Cancer-Associated Fibroblasts Promote Aggressive Gastric Cancer Phenotypes via Heat Shock Factor 1-Mediated Secretion of Extracellular Vesicles.
Animals
Cancer-Associated Fibroblasts
/ pathology
Cells, Cultured
Cohort Studies
Disease Progression
Extracellular Vesicles
/ metabolism
Heat Shock Transcription Factors
/ genetics
Humans
Mice
Mice, 129 Strain
Mice, Inbred BALB C
Mice, Transgenic
Neoplasm Invasiveness
Phenotype
Prognosis
Secretory Pathway
/ physiology
Stomach Neoplasms
/ diagnosis
Survival Analysis
Tumor Microenvironment
/ physiology
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
01 04 2021
01 04 2021
Historique:
received:
19
08
2020
revised:
22
12
2020
accepted:
01
02
2021
pubmed:
7
2
2021
medline:
12
8
2021
entrez:
6
2
2021
Statut:
ppublish
Résumé
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: http://cancerres.aacrjournals.org/content/canres/81/7/1639/F1.large.jpg.
Identifiants
pubmed: 33547159
pii: 0008-5472.CAN-20-2756
doi: 10.1158/0008-5472.CAN-20-2756
pmc: PMC8337092
mid: NIHMS1672347
doi:
Substances chimiques
HSF1 protein, human
0
Heat Shock Transcription Factors
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1639-1653Subventions
Organisme : NIDDK NIH HHS
ID : P01 DK062041
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA046592
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA118875
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK034933
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA087837
Pays : United States
Informations de copyright
©2021 American Association for Cancer Research.
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