BRCA mutational status shapes the stromal microenvironment of pancreatic cancer linking clusterin expression in cancer associated fibroblasts with HSF1 signaling

• DOI: 10.1038/s41467-022-34081-3
• Publication Date: 2022-10-31T14:03:07Z
• Authors: Lee Shaashua; Aviad Ben-Shmuel; Meirav Pevsner-Fi...; Gil Friedman; Oshrat Levi-Galibov; Subhiksha Nandakumar; Debra Barki; Reinat Nevo; Lauren E. Brown; Wenhan Zhang; Yaniv Stein; Chen Lior; Han Sang Kim; Linda Bojmar; William R. Jarnagin; Nicolas Lecomte; Shimrit Mayer; Roni Stok; Hend Bishara; Rawand Hamodi; Ephrat Levy-Lahad; Talia Golan; John A. Porco; Christine A. Iaco...; Nikolaus Schultz; David A. Tuveson; David Lyden; David Kelsen; Ruth Scherz-Shouval
• Keywords: 570; Pancreatic neoplasms; Science; 610; Article; Mice; 03 medical and health sciences; Cancer-Associated Fibroblasts; Heat Shock Transcription Factors; Pancreatic Neoplasms* / pathology; Tumor Microenvironment; Animals; Humans; Cancer-associated fibroblasts; pancreatic ductal; Clusterin* / genetics; Cancer-Associated Fibroblasts* / metabolism; Cancer och onkologi; 0303 health sciences; Carcinoma; Q; Pancreatic Ductal* / pathology; 3. Good health; Pancreatic Neoplasms; Clusterin* / metabolism; Clusterin; Tumor microenvironment; Heat Shock Transcription Factors* / genetics; Cancer and Oncology; Heat shock transcription factors; Heat Shock Transcription Factors* / metabolism; Tumor Microenvironment / genetics; Carcinoma, Pancreatic Ductal

AbstractTumors initiate by mutations in cancer cells, and progress through interactions of the cancer cells with non-malignant cells of the tumor microenvironment. Major players in the tumor microenvironment are cancer-associated fibroblasts (CAFs), which support tumor malignancy, and comprise up to 90% of the tumor mass in pancreatic cancer. CAFs are transcriptionally rewired by cancer cells. Whether this rewiring is differentially affected by different mutations in cancer cells is largely unknown. Here we address this question by dissecting the stromal landscape of BRCA-mutated and BRCA Wild-type pancreatic ductal adenocarcinoma. We comprehensively analyze pancreatic cancer samples from 42 patients, revealing different CAF subtype compositions in germline BRCA-mutated vs. BRCA Wild-type tumors. In particular, we detect an increase in a subset of immune-regulatory clusterin-positive CAFs in BRCA-mutated tumors. Using cancer organoids and mouse models we show that this process is mediated through activation of heat-shock factor 1, the transcriptional regulator of clusterin. Our findings unravel a dimension of stromal heterogeneity influenced by germline mutations in cancer cells, with direct implications for clinical research.