Cancer-Associated Fibroblasts Promote Aggressive Gastric Cancer Phenotypes via Heat Shock Factor 1-Mediated Secretion of Extracellular Vesicles.

TitleCancer-Associated Fibroblasts Promote Aggressive Gastric Cancer Phenotypes via Heat Shock Factor 1-Mediated Secretion of Extracellular Vesicles.
Publication TypeJournal Article
Year of Publication2021
AuthorsGrunberg N, Pevsner-Fischer M, Goshen-Lago T, Diment J, Stein Y, Lavon H, Mayer S, Levi-Galibov O, Friedman G, Ofir-Birin Y, Syu L-J, Migliore C, Shimoni E, Stemmer SM, Brenner B, Dlugosz AA, Lyden D, Regev-Rudzki N, Ben-Aharon I, Scherz-Shouval R
JournalCancer Res
Date Published2021 04 01
KeywordsAnimals, Cancer-Associated Fibroblasts, Cells, Cultured, Cohort Studies, Disease Progression, Extracellular Vesicles, Heat Shock Transcription Factors, Humans, Mice, Mice, 129 Strain, Mice, Inbred BALB C, Mice, Transgenic, Neoplasm Invasiveness, Phenotype, Prognosis, Secretory Pathway, Stomach Neoplasms, Survival Analysis, Tumor Microenvironment

Gastric cancer is the third most lethal cancer worldwide, and evaluation of the genomic status of gastric cancer cells has not translated into effective prognostic or therapeutic strategies. We therefore hypothesize that outcomes may depend on the tumor microenvironment (TME), in particular, cancer-associated fibroblasts (CAF). However, very little is known about the role of CAFs in gastric cancer. To address this, we mapped the transcriptional landscape of human gastric cancer stroma by microdissection and RNA sequencing of CAFs from patients with gastric cancer. A stromal gene signature was associated with poor disease outcome, and the transcription factor heat shock factor 1 (HSF1) regulated the signature. HSF1 upregulated inhibin subunit beta A and thrombospondin 2, which were secreted in CAF-derived extracellular vesicles to the TME to promote cancer. Together, our work provides the first transcriptional map of human gastric cancer stroma and highlights HSF1 and its transcriptional targets as potential diagnostic and therapeutic targets in the genomically stable tumor microenvironment. SIGNIFICANCE: This study shows how HSF1 regulates a stromal transcriptional program associated with aggressive gastric cancer and identifies multiple proteins within this program as candidates for therapeutic intervention. GRAPHICAL ABSTRACT:

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Alternate JournalCancer Res
PubMed ID33547159
PubMed Central IDPMC8337092
Grant ListP01 DK062041 / DK / NIDDK NIH HHS / United States
P30 CA046592 / CA / NCI NIH HHS / United States
R01 CA087837 / CA / NCI NIH HHS / United States
R01 CA118875 / CA / NCI NIH HHS / United States

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