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

Tumors 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. Cancer-associated fibroblasts are transcriptionally rewired by signals from the cancer cells, resulting in heterogeneous populations. Here the authors show that loss of BRCA function in pancreatic cancer cells leads to HSF1-dependent accumulation of immune-regulatory clusterin-positive cancer associated fibroblasts. Funding Agencies|Thompson Family Foundation; ISF [395/21]; ERC [754320]; Laura Gurwin Flug Family Fund; Peter Award; Comisaroff Family Trust; Estate of Annice Anzelewitz; Estate of Mordecai M. Roshwal; Rising Tide Foundation; MSK [P30 CA008748]; NIH [R35GM118173, U01TR002625]; Patricia Gruber Award