Cancer-associated fibroblasts promote aggressive gastric cancer phenotypes via heat shock factor 1-mediated secretion of extracellular vesicles

Nil Grunberg, Meirav Pevsner-Fischer, Tal Goshen-Lago, Judith Diment, Yaniv Stein, Hagar Lavon, Shimrit Mayer, Oshrat Levi-Galibov, Gil Friedman, Yifat Ofir-Birin, Li Jyun Syu, Cristina Migliore, Eyal Shimoni, Salomon M. Stemmer, Baruch Brenner, Andrzej A. Dlugosz, David Lyden, Neta Regev-Rudzki, Irit Ben-Aharon, Ruth Scherz-Shouval

Research output: Contribution to journalArticlepeer-review

Abstract

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, cancerassociated 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.

Original languageEnglish
Pages (from-to)1639-1653
Number of pages15
JournalCancer Research
Volume81
Issue number7
DOIs
StatePublished - Apr 2021

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