TY - JOUR
T1 - Cancer-associated fibroblasts promote aggressive gastric cancer phenotypes via heat shock factor 1-mediated secretion of extracellular vesicles
AU - Grunberg, Nil
AU - Pevsner-Fischer, Meirav
AU - Goshen-Lago, Tal
AU - Diment, Judith
AU - Stein, Yaniv
AU - Lavon, Hagar
AU - Mayer, Shimrit
AU - Levi-Galibov, Oshrat
AU - Friedman, Gil
AU - Ofir-Birin, Yifat
AU - Syu, Li Jyun
AU - Migliore, Cristina
AU - Shimoni, Eyal
AU - Stemmer, Salomon M.
AU - Brenner, Baruch
AU - Dlugosz, Andrzej A.
AU - Lyden, David
AU - Regev-Rudzki, Neta
AU - Ben-Aharon, Irit
AU - Scherz-Shouval, Ruth
N1 - Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/4
Y1 - 2021/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85104832895&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-20-2756
DO - 10.1158/0008-5472.CAN-20-2756
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C2 - 33547159
AN - SCOPUS:85104832895
SN - 0008-5472
VL - 81
SP - 1639
EP - 1653
JO - Cancer Research
JF - Cancer Research
IS - 7
ER -
