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

   

Authors:	Shaashua, L.; Ben-Shmuel, A.; Pevsner-Fischer, M.; Friedman, G.; Levi-Galibov, O.; Nandakumar, S.; Barki, D.; Nevo, R.; Brown, L. E.; Zhang, W.; Stein, Y.; Lior, C.; Kim, H. S.; Bojmar, L.; Jarnagin, W. R.; Lecomte, N.; Mayer, S.; Stok, R.; Bishara, H.; Hamodi, R.; Levy-Lahad, E.; Golan, T.; Porco, J. A. Jr; Iacobuzio-Donahue, C. A.; Schultz, N.; Tuveson, D. A.; Lyden, D.; Kelsen, D.; Scherz-Shouval, R.
Article Title:	BRCA mutational status shapes the stromal microenvironment of pancreatic cancer linking clusterin expression in cancer associated fibroblasts with HSF1 signaling
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. © 2022, The Author(s).
Keywords:	genetics; mutation; pancreatic neoplasms; mouse; animal; metabolism; animals; mice; carcinoma, pancreatic ductal; pathology; pancreas carcinoma; pancreas tumor; tumor; clusterin; cell; heterogeneity; landscape; tumor microenvironment; cancer associated fibroblast; cancer; cancer-associated fibroblasts; heat shock transcription factor; hsf1 protein, mouse; heat shock transcription factors
Journal Title:	Nature Communications
Volume:	13
ISSN:	2041-1723
Publisher:	Nature Publishing Group
Date Published:	2022-10-31
Start Page:	6513
Language:	English
DOI:	10.1038/s41467-022-34081-3
PUBMED:	36316305
PROVIDER:	scopus
PMCID:	PMC9622893
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85140936064&doi=10.1038%2fs41467-022-34081-3&partnerID=40&md5=4365c69641fdcea647b3d488654c830b
Notes:	Article -- Export Date: 1 December 2022 -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/200513