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  • Shaashua, LeeWeizmann Inst Sci, Israel (author)

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

  • Article/chapterEnglish2022

Publisher, publication year, extent ...

  • 2022-10-31
  • Nature Portfolio,2022
  • electronicrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:liu-190123
  • https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-190123URI
  • https://doi.org/10.1038/s41467-022-34081-3DOI

Supplementary language notes

  • Language:English
  • Summary in:English

Part of subdatabase

Classification

  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • 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
  • 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.

Subject headings and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • Ben-Shmuel, AviadWeizmann Inst Sci, Israel (author)
  • Pevsner-Fischer, MeiravWeizmann Inst Sci, Israel (author)
  • Friedman, GilWeizmann Inst Sci, Israel (author)
  • Levi-Galibov, OshratWeizmann Inst Sci, Israel (author)
  • Nandakumar, SubhikshaMem Sloan Kettering Canc Ctr, NY 10021 USA (author)
  • Barki, DebraWeizmann Inst Sci, Israel (author)
  • Nevo, ReinatWeizmann Inst Sci, Israel (author)
  • Brown, Lauren E.Boston Univ, MA 02215 USA; Boston Univ, MA 02215 USA (author)
  • Zhang, WenhanBoston Univ, MA 02215 USA; Boston Univ, MA 02215 USA (author)
  • Stein, YanivWeizmann Inst Sci, Israel (author)
  • Lior, ChenWeizmann Inst Sci, Israel (author)
  • Kim, Han SangWeill Cornell Med, NY USA; Weill Cornell Med, NY USA; Yonsei Univ, South Korea (author)
  • Bojmar, LindaLinköpings universitet,Avdelningen för kirurgi, ortopedi och onkologi,Medicinska fakulteten,Weill Cornell Med, NY USA; Weill Cornell Med, NY USA(Swepub:liu)linbo68 (author)
  • Jarnagin, William R.Mem Sloan Kettering Canc Ctr, NY 10021 USA (author)
  • Lecomte, NicolasMem Sloan Kettering Canc Ctr, NY 10021 USA (author)
  • Mayer, ShimritWeizmann Inst Sci, Israel (author)
  • Stok, RoniWeizmann Inst Sci, Israel (author)
  • Bishara, HendWeizmann Inst Sci, Israel (author)
  • Hamodi, RawandWeizmann Inst Sci, Israel (author)
  • Levy-Lahad, EphratHebrew Univ Jerusalem, Israel (author)
  • Golan, TaliaTel Aviv Univ, Israel (author)
  • Porco, John A. Jr.Boston Univ, MA 02215 USA; Boston Univ, MA 02215 USA (author)
  • Iacobuzio-Donahue, Christine A.Mem Sloan Kettering Canc Ctr, NY 10021 USA (author)
  • Schultz, NikolausMem Sloan Kettering Canc Ctr, NY 10021 USA (author)
  • Tuveson, David A.Cold Spring Harbor Lab, NY USA (author)
  • Lyden, DavidWeill Cornell Med, NY USA; Weill Cornell Med, NY USA (author)
  • Kelsen, DavidWeill Cornell Med Coll, NY USA (author)
  • Scherz-Shouval, RuthWeizmann Inst Sci, Israel (author)
  • Weizmann Inst Sci, IsraelMem Sloan Kettering Canc Ctr, NY 10021 USA (creator_code:org_t)

Related titles

  • In:Nature Communications: Nature Portfolio13:12041-1723

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