and Control Center of the Western Theater Command of the People’s Liberation Army of China, Lanzhou, China
| | - Dongfan Ye
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Third Military Medical University (Army Medical University), Chongqing, China
- Chongqing Key Laboratory of Precision Medicine and Prevention of Major Respiratory Diseases, Chongqing, China
| | - Yuanyue Yi
- Department of Pathology, Second Affiliated Hospital of Third Military Medical University (Army Medical University), Chongqing, China
| | - Yu Liu
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Third Military Medical University (Army Medical University), Chongqing, China
- Chongqing Key Laboratory of Precision Medicine and Prevention of Major Respiratory Diseases, Chongqing, China
| | - Bin Qing
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Third Military Medical University (Army Medical University), Chongqing, China
- Chongqing Key Laboratory of Precision Medicine and Prevention of Major Respiratory Diseases, Chongqing, China
| | - Chuangye Wang
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Third Military Medical University (Army Medical University), Chongqing, China
- Chongqing Key Laboratory of Precision Medicine and Prevention of Major Respiratory Diseases, Chongqing, China
| | - Jincheng Liu
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Third Military Medical University (Army Medical University), Chongqing, China
- Chongqing Key Laboratory of Precision Medicine and Prevention of Major Respiratory Diseases, Chongqing, China
| | - Jian Zhang
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Third Military Medical University (Army Medical University), Chongqing, China
- Chongqing Key Laboratory of Precision Medicine and Prevention of Major Respiratory Diseases, Chongqing, China
| | - Nanbo Wang
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Third Military Medical University (Army Medical University), Chongqing, China
- Chongqing Key Laboratory of Precision Medicine and Prevention of Major Respiratory Diseases, Chongqing, China
| | - Pengfei Wan
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Third Military Medical University (Army Medical University), Chongqing, China
- Chongqing Key Laboratory of Precision Medicine and Prevention of Major Respiratory Diseases, Chongqing, China
| | - Linlin Shen
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Third Military Medical University (Army Medical University), Chongqing, China
- Chongqing Key Laboratory of Precision Medicine and Prevention of Major Respiratory Diseases, Chongqing, China
| | - Zhi Xu
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Third Military Medical University (Army Medical University), Chongqing, China
- Chongqing Key Laboratory of Precision Medicine and Prevention of Major Respiratory Diseases, Chongqing, China
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8
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Wang Y, Sun Q, Li Z, Leng F, Han X, Su Q, Su S. Malignant melanoma complicated with cataract and secondary glaucoma: A case report. Oncol Lett 2024; 28:520. [PMID: 39268160 PMCID: PMC11391252 DOI: 10.3892/ol.2024.14653] [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: 01/29/2024] [Accepted: 07/08/2024] [Indexed: 09/15/2024] Open
Abstract
Uveal melanoma is the most common intraocular malignant tumor in adults. For patients presenting with cataracts and glaucoma, it is recommended to assess whether an intraocular lesion is present as the primary cause. The present study describes the case of a 52-year-old man with primary intraocular malignant melanoma. The patient experienced painless vision loss in the right eye for 1 year, with recent onset of eye swelling and pain in the week prior to seeking medical attention. A slit-lamp examination revealed a shallow anterior chamber in the right eye, a visibly opaque lens and a faint reflection of the tumor surface in the vitreous humor. In addition, the intraocular pressure of this eye was >60 mmHg. Magnetic resonance imaging revealed a large tumor behind the lens measuring 16×18×14 mm. Pathological examination confirmed the diagnosis of malignant melanoma. No BRCA-associated protein-1 somatic mutation was detected, whereas germline mutations of MutL protein homolog 1, RAD54 like, and SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 were identified. Extensive systemic examination excluded the possibility that the tumors originated from another part of the body. The present case report highlights the crucial role of slit-lamp examination in the detection of ocular tumors. It is advocated that for patients presenting with cataracts, attention should be paid to the possibility of intraocular tumors. Meticulous slit-lamp microscopy may reveal a reflection of the surface of a malignant melanoma, preventing misdiagnosis.
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Affiliation(s)
- Yu Wang
- Eye Hospital, The First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Qinqin Sun
- Eye Hospital, The First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Zhijian Li
- Eye Hospital, The First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Fei Leng
- Department of Ophthalmology, Beijing Children's Hospital Affiliated with Capital Medical University, National Center for Children's Health, Beijing 100045, P.R. China
| | - Xuelian Han
- Eye Hospital, The First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Qiqi Su
- Eye Hospital, The First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Sheng Su
- Eye Hospital, The First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
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9
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Duplaquet L, So K, Ying AW, Pal Choudhuri S, Li X, Xu GD, Li Y, Qiu X, Li R, Singh S, Wu XS, Hamilton S, Chien VD, Liu Q, Qi J, Somerville TDD, Heiling HM, Mazzola E, Lee Y, Zoller T, Vakoc CR, Doench JG, Forrester WC, Abrams T, Long HW, Niederst MJ, Drapkin BJ, Kadoch C, Oser MG. Mammalian SWI/SNF complex activity regulates POU2F3 and constitutes a targetable dependency in small cell lung cancer. Cancer Cell 2024; 42:1352-1369.e13. [PMID: 39029464 PMCID: PMC11494612 DOI: 10.1016/j.ccell.2024.06.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 04/22/2024] [Accepted: 06/21/2024] [Indexed: 07/21/2024]
Abstract
Small cell lung cancers (SCLCs) are composed of heterogeneous subtypes marked by lineage-specific transcription factors, including ASCL1, NEUROD1, and POU2F3. POU2F3-positive SCLCs, ∼12% of all cases, are uniquely dependent on POU2F3 itself; as such, approaches to attenuate POU2F3 expression may represent new therapeutic opportunities. Here using genome-scale screens for regulators of POU2F3 expression and SCLC proliferation, we define mSWI/SNF complexes as top dependencies specific to POU2F3-positive SCLC. Notably, chemical disruption of mSWI/SNF ATPase activity attenuates proliferation of all POU2F3-positive SCLCs, while disruption of non-canonical BAF (ncBAF) via BRD9 degradation is effective in pure non-neuroendocrine POU2F3-SCLCs. mSWI/SNF targets to and maintains accessibility over gene loci central to POU2F3-mediated gene regulatory networks. Finally, clinical-grade pharmacologic disruption of SMARCA4/2 ATPases and BRD9 decreases POU2F3-SCLC tumor growth and increases survival in vivo. These results demonstrate mSWI/SNF-mediated governance of the POU2F3 oncogenic program and suggest mSWI/SNF inhibition as a therapeutic strategy for POU2F3-positive SCLCs.
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Affiliation(s)
- Leslie Duplaquet
- Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA
| | - Kevin So
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Biological and Biomedical Sciences Graduate Program, Harvard Medical School, Boston, MA 02115, USA
| | - Alexander W Ying
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Shreoshi Pal Choudhuri
- Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Internal Medicine and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Xinyue Li
- Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA
| | - Grace D Xu
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA
| | - Yixiang Li
- Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA
| | - Xintao Qiu
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Rong Li
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Shilpa Singh
- Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA
| | - Xiaoli S Wu
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY 11724, USA
| | - Seth Hamilton
- Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Internal Medicine and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Victor D Chien
- Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Internal Medicine and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Qi Liu
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Jun Qi
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | | | - Hillary M Heiling
- Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Emanuele Mazzola
- Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Yenarae Lee
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Thomas Zoller
- Novartis BioMedical Research, Cambridge, MA 02139, USA
| | | | - John G Doench
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | | | - Tinya Abrams
- Novartis BioMedical Research, Cambridge, MA 02139, USA
| | - Henry W Long
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | | | - Benjamin J Drapkin
- Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Internal Medicine and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Cigall Kadoch
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
| | - Matthew G Oser
- Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
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10
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Trejo-Villegas OA, Heijink IH, Ávila-Moreno F. Preclinical evidence in the assembly of mammalian SWI/SNF complexes: Epigenetic insights and clinical perspectives in human lung disease therapy. Mol Ther 2024; 32:2470-2488. [PMID: 38910326 PMCID: PMC11405180 DOI: 10.1016/j.ymthe.2024.06.026] [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: 12/11/2023] [Revised: 04/18/2024] [Accepted: 06/20/2024] [Indexed: 06/25/2024] Open
Abstract
The SWI/SNF complex, also known as the BRG1/BRM-associated factor (BAF) complex, represents a critical regulator of chromatin remodeling mechanisms in mammals. It is alternatively referred to as mSWI/SNF and has been suggested to be imbalanced in human disease compared with human health. Three types of BAF assemblies associated with it have been described, including (1) canonical BAF (cBAF), (2) polybromo-associated BAF (PBAF), and (3) non-canonical BAF (ncBAF) complexes. Each of these BAF assemblies plays a role, either functional or dysfunctional, in governing gene expression patterns, cellular processes, epigenetic mechanisms, and biological processes. Recent evidence increasingly links the dysregulation of mSWI/SNF complexes to various human non-malignant lung chronic disorders and lung malignant diseases. This review aims to provide a comprehensive general state-of-the-art and a profound examination of the current understanding of mSWI/SNF assembly processes, as well as the structural and functional organization of mSWI/SNF complexes and their subunits. In addition, it explores their intricate functional connections with potentially dysregulated transcription factors, placing particular emphasis on molecular and cellular pathogenic processes in lung diseases. These processes are reflected in human epigenome aberrations that impact clinical and therapeutic levels, suggesting novel perspectives on the diagnosis and molecular therapies for human respiratory diseases.
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Affiliation(s)
- Octavio A Trejo-Villegas
- Lung Diseases and Functional Epigenomics Laboratory (LUDIFE), Biomedicine Research Unit (UBIMED), Facultad de Estudios Superiores-Iztacala (FES-Iztacala), Universidad Nacional Autónoma de México (UNAM), Avenida de los Barrios #1, Colonia Los Reyes Iztacala, Tlalnepantla de Baz, 54090, Estado de México, México
| | - Irene H Heijink
- Departments of Pathology & Medical Biology and Pulmonology, GRIAC Research Institute, University Medical Center Groningen, University of Groningen, 9713 Groningen, the Netherlands
| | - Federico Ávila-Moreno
- Lung Diseases and Functional Epigenomics Laboratory (LUDIFE), Biomedicine Research Unit (UBIMED), Facultad de Estudios Superiores-Iztacala (FES-Iztacala), Universidad Nacional Autónoma de México (UNAM), Avenida de los Barrios #1, Colonia Los Reyes Iztacala, Tlalnepantla de Baz, 54090, Estado de México, México; Research Unit, Instituto Nacional de Enfermedades Respiratorias (INER), Ismael Cosío Villegas, 14080, Ciudad de México, México; Research Tower, Subdirección de Investigación Básica, Instituto Nacional de Cancerología (INCan), 14080, Ciudad de México, México.
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11
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Xiaoxu D, Xianghong Y. Primary Undifferentiated Gallbladder Carcinoma With SMARCA4 Deletion: A Case Report and Review of the Literature. Int J Surg Pathol 2024; 32:1017-1023. [PMID: 37899615 DOI: 10.1177/10668969231206575] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2023]
Abstract
Background. Undifferentiated gallbladder carcinoma is a rare type of cancer with poor prognosis, due to the absence of specific clinical manifestations, and the final diagnosis depends on pathological and immunohistochemical examinations. However, only a few reports of SMARCA4-deficient undifferentiated gallbladder tumor have been published to date. Therefore, we report the diagnosis and treatment of an undifferentiated gallbladder carcinoma with SMARCA4 deficiency. Case Presentation. A 65-year-old woman with undifferentiated gallbladder carcinoma was treated using traditional Chinese medicine and underwent palliative surgery in our hospital. The postoperative pathology showed SMARCA4-deficient undifferentiated gallbladder carcinoma with metastasis to the abdominal lymph nodes. Conclusions. This case report contributes to the limited literature regarding undifferentiated carcinoma without SMARCA4 in the gallbladder.
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Affiliation(s)
- Deng Xiaoxu
- Pathology Department, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yang Xianghong
- Pathology Department, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
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12
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Li XF, Zhang YP, Wei LL, Wang ZJ, Yang MQ. SMARCA4‑deficient uterine adnexal tumor with ascites: A case report and literature review. Oncol Lett 2024; 28:357. [PMID: 38881708 PMCID: PMC11176891 DOI: 10.3892/ol.2024.14490] [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: 02/01/2024] [Accepted: 04/29/2024] [Indexed: 06/18/2024] Open
Abstract
SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4 (SMARCA4)-deficient tumors are rare and highly aggressive tumors characterized by a loss of SMARCA4 expression, and SMARCA4-deficient tumors in the adnexal area of the uterus are particularly rare. The present study describes the case of a 64-year-old woman who was admitted to Weifang People's Hospital (Weifang, China) with abdominal distension, and was observed to have a mass with ascites in the adnexal area of the uterus. Based on clinical, imaging and pathological findings, the patient was diagnosed with a SMARCA4-deficient adnexal tumor with ascites. Biopsy of the left and right adnexal lesions was performed, and the patient was administered chemotherapy. After one cycle of bevacizumab, sindilizumab and carboplatin, no further treatment was administered. After biopsy and chemotherapy, the abdominal distension was alleviated and the general condition of the patient was satisfactory. The patient was followed up and died 3 months after treatment. Notably, it is important to avoid misdiagnosing this tumor as other types of adnexal uterine tumors, and morphological and immunohistochemical features may be useful for diagnosing primary SMARCA4-deficient tumors in the adnexal area of the uterus.
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Affiliation(s)
- Xiu-Feng Li
- Department of Pathology, Weifang People's Hospital (First Affiliated Hospital of Shandong Second Medical University), Weifang, Shandong 261041, P.R. China
| | - Yu-Ping Zhang
- Department of Pathology, Weifang People's Hospital (First Affiliated Hospital of Shandong Second Medical University), Weifang, Shandong 261041, P.R. China
| | - Li-Li Wei
- Department of Pathology, Changyi Maternal and Child Health Hospital, Changyi, Shandong 261300, P.R. China
| | - Zheng-Jiang Wang
- Department of Pathology, Weifang People's Hospital (First Affiliated Hospital of Shandong Second Medical University), Weifang, Shandong 261041, P.R. China
| | - Mai-Qing Yang
- Department of Pathology, Weifang People's Hospital (First Affiliated Hospital of Shandong Second Medical University), Weifang, Shandong 261041, P.R. China
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13
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Wankhede D, Grover S, Hofman P. SMARCA4 alterations in non-small cell lung cancer: a systematic review and meta-analysis. J Clin Pathol 2024; 77:457-463. [PMID: 38702192 DOI: 10.1136/jcp-2024-209394] [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: 01/05/2024] [Accepted: 04/22/2024] [Indexed: 05/06/2024]
Abstract
AIMS A mutation in the SMARCA4 gene which encodes BRG1, a common catalytic subunit of switch/sucrose non-fermentable chromatin-remodelling complexes, plays a vital role in carcinogenesis. SMARCA4 mutations are present in approximately 10% of non-small cell lung cancers (NSCLC), making it a crucial gene in NSCLC, but with varying prognostic associations. To explore this, we conducted a systematic review and meta-analysis on the prognostic significance of SMARCA4 mutations in NSCLC. METHODS Electronic database search was performed from inception to December 2022. Study characteristics and prognostic data were extracted from each eligible study. Depending on heterogeneity, pooled HR and 95% CI were derived using the random-effects or fixed-effects models. RESULTS 8 studies (11 cohorts) enrolling 8371 patients were eligible for inclusion. Data on overall survival (OS) and progression-free survival (PFS) were available from 8 (10 cohorts) and 1 (3 cohorts) studies, respectively. Comparing SMARCA4-mutated NSCLC patients with SMARCA4-wild-type NSCLC patients, the summary HRs for OS and PFS were 1.49 (95% CI 1.18 to 1.87; I2=84%) and 3.97 (95% CI 1.32 to 11.92; I2=79%), respectively. The results from the trim-and-fill method for publication bias and sensitivity analysis were inconsistent with the primary analyses. Three studies reported NSCLC prognosis for category I and II mutations separately; category I was significantly associated with OS. CONCLUSION Our findings suggest that SMARCA4 mutation negatively affects NSCLC OS and PFS. The prognostic effects of SMARCA4-co-occurring mutations and the predictive role of SMARCA4 mutation status in immunotherapy require further exploration.
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Affiliation(s)
- Durgesh Wankhede
- German Cancer Research Center, Heidelberg, Germany
- Faculty of Medicine, Univeristy of Heidelberg, Heidelberg, Germany
| | - Sandeep Grover
- Center for Human Genetics, Universitatsklinikum Giessen und Marburg - Standort Marburg, Marburg, Germany
| | - Paul Hofman
- Laboratory of Clinical and Experimental Pathology, Pasteur Hospital, University Côte d'Azur, Nice, France
- Hospital-Integrated Biobank BB-0033-00025, Pasteur Hospital, Nice, France
- University Hospital Federation OncoAge, CHU de Nice, University Côte d'Azur, Nice, France
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14
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Lin S, Chen Q, Tan C, Su M, Min L, Ling L, Zhou J, Zhu T. ZEB family is a prognostic biomarker and correlates with anoikis and immune infiltration in kidney renal clear cell carcinoma. BMC Med Genomics 2024; 17:153. [PMID: 38840097 PMCID: PMC11151722 DOI: 10.1186/s12920-024-01895-7] [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: 12/27/2023] [Accepted: 04/28/2024] [Indexed: 06/07/2024] Open
Abstract
BACKGROUND Zinc finger E-box binding homEeobox 1 (ZEB1) and ZEB2 are two anoikis-related transcription factors. The mRNA expressions of these two genes are significantly increased in kidney renal clear cell carcinoma (KIRC), which are associated with poor survival. Meanwhile, the mechanisms and clinical significance of ZEB1 and ZEB2 upregulation in KIRC remain unknown. METHODS Through the Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database, expression profiles, prognostic value and receiver operating characteristic curves (ROCs) of ZEB1 and ZEB2 were evaluated. The correlations of ZEB1 and ZEB2 with anoikis were further assessed in TCGA-KIRC database. Next, miRTarBase, miRDB, and TargetScan were used to predict microRNAs targeting ZEB1 and ZEB2, and TCGA-KIRC database was utilized to discern differences in microRNAs and establish the association between microRNAs and ZEBs. TCGA, TIMER, TISIDB, and TISCH were used to analyze tumor immune infiltration. RESULTS It was found that ZEB1 and ZEB2 expression were related with histologic grade in KIRC patient. Kaplan-Meier survival analyses showed that KIRC patients with low ZEB1 or ZEB2 levels had a significantly lower survival rate. Meanwhile, ZEB1 and ZEB2 are closely related to anoikis and are regulated by microRNAs. We constructed a risk model using univariate Cox and LASSO regression analyses to identify two microRNAs (hsa-miR-130b-3p and hsa-miR-138-5p). Furthermore, ZEB1 and ZEB2 regulate immune cell invasion in KIRC tumor microenvironments. CONCLUSIONS Anoikis, cytotoxic immune cell infiltration, and patient survival outcomes were correlated with ZEB1 and ZEB2 mRNA upregulation in KIRC. ZEB1 and ZEB2 are regulated by microRNAs.
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Affiliation(s)
- Sheng Lin
- Department of Laboratory Medicine, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Qi Chen
- Department of Urology, Foshan First People's Hospital, Foshan City, Guangdong Province, China
| | - Canliang Tan
- Department of general surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong Province, China
| | - Manyi Su
- Department of Laboratory Medicine, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Ling Min
- Department of Laboratory Medicine, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Lv Ling
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Junhao Zhou
- Department of general surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong Province, China.
- KingMed school of Laboratory Medicine, Guangzhou Medical University, Guangzhou, Guangdong Province, China.
| | - Ting Zhu
- Department of Laboratory Medicine, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, China.
- KingMed school of Laboratory Medicine, Guangzhou Medical University, Guangzhou, Guangdong Province, China.
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15
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Liang H, Zheng X, Zhang X, Zhang Y, Zheng J. The role of SWI/SNF complexes in digestive system neoplasms. Med Oncol 2024; 41:119. [PMID: 38630164 DOI: 10.1007/s12032-024-02343-3] [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: 01/08/2024] [Accepted: 02/22/2024] [Indexed: 04/19/2024]
Abstract
Chromatin remodeling is a critical step in the DNA damage response, and the ATP-dependent chromatin remodelers are a group of epigenetic regulators that alter nucleosome assembly and regulate transcription factor accessibility to DNA, preventing genomic instability and tumorigenesis caused by DNA damage. The SWI/SNF chromatin remodeling complex is one of them, and mutations in the gene encoding the SWI/SNF subunit are frequently found in digestive tumors. We review the most recent literature on the role of SWI/SNF complexes in digestive tumorigenesis, with different SWI/SNF subunits playing different roles. They regulate the biological behavior of tumor cells, participate in multiple signaling pathways, interact with multiple genes, and have some correlation with the prognosis of patients. Their carcinogenic properties may help discover new therapeutic targets. Understanding the mutations and defects of SWI/SNF complexes, as well as the underlying functional mechanisms, may lead to new strategies for treating the digestive system by targeting relevant genes or modulating the tumor microenvironment.
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Affiliation(s)
- Hanyun Liang
- Department of Diagnostic Pathology, Shandong Second Medical University, Weifang, 261053, China
| | - Xin Zheng
- Department of Diagnostic Pathology, Shandong Second Medical University, Weifang, 261053, China
| | - Xiao Zhang
- Department of Ultrasound, Weifang People's Hospital, Weifang, 261041, China
| | - Yan Zhang
- Department of Pathology, Affiliated Hospital of Shandong Second Medical University, Weifang, 261053, China.
| | - Jie Zheng
- Department of Diagnostic Pathology, Shandong Second Medical University, Weifang, 261053, China.
- Neurologic Disorders and Regenerative Repair Lab of Shandong Higher Education, Shandong Second Medical University, Weifang, 261053, China.
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16
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Yamashita K, Sewastjanow-Silva M, Yoshimura K, Rogers JE, Rosa Vicentini E, Pool Pizzi M, Fan Y, Zou G, Li JJ, Blum Murphy M, Gan Q, Waters RE, Wang L, Ajani JA. SMARCA4 Mutations in Gastroesophageal Adenocarcinoma: An Observational Study via a Next-Generation Sequencing Panel. Cancers (Basel) 2024; 16:1300. [PMID: 38610978 PMCID: PMC11010836 DOI: 10.3390/cancers16071300] [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: 02/14/2024] [Revised: 03/19/2024] [Accepted: 03/26/2024] [Indexed: 04/14/2024] Open
Abstract
BACKGROUND The clinical impact of SMARCA4 mutations (SMARCA4ms) in gastroesophageal adenocarcinoma (GEA) remains underexplored. This study aimed to examine the association of SMARCA4ms with clinical outcomes and co-occurrence with other gene mutations identified through a next-generation sequencing (NGS) panel in GEA patients. METHODS A total of 256 patients with metastatic or recurrent GEA who underwent NGS panel profiling at the MD Anderson Cancer Center between 2016 and 2022 were included. Comparative analyses were performed to assess clinical outcomes related to SMARCA4ms. The frequency and types of SMARCA4ms and their co-occurrence with other gene mutations were also examined. RESULTS SMARCA4ms were identified in 19 patients (7.4%). These SMARCA4ms were significantly associated with non-signet ring cell subtype (p = 0.044) and PD-L1 positive expression (p = 0.046). No difference in survival between the SMARCA4m and SMARCA4-normal group was observed (p = 0.84). There were significant associations between SMARCA4ms and FANCA, IGF1R, KRAS, FANCL, and PTEN alterations. Notably, 15 of the 19 SMARCA4m cases involved SNV missense mutations, with frequent co-occurrences noted with TP53, KRAS, ARID1A, and ERBB2 mutations. CONCLUSIONS These results serve as the first comprehensive examination of the relationship between SMARCA4ms and clinical outcomes in GEA.
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Affiliation(s)
- Kohei Yamashita
- Departments of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (K.Y.); (M.S.-S.); (K.Y.); (E.R.V.); (M.P.P.); (Y.F.); (G.Z.); (J.J.L.); (M.B.M.)
| | - Matheus Sewastjanow-Silva
- Departments of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (K.Y.); (M.S.-S.); (K.Y.); (E.R.V.); (M.P.P.); (Y.F.); (G.Z.); (J.J.L.); (M.B.M.)
| | - Katsuhiro Yoshimura
- Departments of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (K.Y.); (M.S.-S.); (K.Y.); (E.R.V.); (M.P.P.); (Y.F.); (G.Z.); (J.J.L.); (M.B.M.)
| | - Jane E. Rogers
- Department of Pharmacy Clinical Programs, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Ernesto Rosa Vicentini
- Departments of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (K.Y.); (M.S.-S.); (K.Y.); (E.R.V.); (M.P.P.); (Y.F.); (G.Z.); (J.J.L.); (M.B.M.)
| | - Melissa Pool Pizzi
- Departments of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (K.Y.); (M.S.-S.); (K.Y.); (E.R.V.); (M.P.P.); (Y.F.); (G.Z.); (J.J.L.); (M.B.M.)
| | - Yibo Fan
- Departments of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (K.Y.); (M.S.-S.); (K.Y.); (E.R.V.); (M.P.P.); (Y.F.); (G.Z.); (J.J.L.); (M.B.M.)
| | - Gengyi Zou
- Departments of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (K.Y.); (M.S.-S.); (K.Y.); (E.R.V.); (M.P.P.); (Y.F.); (G.Z.); (J.J.L.); (M.B.M.)
| | - Jenny J. Li
- Departments of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (K.Y.); (M.S.-S.); (K.Y.); (E.R.V.); (M.P.P.); (Y.F.); (G.Z.); (J.J.L.); (M.B.M.)
| | - Mariela Blum Murphy
- Departments of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (K.Y.); (M.S.-S.); (K.Y.); (E.R.V.); (M.P.P.); (Y.F.); (G.Z.); (J.J.L.); (M.B.M.)
| | - Qiong Gan
- Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (Q.G.); (R.E.W.)
| | - Rebecca E. Waters
- Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (Q.G.); (R.E.W.)
| | - Linghua Wang
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Jaffer A. Ajani
- Departments of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (K.Y.); (M.S.-S.); (K.Y.); (E.R.V.); (M.P.P.); (Y.F.); (G.Z.); (J.J.L.); (M.B.M.)
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17
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Basurto-Cayuela L, Guerrero-Martínez JA, Gómez-Marín E, Sánchez-Escabias E, Escaño-Maestre M, Ceballos-Chávez M, Reyes JC. SWI/SNF-dependent genes are defined by their chromatin landscape. Cell Rep 2024; 43:113855. [PMID: 38427563 DOI: 10.1016/j.celrep.2024.113855] [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: 03/31/2023] [Revised: 11/23/2023] [Accepted: 02/08/2024] [Indexed: 03/03/2024] Open
Abstract
SWI/SNF complexes are evolutionarily conserved, ATP-dependent chromatin remodeling machines. Here, we characterize the features of SWI/SNF-dependent genes using BRM014, an inhibitor of the ATPase activity of the complexes. We find that SWI/SNF activity is required to maintain chromatin accessibility and nucleosome occupancy for most enhancers but not for most promoters. SWI/SNF activity is needed for expression of genes with low to medium levels of expression that have promoters with (1) low chromatin accessibility, (2) low levels of active histone marks, (3) high H3K4me1/H3K4me3 ratio, (4) low nucleosomal phasing, and (5) enrichment in TATA-box motifs. These promoters are mostly occupied by the canonical Brahma-related gene 1/Brahma-associated factor (BAF) complex. These genes are surrounded by SWI/SNF-dependent enhancers and mainly encode signal transduction, developmental, and cell identity genes (with almost no housekeeping genes). Machine-learning models trained with different chromatin characteristics of promoters and their surrounding regulatory regions indicate that the chromatin landscape is a determinant for establishing SWI/SNF dependency.
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Affiliation(s)
- Laura Basurto-Cayuela
- Genome Biology Department, Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Consejo Superior de Investigaciones Científicas-Universidad de Sevilla-Universidad Pablo de Olavide (CSIC-USE-UPO), Av. Americo Vespucio, 41092 Seville, Spain
| | - José A Guerrero-Martínez
- Genome Biology Department, Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Consejo Superior de Investigaciones Científicas-Universidad de Sevilla-Universidad Pablo de Olavide (CSIC-USE-UPO), Av. Americo Vespucio, 41092 Seville, Spain
| | - Elena Gómez-Marín
- Genome Biology Department, Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Consejo Superior de Investigaciones Científicas-Universidad de Sevilla-Universidad Pablo de Olavide (CSIC-USE-UPO), Av. Americo Vespucio, 41092 Seville, Spain
| | - Elena Sánchez-Escabias
- Genome Biology Department, Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Consejo Superior de Investigaciones Científicas-Universidad de Sevilla-Universidad Pablo de Olavide (CSIC-USE-UPO), Av. Americo Vespucio, 41092 Seville, Spain
| | - María Escaño-Maestre
- Genome Biology Department, Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Consejo Superior de Investigaciones Científicas-Universidad de Sevilla-Universidad Pablo de Olavide (CSIC-USE-UPO), Av. Americo Vespucio, 41092 Seville, Spain
| | - María Ceballos-Chávez
- Genome Biology Department, Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Consejo Superior de Investigaciones Científicas-Universidad de Sevilla-Universidad Pablo de Olavide (CSIC-USE-UPO), Av. Americo Vespucio, 41092 Seville, Spain
| | - José C Reyes
- Genome Biology Department, Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Consejo Superior de Investigaciones Científicas-Universidad de Sevilla-Universidad Pablo de Olavide (CSIC-USE-UPO), Av. Americo Vespucio, 41092 Seville, Spain.
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18
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Wadapurkar RM, Sivaram A, Vyas R. Computational investigations into structure and function impact of novel mutations identified in targeted exons from ovarian cancer cell lines. J Biomol Struct Dyn 2024:1-15. [PMID: 38334284 DOI: 10.1080/07391102.2024.2310776] [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: 09/29/2023] [Accepted: 01/20/2024] [Indexed: 02/10/2024]
Abstract
The lack of sensitive and specific biomarkers for ovarian cancer leads to late stage diagnosis of the disease in a majority of the cases. Mutation accumulation is the basis for cancer progression, thus identifying mutations is an important step in the disease diagnosis. In the present study, a comprehensive analysis of fifteen Next Generation Sequencing samples from thirteen ovarian cancer cell lines was carried out for the identification of new mutations. The study revealed eight clinically significant novel mutations in six ovarian cancer oncogenes, viz. SMARCA4, ARID1A, PPP2R1A, CTNNB1, DICER1 and PIK3CA. In-depth computational analysis revealed that the mutations affected the structure of the proteins in terms of stability, solvent accessible surface area and molecular dynamics. Moreover, the mutations were present in functionally significant domains of the proteins, thereby adversely affecting the protein functionality. PPI network for SMARCA4, CTNNB1, DICER1, PIK3CA, PPP2R1A and ARID1A showed that these genes were involved in certain significant pathways affecting various hallmarks of cancer. For further validation, in vitro studies were performed that revealed hypermutability of the CTNNB1 gene. Through this study we have identified some key mutations and have analysed their structural and functional impact. The study establishes some key mutations, which can be potentially explored as biomarker and drug target.
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Affiliation(s)
- Rucha M Wadapurkar
- MIT School of Bioengineering Sciences & Research, MIT-ADT University, Pune, Maharashtra, India
| | - Aruna Sivaram
- MIT School of Bioengineering Sciences & Research, MIT-ADT University, Pune, Maharashtra, India
| | - Renu Vyas
- MIT School of Bioengineering Sciences & Research, MIT-ADT University, Pune, Maharashtra, India
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19
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Duplaquet L, So K, Ying AW, Li X, Li Y, Qiu X, Li R, Singh S, Wu XS, Liu Q, Qi J, Somerville TDD, Heiling H, Mazzola E, Lee Y, Zoller T, Vakoc CR, Doench JG, Forrester WC, Abrams T, Long HW, Niederst MJ, Kadoch C, Oser MG. Mammalian SWI/SNF complex activity regulates POU2F3 and constitutes a targetable dependency in small cell lung cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.21.576304. [PMID: 38328215 PMCID: PMC10849479 DOI: 10.1101/2024.01.21.576304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2024]
Abstract
Small cell lung cancers (SCLC) are comprised of heterogeneous subtypes marked by lineage-specific transcription factors, including ASCL1, NEUROD1, and POU2F3. POU2F3-positive SCLC, ∼12% of all cases, are uniquely dependent on POU2F3 itself; as such, approaches to attenuate POU2F3 expression may represent new therapeutic opportunities. Here using genome-scale screens for regulators of POU2F3 expression and SCLC proliferation, we define mSWI/SNF complexes, including non-canonical BAF (ncBAF) complexes, as top dependencies specific to POU2F3-positive SCLC. Notably, clinical-grade pharmacologic mSWI/SNF inhibition attenuates proliferation of all POU2F3-positive SCLCs, while disruption of ncBAF via BRD9 degradation is uniquely effective in pure non-neuroendocrine POU2F3-SCLCs. mSWI/SNF maintains accessibility over gene loci central to POU2F3-mediated gene regulatory networks. Finally, chemical targeting of SMARCA4/2 mSWI/SNF ATPases and BRD9 decrease POU2F3-SCLC tumor growth and increase survival in vivo . Taken together, these results characterize mSWI/SNF-mediated global governance of the POU2F3 oncogenic program and suggest mSWI/SNF inhibition as a therapeutic strategy for SCLC.
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20
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Wang J, Elghawy O, Kurpiel B, Kaur V. Diagnosis and management of gastrointestinal SMARCA4-deficient undifferentiated tumors. Clin J Gastroenterol 2023; 16:807-814. [PMID: 37651059 DOI: 10.1007/s12328-023-01853-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 08/22/2023] [Indexed: 09/01/2023]
Abstract
SMARCA4-deficient undifferentiated tumors are a rare clinical entity with an aggressive clinical course, poor prognosis, and no standard-of-care therapeutic approach. These have most frequently been documented in the lung and thoracic cavity. There is a growing body of evidence for the role of immunotherapy in SMARCA4-deficient lung cancer, a disease process that historically does very poorly with cytotoxic chemotherapy alone. We present three cases where the primary tumors were instead found within the gastrointestinal system: two originating from the small bowel and one from the esophagus. In all three cases, clinical response was seen with pembrolizumab therapy, with two of the three patients receiving long-term benefit. Our series suggests that anti-PD1 immunotherapy may have promising efficacy for undifferentiated carcinomas of the gastrointestinal tract with SMARCA4 deficiency.
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Affiliation(s)
- John Wang
- University of Virginia Cancer Center, Charlottesville, VA, USA
| | - Omar Elghawy
- Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Brett Kurpiel
- Department of Pathology, University of Virginia, Charlottesville, VA, USA
| | - Varinder Kaur
- University of Virginia Cancer Center, Charlottesville, VA, USA.
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21
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Zhang Z, Li Q, Sun S, Li Z, Cui Z, Liu Q, Zhang Y, Xiong S, Zhang S. Expression of SMARCA2 and SMARCA4 in gastric adenocarcinoma and construction of a nomogram prognostic model. Int J Clin Oncol 2023; 28:1487-1500. [PMID: 37634210 DOI: 10.1007/s10147-023-02403-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 08/06/2023] [Indexed: 08/29/2023]
Abstract
BACKGROUND Aberrant expression of SWI/SNF complex subunits is closely associated with tumorigenesis. The clinicopathological and prognostic significance of altered SMARCA2 and SMARCA4 subunits has not been well evaluated in gastric adenocarcinoma. METHODS We collected 1271 postoperative cases of gastric adenocarcinoma and then constructed tissue microarrays (TMA), from which we obtained the immunohistochemistry expression of SMARCA2 and SMARCA4. Next, we screened the variables related to the loss of SMARCA2 and SMARCA4 by univariate correlation analysis and multivariate logistic regression analysis. Then, we identified the variables related to prognosis by univariate and multivariate Cox regression analysis. Finally, we constructed a nomogram prognostic model and evaluated it. RESULTS The loss of SMARCA2 and SMARCA4 occurred in 236 (18.57%) and 86 (6.77%) cases, respectively, including 26 cases of co-loss. After multivariate logistic regression, variables independently associated with SMARCA2 loss were T stage, differentiation status, WHO histological classification, and EBER. Variables independently associated with SMARCA4 loss were differentiation status, WHO histological classification, PD-L1, and MMR. Survival analysis revealed that the SMARCA2 and SMARCA4 lost groups showed worse survival than the corresponding present groups (P = 0.032 and P = 0.0048, respectively). Univariate and multivariate Cox analyses identified independent prognostic factors, including age, T stage, N stage, M stage, SMARCA2, and chemotherapy. CONCLUSION The loss of SMARCA2 and SMARCA4 correlated with poor differentiation, leading to a worse prognosis. SMARCA2, as an independent prognostic factor, combined with other clinicopathological variables, established a novel nomogram prognostic model, which outperformed the AJCC TNM model.
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Affiliation(s)
- Zhenkun Zhang
- Weihai Municipal Hospital, Shandong University, Weihai, 264200, Shandong, China
- Department of Oncology, Shouguang People's Hospital, Weifang, 262700, Shandong, China
| | - Qiujing Li
- Department of Pathology, Weihai Municipal Hospital, Shandong University, No. 70 Heping Road, Huancui District, Weihai, 264200, Shandong, China
| | - Shanshan Sun
- Department of Oncology, Weihai Municipal Hospital, Shandong University, Weihai, 264200, Shandong, China
| | - Zhe Li
- Weifang Medical College, Weifang, 261053, Shandong, China
| | - ZhengGuo Cui
- Department of Environmental Health, University of Fukui School of Medical Sciences, 23-3 Matsuoka Shimoaizuki, Eiheiji, Fukui, 910-1193, Japan
| | - Qian Liu
- Department of Pathology, Weihai Municipal Hospital, Shandong University, No. 70 Heping Road, Huancui District, Weihai, 264200, Shandong, China
| | - Yujie Zhang
- Department of Pathology, Weihai Municipal Hospital, Shandong University, No. 70 Heping Road, Huancui District, Weihai, 264200, Shandong, China
| | - Sili Xiong
- Weifang Medical College, Weifang, 261053, Shandong, China
| | - Shukun Zhang
- Department of Pathology, Weihai Municipal Hospital, Shandong University, No. 70 Heping Road, Huancui District, Weihai, 264200, Shandong, China.
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22
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Thang NX, Han DW, Park C, Lee H, La H, Yoo S, Lee H, Uhm SJ, Song H, Do JT, Park KS, Choi Y, Hong K. INO80 function is required for mouse mammary gland development, but mutation alone may be insufficient for breast cancer. Front Cell Dev Biol 2023; 11:1253274. [PMID: 38020889 PMCID: PMC10646318 DOI: 10.3389/fcell.2023.1253274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 10/16/2023] [Indexed: 12/01/2023] Open
Abstract
The aberrant function of ATP-dependent chromatin remodeler INO80 has been implicated in multiple types of cancers by altering chromatin architecture and gene expression; however, the underlying mechanism of the functional involvement of INO80 mutation in cancer etiology, especially in breast cancer, remains unclear. In the present study, we have performed a weighted gene co-expression network analysis (WCGNA) to investigate links between INO80 expression and breast cancer sub-classification and progression. Our analysis revealed that INO80 repression is associated with differential responsiveness of estrogen receptors (ERs) depending upon breast cancer subtype, ER networks, and increased risk of breast carcinogenesis. To determine whether INO80 loss induces breast tumors, a conditional INO80-knockout (INO80 cKO) mouse model was generated using the Cre-loxP system. Phenotypic characterization revealed that INO80 cKO led to reduced branching and length of the mammary ducts at all stages. However, the INO80 cKO mouse model had unaltered lumen morphology and failed to spontaneously induce tumorigenesis in mammary gland tissue. Therefore, our study suggests that the aberrant function of INO80 is potentially associated with breast cancer by modulating gene expression. INO80 mutation alone is insufficient for breast tumorigenesis.
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Affiliation(s)
- Nguyen Xuan Thang
- Department of Stem Cell and Regenerative Biotechnology, Institute of Advanced Regenerative Science, Konkuk University, Seoul, Republic of Korea
| | - Dong Wook Han
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, Wuyi University, Jiangmen, China
| | - Chanhyeok Park
- Department of Stem Cell and Regenerative Biotechnology, Institute of Advanced Regenerative Science, Konkuk University, Seoul, Republic of Korea
| | - Hyeonji Lee
- Department of Stem Cell and Regenerative Biotechnology, Institute of Advanced Regenerative Science, Konkuk University, Seoul, Republic of Korea
| | - Hyeonwoo La
- Department of Stem Cell and Regenerative Biotechnology, Institute of Advanced Regenerative Science, Konkuk University, Seoul, Republic of Korea
| | - Seonho Yoo
- Department of Stem Cell and Regenerative Biotechnology, Institute of Advanced Regenerative Science, Konkuk University, Seoul, Republic of Korea
| | - Heeji Lee
- Department of Stem Cell and Regenerative Biotechnology, Institute of Advanced Regenerative Science, Konkuk University, Seoul, Republic of Korea
| | - Sang Jun Uhm
- Department of Animal Science, Sangji University, Wonju, Republic of Korea
| | - Hyuk Song
- Department of Stem Cell and Regenerative Biotechnology, Institute of Advanced Regenerative Science, Konkuk University, Seoul, Republic of Korea
| | - Jeong Tae Do
- Department of Stem Cell and Regenerative Biotechnology, Institute of Advanced Regenerative Science, Konkuk University, Seoul, Republic of Korea
| | - Kyoung Sik Park
- Department of Surgery, School of Medicine, Konkuk University, Seoul, Republic of Korea
| | - Youngsok Choi
- Department of Stem Cell and Regenerative Biotechnology, Institute of Advanced Regenerative Science, Konkuk University, Seoul, Republic of Korea
| | - Kwonho Hong
- Department of Stem Cell and Regenerative Biotechnology, Institute of Advanced Regenerative Science, Konkuk University, Seoul, Republic of Korea
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23
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Pervin J, Asad M, Cao S, Jang GH, Feizi N, Haibe-Kains B, Karasinska JM, O’Kane GM, Gallinger S, Schaeffer DF, Renouf DJ, Zogopoulos G, Bathe OF. Clinically impactful metabolic subtypes of pancreatic ductal adenocarcinoma (PDAC). Front Genet 2023; 14:1282824. [PMID: 38028629 PMCID: PMC10643182 DOI: 10.3389/fgene.2023.1282824] [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: 08/24/2023] [Accepted: 10/06/2023] [Indexed: 12/01/2023] Open
Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease characterized by a diverse tumor microenvironment. The heterogeneous cellular composition of PDAC makes it challenging to study molecular features of tumor cells using extracts from bulk tumor. The metabolic features in tumor cells from clinical samples are poorly understood, and their impact on clinical outcomes are unknown. Our objective was to identify the metabolic features in the tumor compartment that are most clinically impactful. Methods: A computational deconvolution approach using the DeMixT algorithm was applied to bulk RNASeq data from The Cancer Genome Atlas to determine the proportion of each gene's expression that was attributable to the tumor compartment. A machine learning algorithm designed to identify features most closely associated with survival outcomes was used to identify the most clinically impactful metabolic genes. Results: Two metabolic subtypes (M1 and M2) were identified, based on the pattern of expression of the 26 most important metabolic genes. The M2 phenotype had a significantly worse survival, which was replicated in three external PDAC cohorts. This PDAC subtype was characterized by net glycogen catabolism, accelerated glycolysis, and increased proliferation and cellular migration. Single cell data demonstrated substantial intercellular heterogeneity in the metabolic features that typified this aggressive phenotype. Conclusion: By focusing on features within the tumor compartment, two novel and clinically impactful metabolic subtypes of PDAC were identified. Our study emphasizes the challenges of defining tumor phenotypes in the face of the significant intratumoral heterogeneity that typifies PDAC. Further studies are required to understand the microenvironmental factors that drive the appearance of the metabolic features characteristic of the aggressive M2 PDAC phenotype.
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Affiliation(s)
- Jannat Pervin
- Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Mohammad Asad
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada
| | - Shaolong Cao
- Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Centre, Houston, TX, United States
| | - Gun Ho Jang
- Ontario Institute for Cancer Research, Toronto, ON, Canada
| | - Nikta Feizi
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | | | | | - Grainne M. O’Kane
- University Health Network, University of Toronto, Toronto, ON, Canada
| | | | - David F. Schaeffer
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Daniel J. Renouf
- Department of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - George Zogopoulos
- Department of Surgery, McGill University Health Centre, McGill University, Montreal, QC, Canada
| | - Oliver F. Bathe
- Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Department of Surgery, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
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24
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Khanna P, Mehta R, Mehta GA, Bhatt V, Guo JY, Gatza ML. SOX4-SMARCA4 complex promotes glycolysis-dependent TNBC cell growth through transcriptional regulation of Hexokinase 2. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.10.557071. [PMID: 37745600 PMCID: PMC10515838 DOI: 10.1101/2023.09.10.557071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
Abstract
Tumor cells rely on increased glycolytic capacity to promote cell growth and progression. While glycolysis is known to be upregulated in the majority of triple negative (TNBC) or basal-like subtype breast cancers, the mechanism remains unclear. Here, we used integrative genomic analyses to identify a subset of basal-like tumors characterized by increased expression of the oncogenic transcription factor SOX4 and its co-factor the SWI/SNF ATPase SMARCA4. These tumors are defined by unique gene expression programs that correspond with increased tumor proliferation and activation of key metabolic pathways, including glycolysis. Mechanistically, we demonstrate that the SOX4-SMARCA4 complex mediates glycolysis through direct transcriptional regulation of Hexokinase 2 (HK2) and that aberrant HK2 expression and altered glycolytic capacity are required to mediate SOX4-SMARCA4-dependent cell growth. Collectively, we have defined the SOX4-SMARCA4-HK2 signaling axis in basal-like breast tumors and established that this axis promotes metabolic reprogramming which is required to maintain tumor cell growth.
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Affiliation(s)
- Pooja Khanna
- Department of Radiation Oncology, Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
| | - Rushabh Mehta
- Department of Radiation Oncology, Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
| | - Gaurav A. Mehta
- Department of Radiation Oncology, Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
| | - Vrushank Bhatt
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
- Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901
- Department of Chemical Biology, Rutgers Ernest Mario School of Pharmacy, Piscataway, New Jersey 08854
| | - Jessie Y. Guo
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
- Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901
- Department of Chemical Biology, Rutgers Ernest Mario School of Pharmacy, Piscataway, New Jersey 08854
| | - Michael L. Gatza
- Department of Radiation Oncology, Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
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25
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Morii E. Tumor heterogeneity from the viewpoint of pathologists. Pathol Int 2023; 73:394-405. [PMID: 37638598 DOI: 10.1111/pin.13366] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 07/30/2023] [Indexed: 08/29/2023]
Abstract
Morphological and functional heterogeneity are found in tumors, with the latter reflecting the different levels of resistance against antitumor therapies. In a therapy-resistant subpopulation, the expression levels of differentiation markers decrease, and those of immature markers increase. In addition, this subpopulation expresses genes involved in drug metabolism, such as aldehyde dehydrogenase 1A1 (ALDH1A1). Because of their similarity to stem cells, cells in the latter therapy-resistant subpopulation are called cancer stem cells (CSCs). Like normal stem cells, CSCs were originally thought not to arise from non-CSCs, but this hierarchical model is too simple. It is now believed that CSCs are generated from non-CSCs. The plasticity of tumor phenotypes between CSCs and non-CSCs causes difficulty in completely curing tumors. In this review, focusing on ALDH1A1 as a marker for CSCs or immature tumor cells, the dynamics of ALDH1A1-expressing tumor cells and their regulatory mechanisms are described, and the plausible regulatory mechanisms of plasticity of ALDH1A1 expression phenotype are discussed. Genetic mutations are a significant factor for tumorigenesis, but non-mutational epigenetic reprogramming factors yielding tumor heterogeneity are also crucial in determining tumor characteristics. Factors influencing non-mutational epigenetic reprogramming in tumors are also discussed.
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Affiliation(s)
- Eiichi Morii
- Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan
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26
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de Miguel FJ, Gentile C, Feng WW, Silva SJ, Sankar A, Exposito F, Cai WL, Melnick MA, Robles-Oteiza C, Hinkley MM, Tsai JA, Hartley AV, Wei J, Wurtz A, Li F, Toki MI, Rimm DL, Homer R, Wilen CB, Xiao AZ, Qi J, Yan Q, Nguyen DX, Jänne PA, Kadoch C, Politi KA. Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer. Cancer Cell 2023; 41:1516-1534.e9. [PMID: 37541244 PMCID: PMC10957226 DOI: 10.1016/j.ccell.2023.07.005] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 05/10/2023] [Accepted: 07/11/2023] [Indexed: 08/06/2023]
Abstract
Acquired resistance to tyrosine kinase inhibitors (TKI), such as osimertinib used to treat EGFR-mutant lung adenocarcinomas, limits long-term efficacy and is frequently caused by non-genetic mechanisms. Here, we define the chromatin accessibility and gene regulatory signatures of osimertinib sensitive and resistant EGFR-mutant cell and patient-derived models and uncover a role for mammalian SWI/SNF chromatin remodeling complexes in TKI resistance. By profiling mSWI/SNF genome-wide localization, we identify both shared and cancer cell line-specific gene targets underlying the resistant state. Importantly, genetic and pharmacologic disruption of the SMARCA4/SMARCA2 mSWI/SNF ATPases re-sensitizes a subset of resistant models to osimertinib via inhibition of mSWI/SNF-mediated regulation of cellular programs governing cell proliferation, epithelial-to-mesenchymal transition, epithelial cell differentiation, and NRF2 signaling. These data highlight the role of mSWI/SNF complexes in supporting TKI resistance and suggest potential utility of mSWI/SNF inhibitors in TKI-resistant lung cancers.
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Affiliation(s)
| | - Claudia Gentile
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - William W Feng
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | - Shannon J Silva
- Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT 06510, USA
| | - Akshay Sankar
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | | | - Wesley L Cai
- Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT 06510, USA
| | | | - Camila Robles-Oteiza
- Department of Immunobiology, Yale School of Medicine, Yale University, New Haven, CT 06510, USA
| | - Madeline M Hinkley
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Jeanelle A Tsai
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | - Antja-Voy Hartley
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | - Jin Wei
- Department of Immunobiology, Yale School of Medicine, Yale University, New Haven, CT 06510, USA; Department of Laboratory Medicine, Yale School of Medicine, Yale University, New Haven, CT 06510, USA
| | - Anna Wurtz
- Yale Cancer Center, New Haven, CT 06520, USA
| | - Fangyong Li
- Yale Center for Analytical Sciences, Yale School of Public Health, Laboratory of Epidemiology and Public Health, 60 College St, New Haven, CT 06510, USA
| | - Maria I Toki
- Yale Cancer Center, New Haven, CT 06520, USA; Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT 06510, USA
| | - David L Rimm
- Yale Cancer Center, New Haven, CT 06520, USA; Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT 06510, USA; Department of Medicine (Section of Medical Oncology), Yale School of Medicine, Yale University, New Haven, CT 06510, USA
| | - Robert Homer
- Yale Cancer Center, New Haven, CT 06520, USA; Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT 06510, USA
| | - Craig B Wilen
- Department of Immunobiology, Yale School of Medicine, Yale University, New Haven, CT 06510, USA; Department of Laboratory Medicine, Yale School of Medicine, Yale University, New Haven, CT 06510, USA
| | - Andrew Z Xiao
- Department of Genetics, Yale School of Medicine, Yale University, New Haven, CT 06510, USA; Yale Stem Cell Center, Yale School of Medicine, Yale University, New Haven, CT 06510, USA
| | - Jun Qi
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Qin Yan
- Yale Cancer Center, New Haven, CT 06520, USA; Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT 06510, USA; Yale Stem Cell Center, Yale School of Medicine, Yale University, New Haven, CT 06510, USA
| | - Don X Nguyen
- Yale Cancer Center, New Haven, CT 06520, USA; Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT 06510, USA; Department of Medicine (Section of Medical Oncology), Yale School of Medicine, Yale University, New Haven, CT 06510, USA; Yale Stem Cell Center, Yale School of Medicine, Yale University, New Haven, CT 06510, USA
| | - Pasi A Jänne
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | - Cigall Kadoch
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
| | - Katerina A Politi
- Yale Cancer Center, New Haven, CT 06520, USA; Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT 06510, USA; Department of Medicine (Section of Medical Oncology), Yale School of Medicine, Yale University, New Haven, CT 06510, USA; Yale Stem Cell Center, Yale School of Medicine, Yale University, New Haven, CT 06510, USA.
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27
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Pallauf M, Ged Y, Singla N. Molecular differences in renal cell carcinoma between males and females. World J Urol 2023; 41:1727-1739. [PMID: 36905442 DOI: 10.1007/s00345-023-04347-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 02/23/2023] [Indexed: 03/12/2023] Open
Abstract
PURPOSE The disparity in renal cell carcinoma (RCC) risk and treatment outcome between males and females is well documented, but the underlying molecular mechanisms remain poorly elucidated. METHODS We performed a narrative review synthesizing contemporary evidence on sex-specific molecular differences in healthy kidney tissue and RCC. RESULTS In healthy kidney tissue, gene expression differs significantly between males and females, including autosomal and sex-chromosome-linked genes. The differences are most prominent for sex-chromosome-linked genes and attributable to Escape from X chromosome-linked inactivation and Y chromosome loss. The frequency distribution of RCC histologies varies between the sexes, particularly for papillary, chromophobe, and translocation RCC. In clear-cell and papillary RCC, sex-specific gene expressions are pronounced, and some of these genes are amenable to pharmacotherapy. However, for many, the impact on tumorigenesis remains poorly understood. In clear-cell RCC, molecular subtypes and gene expression pathways have distinct sex-specific trends, which also apply to the expression of genes implicated in tumor progression. CONCLUSION Current evidence suggests meaningful genomic differences between male and female RCC, highlighting the need for sex-specific RCC research and personalized sex-specific treatment approaches.
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Affiliation(s)
- Maximilian Pallauf
- Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Park 213, Baltimore, MD, 21287, USA
- Department of Urology, University Hospital Salzburg, Paracelsus Medical University, Salzburg, Austria
| | - Yasser Ged
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Nirmish Singla
- Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Park 213, Baltimore, MD, 21287, USA.
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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28
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Wang L, Tang J. SWI/SNF complexes and cancers. Gene 2023; 870:147420. [PMID: 37031881 DOI: 10.1016/j.gene.2023.147420] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Revised: 03/29/2023] [Accepted: 04/03/2023] [Indexed: 04/11/2023]
Abstract
Epigenetics refers to the study of genetic changes that can affect gene expression without altering the underlying DNA sequence, including DNA methylation, histone modification, chromatin remodelling, X chromosome inactivation and non-coding RNA regulation. Of these, DNA methylation, histone modification and chromatin remodelling constitute the three classical modes of epigenetic regulation. These three mechanisms alter gene transcription by adjusting chromatin accessibility, thereby affecting cell and tissue phenotypes in the absence of DNA sequence changes. In the presence of ATP hydrolases, chromatin remodelling alters the structure of chromatin and thus changes the transcription level of DNA-guided RNA. To date, four types of ATP-dependent chromatin remodelling complexes have been identified in humans, namely SWI/SNF, ISWI, INO80 and NURD/MI2/CHD. SWI/SNF mutations are prevalent in a wide variety of cancerous tissues and cancer-derived cell lines as discovered by next-generation sequencing technologies.. SWI/SNF can bind to nucleosomes and use the energy of ATP to disrupt DNA and histone interactions, sliding or ejecting histones, altering nucleosome structure, and changing transcriptional and regulatory mechanisms. Furthermore, mutations in the SWI/SNF complex have been observed in approximately 20% of all cancers. Together, these findings suggest that mutations targeting the SWI/SNF complex may have a positive impact on tumorigenesis and cancer progression.
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Affiliation(s)
- Liyuan Wang
- The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Department of Oncology and Hematology, Jinan 250000, Shandong Province, China
| | - Jinglong Tang
- Adicon Medical Laboratory Center, Molecular Genetic Diagnosis Center, Pathological Diagnosis Center, Jinan 250014, Shandong Province, China.
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29
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Kido K, Nojima S, Motooka D, Nomura Y, Kohara M, Sato K, Ohshima K, Tahara S, Kurashige M, Umeda D, Takashima T, Kiyokawa H, Ukon K, Matsui T, Okuzaki D, Morii E. Ovarian high-grade serous carcinoma cells with low SMARCA4 expression and high SMARCA2 expression contribute to platinum resistance. J Pathol 2023; 260:56-70. [PMID: 36763038 DOI: 10.1002/path.6064] [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: 09/16/2022] [Revised: 12/31/2022] [Accepted: 02/08/2023] [Indexed: 02/11/2023]
Abstract
Platinum resistance is a major obstacle to the treatment of ovarian cancer and is correlated with poor clinical outcomes. Intratumor heterogeneity plays a key role in chemoresistance. Recent studies have emphasized the contributions of genetic and epigenetic factors to the development of intratumor heterogeneity. Although the clinical significance of multi-subunit chromatin remodeler, switch/sucrose nonfermenting (SWI/SNF) complexes in cancers has been reported, the impacts of SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4/subfamily A, member 2 (SMARCA4/A2) expression patterns in human cancer tissues have not been fully elucidated. Here, we show that low expression of SMARCA4 and high expression of SMARCA2 are associated with platinum resistance in ovarian high-grade serous carcinoma (HGSC) cells. We used fluorescence multiplex immunohistochemistry (fmIHC) to study resected specimens; we examined heterogeneity in human HGSC tissues at the single-cell level, which revealed that the proportion of cells with the SMARCA4low /SMARCA2high phenotype was positively correlated with clinical platinum-resistant recurrence. We used stable transfection of SMARCA2 and siRNA knockdown of SMARCA4 to generate HGSC cells with the SMARCA4low /SMARCA2high phenotype; these cells had the greatest resistance to carboplatin. Bioinformatics analyses revealed that the underlying mechanism involved in substantial alterations to chromatin accessibility and resultant fibroblast growth factor (FGF) signaling activation, MAPK pathway activation, BCL2 overexpression, and reduced carboplatin-induced apoptosis; these were confirmed by in vitro functional experiments. Furthermore, in vivo experiments in an animal model demonstrated that combination therapy with carboplatin and a fibroblast growth factor receptor (FGFR) inhibitor promoted cell death in HGSC xenografts. Taken together, these observations reveal a specific subpopulation of HGSC cells that is associated with clinical chemoresistance, which may lead to the establishment of a histopathological prediction system for carboplatin response. Our findings may facilitate the development of novel therapeutic strategies for platinum-resistant HGSC cells. © 2023 The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Kansuke Kido
- Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Satoshi Nojima
- Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Daisuke Motooka
- Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.,Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.,Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan
| | - Yusuke Nomura
- Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Masaharu Kohara
- Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Kazuaki Sato
- Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Kenji Ohshima
- Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Shinichiro Tahara
- Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Masako Kurashige
- Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Daisuke Umeda
- Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Tsuyoshi Takashima
- Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hiroki Kiyokawa
- Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Koto Ukon
- Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Takahiro Matsui
- Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Daisuke Okuzaki
- Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.,Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.,Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan
| | - Eiichi Morii
- Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.,Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan
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30
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Mollapour Sisakht M, Amirkhani MA, Nilforoushzadeh MA. SWI/SNF complex, promising target in melanoma therapy: Snapshot view. Front Med (Lausanne) 2023; 10:1096615. [PMID: 36844227 PMCID: PMC9947295 DOI: 10.3389/fmed.2023.1096615] [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: 11/12/2022] [Accepted: 01/20/2023] [Indexed: 02/11/2023] Open
Abstract
Therapeutic strategies based on epigenetic regulators are rapidly increasing in light of recent advances in discovering the role of epigenetic factors in response and sensitivity to therapy. Although loss-of-function mutations in genes encoding the SWItch/Sucrose NonFermentable (SWI/SNF) subunits play an important role in the occurrence of ~34% of melanomas, the potential of using inhibitors and synthetic lethality interactions between key subunits of the complex that play an important role in melanoma progression must be considered. Here, we discuss the importance of the clinical application of SWI/SNF subunits as a promising potential therapeutic in melanoma.
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Affiliation(s)
- Mahsa Mollapour Sisakht
- Biotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran,Department of Biochemistry, Erasmus University Medical Center, Rotterdam, Netherlands,*Correspondence: Mahsa Mollapour Sisakht ✉ ; ✉
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31
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Czerwinska P, Mackiewicz AA. Bromodomain (BrD) Family Members as Regulators of Cancer Stemness-A Comprehensive Review. Int J Mol Sci 2023; 24:995. [PMID: 36674511 PMCID: PMC9861003 DOI: 10.3390/ijms24020995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 12/30/2022] [Accepted: 12/31/2022] [Indexed: 01/06/2023] Open
Abstract
Epigenetic mechanisms involving DNA methylation and chromatin modifications have emerged as critical facilitators of cancer heterogeneity, substantially affecting cancer development and progression, modulating cell phenotypes, and enhancing or inhibiting cancer cell malignant properties. Not surprisingly, considering the importance of epigenetic regulators in normal stem cell maintenance, many chromatin-related proteins are essential to maintaining the cancer stem cell (CSC)-like state. With increased tumor-initiating capacities and self-renewal potential, CSCs promote tumor growth, provide therapy resistance, spread tumors, and facilitate tumor relapse after treatment. In this review, we characterized the epigenetic mechanisms that regulate the acquisition and maintenance of cancer stemness concerning selected epigenetic factors belonging to the Bromodomain (BrD) family of proteins. An increasing number of BrD proteins reinforce cancer stemness, supporting the maintenance of the cancer stem cell population in vitro and in vivo via the utilization of distinct mechanisms. As bromodomain possesses high druggable potential, specific BrD proteins might become novel therapeutic targets in cancers exhibiting de-differentiated tumor characteristics.
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Affiliation(s)
- Patrycja Czerwinska
- Department of Cancer Immunology, Poznan University of Medical Sciences, 61-866 Poznan, Poland
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 61-866 Poznan, Poland
| | - Andrzej Adam Mackiewicz
- Department of Cancer Immunology, Poznan University of Medical Sciences, 61-866 Poznan, Poland
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 61-866 Poznan, Poland
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32
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Wang H, Tran TT, Duong KT, Nguyen T, Le UM. Options of Therapeutics and Novel Delivery Systems of Drugs for the Treatment of Melanoma. Mol Pharm 2022; 19:4487-4505. [PMID: 36305753 DOI: 10.1021/acs.molpharmaceut.2c00775] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Melanoma is one of the most severe cancerous diseases. The cells employ multiple signaling pathways, such as ERK, HGF/c-MET, WNT, and COX-2 to cause the cell proliferation, survival, and metastasis. Treatment of melanoma, including surgery, chemotherapy, immunotherapy, radiation, and targeted therapy, is based on 4 major or 11 substages of the disease. Fourteen drugs, including dacarbazine, interferon α-2b, interleukin-12, ipilimumab, peginterferon α-2b, vemurafenib, trametinib, talimogene laherparepvec, cobimetinib, pembrolizumab, dabrafenib, binimetinib, encorafenib, and nivolumab, have been approved by the FDA for the treatment of melanoma. All of them are in conventional dosage forms of injection solutions, suspensions, oral tablets, or capsules. Major drawbacks of the treatment are side effects of the drugs and patients' incompliance to them. These are consequences of high doses and long-term treatments for the diseases. Currently more than 350 NCI-registered clinical trials are being carried out to treat advanced and/or metastatic melanoma using novel treatment methods, such as immune cell therapy, cancer vaccines, and new therapeutic targets. In addition, novel delivery systems using biomaterials of the approved drugs have been developed attempting to increase the drug delivery, targeting, stability, bioavailability, thus potentially reducing the toxicity and increasing the treatment effectiveness. Nanoparticles and liposomes have been emerging as advanced delivery systems which can improve drug stability and systemic circulation time. In this review, the most recent findings in the options for treatment and development of novel drug delivery systems for the treatment of melanoma are comprehensively discussed.
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Affiliation(s)
- Hongbin Wang
- College of Pharmacy, California Northstate University, 9700 West Taron Drive, Elk Grove, California 95757, United States
- Master of Pharmaceutical Sciences College of Graduate Study, California Northstate University, 9700 West Taron Drive, Elk Grove, California 95757, United States
| | - Tuan T Tran
- College of Pharmacy, California Northstate University, 9700 West Taron Drive, Elk Grove, California 95757, United States
| | - Katherine T Duong
- CVS Pharmacy, 18872 Beach Boulevard, Huntington Beach, California 92648, United States
| | - Trieu Nguyen
- College of Pharmacy, California Northstate University, 9700 West Taron Drive, Elk Grove, California 95757, United States
| | - Uyen M Le
- College of Pharmacy, California Northstate University, 9700 West Taron Drive, Elk Grove, California 95757, United States
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Zhang Z, Li Q, Sun S, Li Z, Cui ZG, Zhang M, Liu Q, Zhang Y, Xiong S, Zhang S. Clinicopathological and prognostic significance of SWI/SNF complex subunits in undifferentiated gastric carcinoma. World J Surg Oncol 2022; 20:383. [PMID: 36464671 PMCID: PMC9721057 DOI: 10.1186/s12957-022-02847-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Accepted: 11/20/2022] [Indexed: 12/05/2022] Open
Abstract
BACKGROUND The switch/sucrose nonfermentable (SWI/SNF) complex is an evolutionarily conserved chromatin remodeling complex that displays dysfunction in many tumors, especially undifferentiated carcinoma. Cancer stem cells (CSC), a special type of undifferentiated cancer cells with stem cell-like properties, play an essential role in tumor cell proliferation, invasion, and metastasis. In undifferentiated gastric carcinomas, the association of SWI/SNF complexes with clinicopathological features, CSC phenotype, and the prognosis is not fully understood. METHODS We collected a cohort of 21 patients with undifferentiated/dedifferentiated gastric carcinoma. We next performed immunohistochemistry staining for the five subunits of the SWI/SNF complex (ARID1A, ARID1B, SMARCA2, SMARCA4, and SMARCB1), and four mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6), as well as other markers such as p53, PD-L1, and cancer stem cell (CSC) markers (SOX2, SALL4). Then, we investigated the correlation of SWI/SNF complex subunits with clinicopathological characters and performed prognostic analysis. RESULTS We observed SMARCA2 loss in 12 cases (57.14%), followed by ARID1A (5 cases, 23.81%) and SMARCA4 (3 cases, 14.29%). Fourteen cases (66.67%) lost any one of the SWI/SNF complex subunits, including 3 cases with SMARCA2 and ARID1A co-loss, and 3 cases with SMARCA2 and SMARCA4 co-loss. Correlation analysis revealed that the CSC phenotype occurred more frequently in the SWI/SNF complex deficient group (P = 0.0158). Survival analysis revealed that SWI/WNF complex deficiency, undifferentiated status, CSC phenotype, and the loss of SMARCA2 and SMARCA4 resulted in worse survival. Univariate and multivariate Cox regression analyses screened out three independent factors associated with worse prognosis: undifferentiated status, SWI/SNF complex deficiency, and lymph node metastasis. CONCLUSIONS The SWI/SNF complex deficiency was more likely to result in a CSC phenotype and worse survival and was an independent prognostic factor in undifferentiated/dedifferentiated gastric carcinoma.
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Affiliation(s)
- Zhenkun Zhang
- Weihai Municipal Hospital, Shandong University, Weihai, 264200, Shandong, China.,Department of Oncology, Shouguang People's Hospital, Weifang, 262700, Shandong, China
| | - Qiujing Li
- Department of Pathology, Weihai Municipal Hospital, Shandong University, Weihai, 264200, Shandong, China
| | - Shanshan Sun
- Department of Oncology, Weihai Municipal Hospital, Shandong University, Weihai, 264200, Shandong, China
| | - Zhe Li
- Weifang Medical College, Weifang, 261053, Shandong, China
| | - Zheng Guo Cui
- Department of Environmental Health, University of Fukui School of Medical Science, 23-3 Matsuoka Shimoaizuki, Eiheiji, Fukui, 910-1193, Japan
| | - Menglan Zhang
- Department of Pathology, Qinghai Provincial People's Hospital, Xining, 810000, Qinghai, China
| | - Qian Liu
- Department of Pathology, Weihai Municipal Hospital, Shandong University, Weihai, 264200, Shandong, China
| | - Yujie Zhang
- Department of Pathology, Weihai Municipal Hospital, Shandong University, Weihai, 264200, Shandong, China
| | - Sili Xiong
- Weifang Medical College, Weifang, 261053, Shandong, China
| | - Shukun Zhang
- Department of Pathology, Weihai Municipal Hospital, Shandong University, Weihai, 264200, Shandong, China.
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Al-Shbool G, Krishnan Nair H. SMARCA4-Deficient Undifferentiated Tumor: A Rare Malignancy With Distinct Clinicopathological Characteristics. Cureus 2022; 14:e30708. [DOI: 10.7759/cureus.30708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/25/2022] [Indexed: 11/07/2022] Open
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35
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Zhang L, Sun T, Wu XY, Fei FM, Gao ZZ. Delineation of a SMARCA4-specific competing endogenous RNA network and its function in hepatocellular carcinoma. World J Clin Cases 2022; 10:10501-10515. [PMID: 36312469 PMCID: PMC9602240 DOI: 10.12998/wjcc.v10.i29.10501] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 08/14/2022] [Accepted: 08/30/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a common malignancy worldwide, and the mortality rate continues to rise each year. SMARCA4 expression has been associated with poor prognosis in various types of cancer; however, the specific mechanism of action of SMARCA4 in HCC needs to be fully elucidated.
AIM To explore the specific mechanism of action of SMARCA4 in HCC.
METHODS Herein, the expression level of SMARCA4 as well as its association with HCC prognosis were evaluated using transcriptome profiling and clinical data of 18 different types of cancer collected from The Cancer Genome Atlas database. Furthermore, SMARCA4-high and -low groups were identified. Thereafter, gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to identify the function of SMARCA4, followed by construction of a SMARCA4-specific competing endogenous RNA (ceRNA) network using starBase database. The role of SMARCA4 in immunotherapy and its association with immune cells were assessed using correlation analysis.
RESULTS It was observed that SMARCA4 was overexpressed and negatively correlated with prognosis in HCC. Further, SMARCA4 expression was positively associated with tumor mutational burden, microsatellite stability, and immunotherapy efficacy. The SNHG3/THUMP3-AS1-miR-139-5p-SMARCA4 ceRNA network was established and could be assumed to serve as a stimulatory mechanism in HCC.
CONCLUSION The findings of this study demonstrated that SMARCA4 plays a significant role in progression and immune infiltration in HCC. Moreover, a ceRNA network was detected, which was found to be correlated with poor prognosis in HCC. The findings of this study could contribute towards the identification of predictive markers for immunotherapy and a novel mechanism of action for HCC treatment.
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Affiliation(s)
- Lei Zhang
- Department of Clinical Oncology, Jiaxing Second Hospital, Jiaxing 314000, Zhejiang Province, China
| | - Ting Sun
- Department of Clinical Oncology, Jiaxing Second Hospital, Jiaxing 314000, Zhejiang Province, China
| | - Xiao-Ye Wu
- Department of Clinical Oncology, Jiaxing Second Hospital, Jiaxing 314000, Zhejiang Province, China
| | - Fa-Ming Fei
- Department of Clinical Oncology, The Second Affiliated Hospital of Jiaxing University, Jiaxing 314000, Zhejiang Province, China
| | - Zhen-Zhen Gao
- Department of Clinical Oncology, The Second Affiliated Hospital of Jiaxing University, Jiaxing 314000, Zhejiang Province, China
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36
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Kurabi A, Hur DG, Pak K, Gibson M, Webster NJG, Baird A, Eliceiri BP, Ryan AF. The ECRG4 cleavage product augurin binds the endotoxin receptor and influences the innate immune response during otitis media. Front Genet 2022; 13:932555. [PMID: 36092940 PMCID: PMC9461705 DOI: 10.3389/fgene.2022.932555] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 07/18/2022] [Indexed: 11/13/2022] Open
Abstract
Otitis media (OM), the most common disease of childhood, is typically characterized by bacterial infection of the middle ear (ME). Prominent features of OM include hyperplasia of the ME mucosa, which transforms from a monolayer of simple squamous epithelium with minimal stroma into a full-thickness respiratory epithelium in 2-3 days after infection. Analysis of the murine ME transcriptome during OM showed down-regulation of the tumor suppressor gene Ecrg4 that was temporally related to mucosal hyperplasia and identified stromal cells as the primary ECRG4 source. The reduction in Ecrg4 gene expression coincided with the cleavage of ECRG4 protein to release an extracellular fragment, augurin. The duration of mucosal hyperplasia during OM was greater in Ecrg4 -/- mice, the number of infiltrating macrophages was enhanced, and ME infection cleared more rapidly. ECRG4-null macrophages showed increased bacterial phagocytosis. Co-immunoprecipitation identified an association of augurin with TLR4, CD14 and MD2, the components of the lipopolysaccharide (LPS) receptor. The results suggest that full-length ECRG4 is a sentinel molecule that potentially inhibits growth of the ME stroma. Processing of ECRG4 protein during inflammation, coupled with a decline in Ecrg4 gene expression, also influences the behavior of cells that do not express the gene, limiting the production of growth factors by epithelial and endothelial cells, as well as the activity of macrophages.
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Affiliation(s)
- Arwa Kurabi
- Department of Otolaryngology, University of California, San Diego, La Jolla, CA, United States,*Correspondence: Arwa Kurabi,
| | - Dong Gu Hur
- Department of Otolaryngology, University of California, San Diego, La Jolla, CA, United States,Department of Otorhinolaryngology, Gyeongsang National University Changwon Hospital, Changwon, South Korea
| | - Kwang Pak
- Department of Otolaryngology, University of California, San Diego, La Jolla, CA, United States
| | - Madeline Gibson
- Department of Otolaryngology, University of California, San Diego, La Jolla, CA, United States
| | - Nicholas J. G. Webster
- Department of Medicine, University of California, San Diego, La Jolla, CA, United States,San Diego Veterans Administration Healthcare System, San Diego, CA, United States
| | - Andrew Baird
- Department of Surgery, University of California, San Diego, La Jolla, CA, United States
| | - Brian P. Eliceiri
- Department of Surgery, University of California, San Diego, La Jolla, CA, United States
| | - Allen F. Ryan
- Department of Otolaryngology, University of California, San Diego, La Jolla, CA, United States,San Diego Veterans Administration Healthcare System, San Diego, CA, United States
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Yoshikawa T, Fukuda A, Omatsu M, Namikawa M, Sono M, Yuichi F, Masuda T, Araki O, Nagao M, Ogawa S, Masuo K, Goto N, Hiramatsu Y, Muta Y, Tsuda M, Maruno T, Nakanishi Y, Kawada K, Takaishi S, Seno H. JNK pathway plays a critical role for expansion of human colorectal cancer in the context of BRG1 suppression. Cancer Sci 2022; 113:3417-3427. [PMID: 35924439 PMCID: PMC9530857 DOI: 10.1111/cas.15520] [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: 01/26/2022] [Revised: 07/14/2022] [Accepted: 07/26/2022] [Indexed: 12/09/2022] Open
Abstract
Tumor stem cells (TSCs), capable of self‐renewal and continuous production of progeny cells, could be potential therapeutic targets. We have recently reported that chromatin remodeling regulator Brg1 is required for maintenance of murine intestinal TSCs and stemness feature of human colorectal cancer (CRC) cells by inhibiting apoptosis. However, it is still unclear how BRG1 suppression changes the underlying intracellular mechanisms of human CRC cells. We found that Brg1 suppression resulted in upregulation of the JNK signaling pathway in human CRC cells and murine intestinal TSCs. Simultaneous suppression of BRG1 and the JNK pathway, either by pharmacological inhibition or silencing of c‐JUN, resulted in even stronger inhibition of the expansion of human CRC cells compared to Brg1 suppression alone. Consistently, high c‐JUN expression correlated with worse prognosis for survival in human CRC patients with low BRG1 expression. Therefore, the JNK pathway plays a critical role for expansion and stemness of human CRC cells in the context of BRG1 suppression, and thus a combined blockade of BRG1 and the JNK pathway could be a novel therapeutic approach against human CRC.
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Affiliation(s)
- Takaaki Yoshikawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.,Department of Gastroenterology and Hepatology, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Japan
| | - Akihisa Fukuda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Mayuki Omatsu
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Mio Namikawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Makoto Sono
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Fukunaga Yuichi
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.,Department of Drug Discovery Medicine, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tomonori Masuda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Osamu Araki
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Munemasa Nagao
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Satoshi Ogawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Kenji Masuo
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.,Laboratory for Malignancy Control Research (DSK project), Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Norihiro Goto
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yukiko Hiramatsu
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yu Muta
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Motoyuki Tsuda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Takahisa Maruno
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yuki Nakanishi
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Kenji Kawada
- Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Shigeo Takaishi
- Laboratory for Malignancy Control Research (DSK project), Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
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Liu G, Sun BY, Sun J, Zhou PY, Guan RY, Zhou C, Yang ZF, Wang ZT, Zhou J, Fan J, Yi Y, Qiu SJ. BRG1 regulates lipid metabolism in hepatocellular carcinoma through the PIK3AP1/PI3K/AKT pathway by mediating GLMP expression. Dig Liver Dis 2022; 54:692-700. [PMID: 34158256 DOI: 10.1016/j.dld.2021.05.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 05/03/2021] [Accepted: 05/04/2021] [Indexed: 12/30/2022]
Abstract
BACKGROUND Brahma-related gene 1 (BRG1) is essential for embryogenesis and cellular metabolism. A deficiency of BRG1 in vivo decreases lipid droplets, but the molecular mechanism underlying its role in lipid metabolism associated with hepatocellular carcinoma (HCC) remains unknown. AIMS We aimed to determine the role of BRG1 in lipid metabolism in HCC. METHODS We assessed the differential expression of BRG1 in HCC and adjacent non-tumorous tissues using tissue microarrays. We stained lipid droplets in HCC cells with Bodipy fluorescence and Oil Red O, and verified BRG1 binding to the promoter region of glycosylated lysosomal membrane protein (GLMP) using chromatin immunoprecipitation. RESULTS The expression of GLMP, a potential lipid metabolism regulator, was suppressed by BRG1 via transcriptional activity. Knockdown of BRG1 decreased lipid droplets, increased GLMP expression and altered the phosphoinositide-3-kinase adaptor protein 1 (PIK3AP1)/phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT) pathway in HCC, which further GLMP knockdown partially restored. Thus, GLMP knockdown increased lipid droplets and differentially altered the PI3K/AKT pathway. CONCLUSIONS Downregulating BRG1 decreased lipid droplet deposition in HCC cells by upregulating GLMP and altering the PI3K/AKT pathway. Both BRG1 and GLMP might serve as therapeutic targets for disorders associated with dysregulated lipid metabolism, such as NAFLD and NAFLD-associated HCC.
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Affiliation(s)
- Gao Liu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Biomedical Research Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, People's Republic of China
| | - Bao-Ye Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Biomedical Research Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, People's Republic of China
| | - Jian Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Biomedical Research Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, People's Republic of China
| | - Pei-Yun Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Biomedical Research Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, People's Republic of China
| | - Ruo-Yu Guan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Biomedical Research Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, People's Republic of China
| | - Cheng Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Biomedical Research Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, People's Republic of China
| | - Zhang-Fu Yang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Biomedical Research Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, People's Republic of China
| | - Zhu-Tao Wang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Biomedical Research Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, People's Republic of China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Biomedical Research Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, People's Republic of China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Biomedical Research Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, People's Republic of China
| | - Yong Yi
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Biomedical Research Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, People's Republic of China.
| | - Shuang-Jian Qiu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Biomedical Research Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, People's Republic of China.
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Asselstine V, Medrano JF, Cánovas A. Identification of novel alternative splicing associated with mastitis disease in Holstein dairy cows using large gap read mapping. BMC Genomics 2022; 23:222. [PMID: 35305573 PMCID: PMC8934477 DOI: 10.1186/s12864-022-08430-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 02/24/2022] [Indexed: 12/16/2022] Open
Abstract
Background Mastitis is a very common disease in the dairy industry that producers encounter daily. Transcriptomics, using RNA-Sequencing (RNA - Seq) technology, can be used to study the functional aspect of mastitis resistance to identify animals that have a better immune response to mastitis. When the cow has mastitis, not only genes but also specific mRNA isoforms generated via alternative splicing (AS) could be differentially expressed (DE), leading to the phenotypic variation observed. Therefore, the objective of this study was to use large gap read mapping to identify mRNA isoforms DE between healthy and mastitic milk somatic cell samples (N = 12). These mRNA isoforms were then categorized based on being 1) annotated mRNA isoforms for gene name and length, 2) annotated mRNA isoforms with different transcript length and 3) novel mRNA isoforms of non - annotated genes. Results Analysis identified 333 DE transcripts (with at least 2 mRNA isoforms annotated, with at least one being DE) between healthy and mastitic samples corresponding to 303 unique genes. Of these 333 DE transcripts between healthy and mastitic samples, 68 mRNA isoforms are annotated in the bovine genome reference (ARS.UCD.1.2), 249 mRNA isoforms had novel transcript lengths of known genes and 16 were novel transcript lengths of non - annotated genes in the bovine genome reference (ARS.UCD.1.2). Functional analysis including gene ontology, gene network and metabolic pathway analysis was performed on the list of 288 annotated and unique DE mRNA isoforms. In total, 67 significant metabolic pathways were identified including positive regulation of cytokine secretion and immune response. Additionally, numerous DE novel mRNA isoforms showed potential involvement with the immune system or mastitis. Lastly, QTL annotation analysis was performed on coding regions of the DE mRNA isoforms, identifying overlapping QTLs associated with clinical mastitis and somatic cell score. Conclusion This study identified novel mRNA isoforms generated via AS that could lead to differences in the immune response of Holstein dairy cows and be potentially implemented in future breeding programs. Supplementary Information The online version contains supplementary material available at 10.1186/s12864-022-08430-x.
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He Y, Yang C, Wang Y, Sacher JR, Sims MM, Pfeffer LM, Miller DD. Novel structural-related analogs of PFI-3 (SRAPs) that target the BRG1 catalytic subunit of the SWI/SNF complex increase the activity of temozolomide in glioblastoma cells. Bioorg Med Chem 2022; 53:116533. [PMID: 34863065 DOI: 10.1016/j.bmc.2021.116533] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/23/2021] [Accepted: 11/23/2021] [Indexed: 11/02/2022]
Abstract
Glioblastoma (GBM) is the most aggressive and treatment-refractory malignant adult brain cancer. After standard of care therapy, the overall median survival for GBM is only ∼6 months with a 5-year survival <10%. Although some patients initially respond to the DNA alkylating agent temozolomide (TMZ), unfortunately most patients become resistant to therapy and brain tumors eventually recur. We previously found that knockout of BRG1 or treatment with PFI-3, a small molecule inhibitor of the BRG1 bromodomain, enhances sensitivity of GBM cells to temozolomide in vitro and in vivo GBM animal models. Those results demonstrated that the BRG1 catalytic subunit of the SWI/SNF chromatin remodeling complex appears to play a critical role in regulating TMZ-sensitivity. In the present study we designed and synthesized Structurally Related Analogs of PFI-3 (SRAPs) and tested their bioactivity in vitro. Among of the SRAPs, 9f and 11d show better efficacy than PFI-3 in sensitizing GBM cells to the antiproliferative and cell death inducing effects of temozolomide in vitro, as well as enhancing the inhibitor effect of temozolomide on the growth of subcutaneous GBM tumors.
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Affiliation(s)
- Yali He
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, United States
| | - Chuanhe Yang
- Department of Pathology and Laboratory Medicine, and Center for Cancer Research, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, United States
| | - Yinan Wang
- Department of Pathology and Laboratory Medicine, and Center for Cancer Research, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, United States
| | - Joshua R Sacher
- Cyclica, Inc., 207 Queens Quay West, Suite 420, Toronto, Ontario M5J 1A7, Canada
| | - Michelle M Sims
- Department of Pathology and Laboratory Medicine, and Center for Cancer Research, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, United States
| | - Lawrence M Pfeffer
- Department of Pathology and Laboratory Medicine, and Center for Cancer Research, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, United States
| | - Duane D Miller
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, United States.
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Sun S, Li Q, Zhang Z, Xiong S, Zhang Y, Liu Q, Li Z, Yang F, Zhang S. SMARCA2 deficiency in NSCLC: a clinicopathologic and immunohistochemical analysis of a large series from a single institution. Environ Health Prev Med 2022; 27:3. [PMID: 35289322 PMCID: PMC9093611 DOI: 10.1265/ehpm.21-00254] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Affiliation(s)
- Shanshan Sun
- Department of Oncology, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University
| | - Qiujing Li
- Department of Pathology, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University
| | | | | | - Yujie Zhang
- Department of Pathology, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University
| | - Qian Liu
- Department of Pathology, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University
| | | | - Fujun Yang
- Department of Oncology, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University
| | - Shukun Zhang
- Department of Pathology, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University
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42
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Ahadi MS, Fuchs TL, Clarkson A, Sheen A, Sioson L, Chou A, Gill AJ. SWI/SNF complex (SMARCA4, SMARCA2, INI1/SMARCB1) deficient colorectal carcinomas are strongly associated with microsatellite instability: An incidence study in 4508 colorectal carcinomas. Histopathology 2021; 80:906-921. [DOI: 10.1111/his.14612] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 11/28/2021] [Accepted: 12/21/2021] [Indexed: 11/29/2022]
Affiliation(s)
- Mahsa S Ahadi
- Cancer Diagnosis and Pathology Group Kolling Institute of Medical Research, Royal North Shore Hospital St Leonards NSW 2065 Australia
- NSW Health Pathology, Department of Anatomical Pathology Royal North Shore Hospital Sydney NSW 2065 Australia
- Sydney Medical School University of Sydney Sydney NSW 2006 Australia
| | - Talia L Fuchs
- Cancer Diagnosis and Pathology Group Kolling Institute of Medical Research, Royal North Shore Hospital St Leonards NSW 2065 Australia
- NSW Health Pathology, Department of Anatomical Pathology Royal North Shore Hospital Sydney NSW 2065 Australia
- Sydney Medical School University of Sydney Sydney NSW 2006 Australia
| | - Adele Clarkson
- Cancer Diagnosis and Pathology Group Kolling Institute of Medical Research, Royal North Shore Hospital St Leonards NSW 2065 Australia
- NSW Health Pathology, Department of Anatomical Pathology Royal North Shore Hospital Sydney NSW 2065 Australia
| | - Amy Sheen
- Cancer Diagnosis and Pathology Group Kolling Institute of Medical Research, Royal North Shore Hospital St Leonards NSW 2065 Australia
- NSW Health Pathology, Department of Anatomical Pathology Royal North Shore Hospital Sydney NSW 2065 Australia
| | - Loretta Sioson
- Cancer Diagnosis and Pathology Group Kolling Institute of Medical Research, Royal North Shore Hospital St Leonards NSW 2065 Australia
- NSW Health Pathology, Department of Anatomical Pathology Royal North Shore Hospital Sydney NSW 2065 Australia
| | - Angela Chou
- Cancer Diagnosis and Pathology Group Kolling Institute of Medical Research, Royal North Shore Hospital St Leonards NSW 2065 Australia
- NSW Health Pathology, Department of Anatomical Pathology Royal North Shore Hospital Sydney NSW 2065 Australia
- Sydney Medical School University of Sydney Sydney NSW 2006 Australia
| | - Anthony J Gill
- Cancer Diagnosis and Pathology Group Kolling Institute of Medical Research, Royal North Shore Hospital St Leonards NSW 2065 Australia
- NSW Health Pathology, Department of Anatomical Pathology Royal North Shore Hospital Sydney NSW 2065 Australia
- Sydney Medical School University of Sydney Sydney NSW 2006 Australia
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Jamali L, Sadeghi H, Ghasemi MR, Mohseni R, Nazemalhosseini-Mojarad E, Yassaee VR, Larki P, Zali MR, Mirfakhraie R. Autophagy ATG16L1 rs2241880 impacts the colorectal cancer risk: A case-control study. J Clin Lab Anal 2021; 36:e24169. [PMID: 34894411 PMCID: PMC8761398 DOI: 10.1002/jcla.24169] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 11/08/2021] [Accepted: 11/09/2021] [Indexed: 11/29/2022] Open
Abstract
Background Despite many efforts to discover the important role of the autophagy process in the pathogenesis of colorectal cancer (CRC), the exact involved molecular mechanism still remains to be elucidated. Recently, a limited number of studies have been employed to discover the impact of autophagy genes’ variants on the development and progression of CRC. Here, we evaluated the association between two single‐nucleotide polymorphisms (SNPs) in the main components of the autophagy genes, ATG16L1 rs2241880, and ATG5 rs1475270, and the CRC risk in an Iranian population. Methods During this investigation, a total of 369 subjects, including 179 CRC patients and 190 non‐cancer controls have been genotyped using Tetra‐primer amplification refractory mutation system‐polymerase chain reaction (TP‐ARMS‐PCR) method. Result The results demonstrated that the T allele of the ATG16L1 rs2241880 was significantly associated with the increased risk of CRC in the studied population (OR 1.64, 95% CI: 1.21–2.22, p = 0.0015). Moreover, ATG16L1 rs2241880 TT genotype increased the susceptibility to CRC (OR 3.31, 95% CI: 1.64–6.69, p = 0.0008). Furthermore, a significant association was observed under the recessive and dominant inheritance models (p = 0.0015 and p = 0.017, respectively). No statistically significant differences were found in the ATG5 rs1475270 alleles and genotypes between the cases and controls. Conclusion The results of the present study may be helpful concerning the risk stratification in CRC patients based on the genotyping approach of autophagy pathways and emphasize the need for further investigations among different populations and ethnicities to refine our conclusions.
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Affiliation(s)
- Leila Jamali
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hossein Sadeghi
- Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad-Reza Ghasemi
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Roohollah Mohseni
- Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Ehsan Nazemalhosseini-Mojarad
- Department of Gastrointestinal Cancer, Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vahid Reza Yassaee
- Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Pegah Larki
- Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Department of Gastrointestinal Cancer, Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Reza Mirfakhraie
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Valori M, Jansson L, Tienari PJ. CD8+ cell somatic mutations in multiple sclerosis patients and controls-Enrichment of mutations in STAT3 and other genes implicated in hematological malignancies. PLoS One 2021; 16:e0261002. [PMID: 34874980 PMCID: PMC8651110 DOI: 10.1371/journal.pone.0261002] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 11/23/2021] [Indexed: 01/14/2023] Open
Abstract
Somatic mutations have a central role in cancer but their role in other diseases such as common autoimmune disorders is not clear. Previously we and others have demonstrated that especially CD8+ T cells in blood can harbor persistent somatic mutations in some patients with multiple sclerosis (MS) and rheumatoid arthritis. Here we concentrated on CD8+ cells in more detail and tested (i) how commonly somatic mutations are detectable, (ii) does the overall mutation load differ between MS patients and controls, and (iii) do the somatic mutations accumulate non-randomly in certain genes? We separated peripheral blood CD8+ cells from newly diagnosed relapsing MS patients (n = 21) as well as matched controls (n = 21) and performed next-generation sequencing of the CD8+ cells' DNA, limiting our search to a custom panel of 2524 immunity and cancer related genes, which enabled us to obtain a median sequencing depth of over 2000x. We discovered nonsynonymous somatic mutations in all MS patients' and controls' CD8+ cell DNA samples, with no significant difference in number between the groups (p = 0.60), at a median allelic fraction of 0.5% (range 0.2-8.6%). The mutations showed statistically significant clustering especially to the STAT3 gene, and also enrichment to the SMARCA2, DNMT3A, SOCS1 and PPP3CA genes. Known activating STAT3 mutations were found both in MS patients and controls and overall 1/5 of the mutations were previously described cancer mutations. The detected clustering suggests a selection advantage of the mutated CD8+ clones and calls for further research on possible phenotypic effects.
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Affiliation(s)
- Miko Valori
- Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
- * E-mail:
| | - Lilja Jansson
- Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
- Department of Neurology, Neurocenter, Helsinki University Hospital, Helsinki, Finland
| | - Pentti J. Tienari
- Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
- Department of Neurology, Neurocenter, Helsinki University Hospital, Helsinki, Finland
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SMARCA4 Depletion Induces Cisplatin Resistance by Activating YAP1-Mediated Epithelial-to-Mesenchymal Transition in Triple-Negative Breast Cancer. Cancers (Basel) 2021; 13:cancers13215474. [PMID: 34771636 PMCID: PMC8582548 DOI: 10.3390/cancers13215474] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 10/26/2021] [Accepted: 10/27/2021] [Indexed: 01/02/2023] Open
Abstract
Simple Summary SMARCA4 mutations were over-representative in cisplatin resistance and metastatic triple-negative breast cancer (TNBC). Additionally, SMARCA4 inactivation induced the mesenchymal-like subtype TNBC. The epithelial-to-mesenchymal transition and Hippo-YAP/TAZ pathways were activated in SMARCA4 inactivation samples of both SMARCA4 knockout cell lines and TNBC patients. In SMARCA4 knockout cells, the YAP1 inhibitor verteporfin suppressed YAP1 target genes. This study depicts the clinical importance of SMARCA4 depletion in TNBC and suggests YAP/TAZ as a novel target for cisplatin-resistant patients. Abstract The role of SMARCA4, an ATPase subunit of the SWI/SNF chromatin remodeling complex, in genomic organization is well studied in various cancer types. However, its oncogenic role and therapeutic implications are relatively unknown in triple-negative breast cancer (TNBC). We investigated the clinical implication and downstream regulation induced by SMARCA4 inactivation using large-scale genome and transcriptome profiles. Additionally, SMARCA4 was knocked out in MDA-MB-468 and MDA-MB-231 using CRISPR/Cas9 to identify gene regulation and a targetable pathway. First, we observed an increase in SMARCA4 mutations in cisplatin resistance and metastasis in TNBC patients. Its inactivation was associated with the mesenchymal-like (MSL) subtype. Gene expression analysis showed that the epithelial-to-mesenchymal transition (EMT) pathway was activated in SMARCA4-deficient patients. Next, the Hippo pathway was activated in the SMARCA4 inactivation group, as evidenced by the higher CTNNB1, TGF-β, and YAP1 oncogene signature scores. In SMARCA4 knockout cells, EMT was upregulated, and the cell line transcriptome changed from the SL to the MSL subtype. SMARCA4 knockout cells showed cisplatin resistance and Hippo-YAP/TAZ target gene activation. The YAP1 inhibitor verteporfin suppressed the expression of YAP1 target genes, and decreased cell viability and invasiveness on SMARCA4 knockout cells. SMARCA4 inactivation in TNBC endowed the resistance to cisplatin via EMT activation. The YAP1 inhibitor could become a novel strategy for patients with SMARCA4-inactivated TNBC.
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Peng L, Li J, Wu J, Xu B, Wang Z, Giamas G, Stebbing J, Yu Z. A Pan-Cancer Analysis of SMARCA4 Alterations in Human Cancers. Front Immunol 2021; 12:762598. [PMID: 34675941 PMCID: PMC8524462 DOI: 10.3389/fimmu.2021.762598] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 09/13/2021] [Indexed: 01/04/2023] Open
Abstract
Background SMARCA4, the essential ATPase subunit of SWI/SNF chromatin remodeling complex, regulates transcription through the control of chromatin structure and is increasingly thought to play significant roles in human cancers. This study aims to explore the potential role of SMARCA4 with a view to providing insights on pathologic mechanisms implicated here. Methods The potential roles of SMARCA4 in different tumors were explored based on The Cancer Genome Atlas (TCGA), Genotype-tissue expression (GTEx), Tumor Immune Estimation Resource (TIMER), and Gene Set Enrichment Analysis (GSEA) datasets. The expression difference, mutation and phosphorylation status, survival, pathological stage, DNA methylation, tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), tumor microenvironment (TME), and immune cell infiltration related to SMARCA4 were analyzed. Results High expression levels of SMARCA4 were observed in most cancer types. SMARCA4 expression in tumor samples correlates with poor overall survival in several cancers. Lung adenocarcinoma cases with altered SMARCA4 showed a poorer prognosis. Enhanced phosphorylation levels of S613, S695, S699, and S1417 were observed in several tumors, including breast cancer. SMARCA4 correlated with tumor immunity and associated with different immune cells and genes in different cancer types. TMB, MSI, MMR, and DNA methylation correlated with SMARCA4 dysregulation in cancers. SMARCA4 expression was negatively associated with CD8+ T-cell infiltration in several tumors. Furthermore, the SWI/SNF superfamily-type complex and ATPase complex may be involved in the functional mechanisms of SMARCA4, albeit these data require further confirmation. Conclusions Our study offers a comprehensive understanding of the oncogenic roles of SMARCA4 across different tumors. SMARCA4 may correlate with tumor immunity.
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Affiliation(s)
- Ling Peng
- Department of Respiratory Disease, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Jisheng Li
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jie Wu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Bin Xu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhiqiang Wang
- Department of Urology, Shouguang Hospital of Traditional Chinese Medicine, Shouguang, China
| | - Georgios Giamas
- Department of Biochemistry and Biomedicine, School of Life Sciences, University of Sussex, Brighton, United Kingdom
| | - Justin Stebbing
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| | - Zhentao Yu
- Department of Thoracic Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
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47
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Bayona-Feliu A, Aguilera A. The SWI/SNF complex, transcription-replication conflicts and cancer: a connection with high therapeutic potential. Mol Cell Oncol 2021; 8:1976582. [PMID: 34616879 DOI: 10.1080/23723556.2021.1976582] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Genome instability is a hallmark of cancer. ATP-dependent chromatin remodelers are frequently altered in cancer. We have recently reported that the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex protects the genome by limiting R-loop-mediated genome instability, mainly that caused by transcription-replication conflicts. Here we discuss the significance and biomedical applications of this finding.
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Affiliation(s)
- Aleix Bayona-Feliu
- Centro Andaluz de Biología Molecular y Medicina Regenerativa CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de Olavide, Sevilla, Spain.,Departamento de Genética, Facultad de Biología, Universidad de Sevilla, Seville, Spain
| | - Andrés Aguilera
- Centro Andaluz de Biología Molecular y Medicina Regenerativa CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de Olavide, Sevilla, Spain.,Departamento de Genética, Facultad de Biología, Universidad de Sevilla, Seville, Spain
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48
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Benfatto S, Serçin Ö, Dejure FR, Abdollahi A, Zenke FT, Mardin BR. Uncovering cancer vulnerabilities by machine learning prediction of synthetic lethality. Mol Cancer 2021; 20:111. [PMID: 34454516 PMCID: PMC8401190 DOI: 10.1186/s12943-021-01405-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 08/10/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Synthetic lethality describes a genetic interaction between two perturbations, leading to cell death, whereas neither event alone has a significant effect on cell viability. This concept can be exploited to specifically target tumor cells. CRISPR viability screens have been widely employed to identify cancer vulnerabilities. However, an approach to systematically infer genetic interactions from viability screens is missing. METHODS Here we describe PAn-canceR Inferred Synthetic lethalities (PARIS), a machine learning approach to identify cancer vulnerabilities. PARIS predicts synthetic lethal (SL) interactions by combining CRISPR viability screens with genomics and transcriptomics data across hundreds of cancer cell lines profiled within the Cancer Dependency Map. RESULTS Using PARIS, we predicted 15 high confidence SL interactions within 549 DNA damage repair (DDR) genes. We show experimental validation of an SL interaction between the tumor suppressor CDKN2A, thymidine phosphorylase (TYMP) and the thymidylate synthase (TYMS), which may allow stratifying patients for treatment with TYMS inhibitors. Using genome-wide mapping of SL interactions for DDR genes, we unraveled a dependency between the aldehyde dehydrogenase ALDH2 and the BRCA-interacting protein BRIP1. Our results suggest BRIP1 as a potential therapeutic target in ~ 30% of all tumors, which express low levels of ALDH2. CONCLUSIONS PARIS is an unbiased, scalable and easy to adapt platform to identify SL interactions that should aid in improving cancer therapy with increased availability of cancer genomics data.
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Affiliation(s)
- Salvatore Benfatto
- BioMed X Institute (GmbH), Im Neuenheimer Feld 583, 69120, Heidelberg, Germany
| | - Özdemirhan Serçin
- BioMed X Institute (GmbH), Im Neuenheimer Feld 583, 69120, Heidelberg, Germany
| | - Francesca R Dejure
- BioMed X Institute (GmbH), Im Neuenheimer Feld 583, 69120, Heidelberg, Germany
| | - Amir Abdollahi
- Division of Molecular and Translational Radiation Oncology, National Centre for Tumour Diseases (NCT), Heidelberg University Hospital, 69120, Heidelberg, Germany
| | - Frank T Zenke
- Translational Innovation Platform Oncology & Immuno-Oncology, Merck KGaA, Frankfurter Str. 250, 64293, Darmstadt, Germany
| | - Balca R Mardin
- BioMed X Institute (GmbH), Im Neuenheimer Feld 583, 69120, Heidelberg, Germany.
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49
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Yoshikawa T, Fukuda A, Omatsu M, Namikawa M, Sono M, Fukunaga Y, Masuda T, Araki O, Nagao M, Ogawa S, Masuo K, Goto N, Hiramatsu Y, Muta Y, Tsuda M, Maruno T, Nakanishi Y, Kawada K, Takaishi S, Seno H. Brg1 is required to maintain colorectal cancer stem cells. J Pathol 2021; 255:257-269. [PMID: 34415580 DOI: 10.1002/path.5759] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 06/08/2021] [Accepted: 07/13/2021] [Indexed: 01/09/2023]
Abstract
Tumor cells capable of self-renewal and continuous production of progeny cells are called tumor stem cells (TSCs) and are considered to be potential therapeutic targets. However, the mechanisms underlying the survival and function of TSCs are not fully understood. We previously reported that chromatin remodeling regulator Brg1 is essential for intestinal stem cells in mice and Dclk1 is an intestinal TSC marker. In this study, we investigated the role of Brg1 in Dclk1+ intestinal tumor cells for the maintenance of intestinal tumors in mice. Specific ablation of Brg1 in Dclk1+ intestinal tumor cells reduced intestinal tumors in ApcMin mice, and continuous ablation of Brg1 maintained the reduction of intestinal tumors. Lineage tracing in the context of Brg1 ablation in Dclk1+ intestinal tumor cells revealed that Brg1-null Dclk1+ intestinal tumor cells did not give rise to their descendent tumor cells, indicating that Brg1 is essential for the self-renewal of Dclk1+ intestinal tumor cells. Five days after Brg1 ablation, we observed increased apoptosis in Dclk1+ tumor cells. Furthermore, Brg1 was crucial for the stemness of intestinal tumor cells in a spheroid culture system. BRG1 knockdown also impaired cell proliferation and increased apoptosis in human colorectal cancer (CRC) cells. Microarray analysis revealed that apoptosis-related genes were upregulated and stem cell-related genes were downregulated in human CRC cells by BRG1 suppression. Consistently, high BRG1 expression correlated with poor disease-specific survival in human CRC patients. These data indicate that Brg1 plays a crucial role in intestinal TSCs in mice by inhibiting apoptosis and is critical for cell survival and stem cell features in human CRC cells. Thus, BRG1 represents a new therapeutic target for human CRC. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Takaaki Yoshikawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Akihisa Fukuda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Mayuki Omatsu
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Mio Namikawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Makoto Sono
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yuichi Fukunaga
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.,Department of Drug Discovery Medicine, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tomonori Masuda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Osamu Araki
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Munemasa Nagao
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Satoshi Ogawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Kenji Masuo
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.,Laboratory for Malignancy Control Research (DSK Project), Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Norihiro Goto
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yukiko Hiramatsu
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yu Muta
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Motoyuki Tsuda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Takahisa Maruno
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yuki Nakanishi
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Kenji Kawada
- Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Shigeo Takaishi
- Laboratory for Malignancy Control Research (DSK Project), Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
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50
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Glückstein MI, Dintner S, Arndt TT, Vlasenko D, Schenkirsch G, Agaimy A, Müller G, Märkl B, Grosser B. Comprehensive Immunohistochemical Study of the SWI/SNF Complex Expression Status in Gastric Cancer Reveals an Adverse Prognosis of SWI/SNF Deficiency in Genomically Stable Gastric Carcinomas. Cancers (Basel) 2021; 13:3894. [PMID: 34359794 PMCID: PMC8345509 DOI: 10.3390/cancers13153894] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 07/30/2021] [Indexed: 12/24/2022] Open
Abstract
The SWI/SNF complex has important functions in the mobilization of nucleosomes and consequently influences gene expression. Numerous studies have demonstrated that mutations or deficiency of one or more subunits can have an oncogenic effect and influence the development, progression, and eventual therapy resistance of tumor diseases. Genes encoding subunits of the SWI/SNF complex are mutated in approximately 20% of all human tumors. This study aimed to investigate the frequency, association with clinicopathological characteristics, and prognosis of immunohistochemical expression of proteins of the SWI/SNF complexes, SMARCA2, SMARCA4 SMARCB1, ARID1A, ARID1B, and PBRM1 in 477 adenocarcinomas of the stomach and gastroesophageal junction. Additionally, the tumors were classified immunohistochemically in analogy to The Cancer Genome Atlas (TCGA) classification. Overall, 32% of cases demonstrated aberrant expression of the SWI/SNF complex. Complete loss of SMARCA4 was detected in three cases (0.6%) and was associated with adverse clinical characteristics. SWI/SNF aberration emerged as an independent negative prognostic factor for overall survival in genomically stable patients in analogy to TCGA. In conclusion, determination of SWI/SNF status could be suggested in routine diagnostics in genomically stable tumors to identify patients who might benefit from new therapeutic options.
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Affiliation(s)
- Marie-Isabelle Glückstein
- Institute of General Pathology and Molecular Diagnostics, University Hospital Augsburg, 86156 Augsburg, Germany; (M.-I.G.); (S.D.); (T.T.A.); (B.M.)
| | - Sebastian Dintner
- Institute of General Pathology and Molecular Diagnostics, University Hospital Augsburg, 86156 Augsburg, Germany; (M.-I.G.); (S.D.); (T.T.A.); (B.M.)
| | - Tim Tobias Arndt
- Institute of General Pathology and Molecular Diagnostics, University Hospital Augsburg, 86156 Augsburg, Germany; (M.-I.G.); (S.D.); (T.T.A.); (B.M.)
- Institute of Mathematics and Computational Statistics, University of Augsburg, 86159 Augsburg, Germany;
| | - Dmytro Vlasenko
- Department of General, Visceral and Transplantation Surgery, University Hospital Augsburg, 86156 Augsburg, Germany;
| | - Gerhard Schenkirsch
- Tumor Data Management, University Hospital Augsburg, 86156 Augsburg, Germany;
| | - Abbas Agaimy
- Institute of Pathology, Friedrich-Alexander-University Erlangen-Nürnberg, University Hospital Erlangen, 91054 Erlangen, Germany;
| | - Gernot Müller
- Institute of Mathematics and Computational Statistics, University of Augsburg, 86159 Augsburg, Germany;
| | - Bruno Märkl
- Institute of General Pathology and Molecular Diagnostics, University Hospital Augsburg, 86156 Augsburg, Germany; (M.-I.G.); (S.D.); (T.T.A.); (B.M.)
| | - Bianca Grosser
- Institute of General Pathology and Molecular Diagnostics, University Hospital Augsburg, 86156 Augsburg, Germany; (M.-I.G.); (S.D.); (T.T.A.); (B.M.)
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