BRCA mutational status shapes the stromal microenvironment of pancreatic cancer linking CLU + CAF expression with HSF1 signaling
BRCA mutational status shapes the stromal microenvironment of pancreatic cancer linking CLU + CAF expression with HSF1 signaling
Abstract Cancer-associated fibroblasts (CAFs) give rise to desmoplastic stroma, which supports tumor progression and metastasis, and comprises up to 90% of the tumor mass in pancreatic cancer. Recent work by us and others has shown that CAFs are transcriptionally rewired by adjacent cancer cells to form heterogeneous subtypes. Whether this rewiring is differentially affected by different driver mutations in cancer cells is largely unknown. Here we address this question by dissecting and comparing the stromal landscape of BRCA-mutated and BRCA Wild-type (WT) pancreatic ductal adenocarcinoma (PDAC). We comprehensively analyze PDAC samples from a cohort of 42 patients by laser-capture microdissection, RNA-sequencing and multiplexed immunofluorescence, revealing different CAF subtype compositions in germline BRCA-mutated vs. BRCA-WT tumors. In particular, we detect an increase in a subset of Clusterin (CLU)-positive CAFs in BRCA-mutated tumors. We further unravel a network of stress responses upregulated in BRCA-mutated tumors. Using cancer organoids and cell co-cultures, we show that the transcriptional shift of pancreatic stellate cells into CLU+ CAFs is mediated through activation of heat-shock factor 1 (HSF1), the transcriptional regulator of Clu. Our findings unravel a new dimension of stromal heterogeneity, influenced by germline mutations in cancer cells, with direct translational implications for clinical research. SignificanceBRCA1/2 mutations initiate some of the deadliest cancers, yet the fibroblastic microenvironment of BRCA-mutated cancers remains uncharted. Our work addresses a major unsolved question – to what extent is the tumor microenvironment determined by cancer mutations? We find that BRCA mutations in the cancer cells affect the composition of CAFs in PDAC. These findings have direct implications for diagnosis and for efforts to exploit CAFs for therapy.
Nevo Reinat、Levy-Lahad Ephrat、Iacobuzio-Donahue Christine A.、Shaashua Lee、Friedman Gil、Kim Han Sang、Bojmar Linda、Hamodi Rawand、Porco John A. Jr.、Schultz Nikolaus、Scherz-Shouval Ruth、Nandakumar Subhiksha、Levi-Galibov Oshrat、Zhang Wenhan、Lecomte Nicolas、Kelsen David、Tuveson David A.、Brown Lauren E.、Lyden David、Pevsner-Fischer Meirav、Bishara Hend、Jarnagin William R.、Stein Yaniv、Stok Roni、Golan Talia
Department of Biomolecular Sciences, The Weizmann Institute of ScienceThe Fuld Family Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Faculty of Medicine, The Hebrew University of JerusalemDavid M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer CenterDepartment of Biomolecular Sciences, The Weizmann Institute of ScienceDepartment of Biomolecular Sciences, The Weizmann Institute of ScienceChildren?ˉs Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children?ˉs Health, Meyer Cancer Center, Weill Cornell Medicine||Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Brain Korea 21 Plus Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of MedicineChildren?ˉs Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children?ˉs Health, Meyer Cancer Center, Weill Cornell Medicine||Department of Clinical and Experimental Medicine, Link?ping UniversityDepartment of Biomolecular Sciences, The Weizmann Institute of ScienceDepartment of Chemistry and Center for Molecular Discovery (BU-CMD), Boston UniversityHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer CenterDepartment of Biomolecular Sciences, The Weizmann Institute of ScienceHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer CenterDepartment of Biomolecular Sciences, The Weizmann Institute of ScienceDepartment of Chemistry and Center for Molecular Discovery (BU-CMD), Boston UniversityDavid M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer CenterGastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, and Weil Cornell Medical CollegeCancer Center, Cold Spring Harbor Laboratory, Cold Spring HarborDepartment of Chemistry and Center for Molecular Discovery (BU-CMD), Boston UniversityChildren?ˉs Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children?ˉs Health, Meyer Cancer Center, Weill Cornell MedicineDepartment of Biomolecular Sciences, The Weizmann Institute of ScienceDepartment of Biomolecular Sciences, The Weizmann Institute of ScienceHepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer CenterDepartment of Biomolecular Sciences, The Weizmann Institute of ScienceDepartment of Biomolecular Sciences, The Weizmann Institute of ScienceOncology Institute, Sheba Medical Center at Tel-Hashomer, Tel Aviv University
肿瘤学基础医学生物科学研究方法、生物科学研究技术
Nevo Reinat,Levy-Lahad Ephrat,Iacobuzio-Donahue Christine A.,Shaashua Lee,Friedman Gil,Kim Han Sang,Bojmar Linda,Hamodi Rawand,Porco John A. Jr.,Schultz Nikolaus,Scherz-Shouval Ruth,Nandakumar Subhiksha,Levi-Galibov Oshrat,Zhang Wenhan,Lecomte Nicolas,Kelsen David,Tuveson David A.,Brown Lauren E.,Lyden David,Pevsner-Fischer Meirav,Bishara Hend,Jarnagin William R.,Stein Yaniv,Stok Roni,Golan Talia.BRCA mutational status shapes the stromal microenvironment of pancreatic cancer linking CLU + CAF expression with HSF1 signaling[EB/OL].(2025-03-28)[2025-06-10].https://www.biorxiv.org/content/10.1101/2021.08.18.456576.点此复制
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