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.

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

Migliore C.;
2021

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.
81
7
1639
1653
Animals; 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
Grunberg 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 S.M.; Brenner B.; Dlugosz A.A.; Lyden D.; Regev-Rudzki N.; Ben-Aharon I.; Scherz-Shouval R.
File in questo prodotto:
File Dimensione Formato  
CAN-20-2756_proof.pdf

Accesso riservato

Tipo di file: POSTPRINT (VERSIONE FINALE DELL’AUTORE)
Dimensione 2.05 MB
Formato Adobe PDF
2.05 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1797873
Citazioni
  • ???jsp.display-item.citation.pmc??? 16
  • Scopus 25
  • ???jsp.display-item.citation.isi??? 23
social impact