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

Shaashua, Lee, Ben-Shmuel, Aviad, Pevsner-Fischer, Meirav, Friedman, Gil, Levi-Galibov, Oshrat, Nandakumar, Subhiksha, Barki, Debra, Nevo, Reinat, Brown, Lauren E, Zhang, Wenhan, Stein, Yaniv, Lior, Chen, Kim, Han Sang, Bojmar, Linda, Jarnagin, William R, Lecomte, Nicolas, Mayer, Shimrit, Stok, Roni, Bishara, Hend, Hamodi, Rawand, Levy-Lahad, Ephrat, Golan, Talia, Porco, John A, Iacobuzio-Donahue, Christine A, Schultz, Nikolaus, Tuveson, David A, Lyden, David, Kelsen, David, Scherz-Shouval, Ruth (October 2022) BRCA mutational status shapes the stromal microenvironment of pancreatic cancer linking clusterin expression in cancer associated fibroblasts with HSF1 signaling. Nature Communications, 13 (1). p. 6513. ISSN 2041-1723

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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.

Item Type:	Paper
Subjects:	bioinformatics diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics diseases & disorders > neoplasms bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification organism description > animal organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions organs, tissues, organelles, cell types and functions > cell types and functions > cell types > fibroblasts organs, tissues, organelles, cell types and functions > cell types and functions > cell types > fibroblasts organs, tissues, organelles, cell types and functions > cell types and functions > cell types > fibroblasts organism description > animal > mammal organism description > animal > mammal > rodent > mouse bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mutations organs, tissues, organelles, cell types and functions diseases & disorders > cancer > cancer types > pancreatic cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types organism description > animal > mammal > rodent bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor diseases & disorders > cancer > cancer types
CSHL Authors:	Tuveson, David A.
Communities:	CSHL labs > Tuveson lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	31 October 2022
Date Deposited:	09 Nov 2022 15:19
Last Modified:	17 Jan 2024 15:02
PMCID:	PMC9622893
URI:	https://repository.cshl.edu/id/eprint/40752

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