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

Lee Shaashua, Aviad Ben-Shmuel, Meirav Pevsner-Fischer, 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. Iacobuzio-Donahue, Nikolaus Schultz, David A. Tuveson, David Lyden, David Kelsen and Ruth Scherz-Shouval ()
Additional contact information
Lee Shaashua: The Weizmann Institute of Science
Aviad Ben-Shmuel: The Weizmann Institute of Science
Meirav Pevsner-Fischer: The Weizmann Institute of Science
Gil Friedman: The Weizmann Institute of Science
Oshrat Levi-Galibov: The Weizmann Institute of Science
Subhiksha Nandakumar: Memorial Sloan Kettering Cancer Center
Debra Barki: The Weizmann Institute of Science
Reinat Nevo: The Weizmann Institute of Science
Lauren E. Brown: Boston University
Wenhan Zhang: Boston University
Yaniv Stein: The Weizmann Institute of Science
Chen Lior: The Weizmann Institute of Science
Han Sang Kim: Weill Cornell Medicine
Linda Bojmar: Weill Cornell Medicine
William R. Jarnagin: Memorial Sloan Kettering Cancer Center
Nicolas Lecomte: Memorial Sloan Kettering Cancer Center
Shimrit Mayer: The Weizmann Institute of Science
Roni Stok: The Weizmann Institute of Science
Hend Bishara: The Weizmann Institute of Science
Rawand Hamodi: The Weizmann Institute of Science
Ephrat Levy-Lahad: The Fuld Family Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Faculty of Medicine, The Hebrew University of Jerusalem
Talia Golan: Sheba Medical Center at Tel-Hashomer, Tel Aviv University
John A. Porco: Boston University
Christine A. Iacobuzio-Donahue: Memorial Sloan Kettering Cancer Center
Nikolaus Schultz: Memorial Sloan Kettering Cancer Center
David A. Tuveson: Cold Spring Harbor
David Lyden: Weill Cornell Medicine
David Kelsen: Weill Cornell Medical College
Ruth Scherz-Shouval: The Weizmann Institute of Science

Nature Communications, 2022, vol. 13, issue 1, 1-21

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-34081-3

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