STAT3 induces breast cancer growth via ANGPTL4, MMP13 and STC1 secretion by cancer associated fibroblasts.
Angiopoietin-Like Protein 4
/ genetics
Animals
Breast Neoplasms
/ pathology
Cancer-Associated Fibroblasts
/ metabolism
Cell Line, Tumor
Female
Fibroblasts
/ metabolism
Glycoproteins
Humans
Interleukin-6
/ genetics
Matrix Metalloproteinase 13
/ genetics
Mice
STAT3 Transcription Factor
/ genetics
Signal Transduction
/ physiology
Tumor Microenvironment
/ genetics
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
03 2022
03 2022
Historique:
received:
31
01
2021
accepted:
30
12
2021
revised:
07
12
2021
pubmed:
20
1
2022
medline:
19
4
2022
entrez:
19
1
2022
Statut:
ppublish
Résumé
In the tumor microenvironment, Cancer Associated Fibroblasts (CAFs) become activated by cancer cells and increase their secretory activity to produce soluble factors that contribute to tumor cells proliferation, invasion and dissemination to distant organs. The pro-tumorigenic transcription factor STAT3 and its canonical inducer, the pro-inflammatory cytokine IL-6, act conjunctly in a positive feedback loop that maintains high levels of IL-6 secretion and STAT3 activation in both tumor and stromal cells. Here, we demonstrate that STAT3 is essential for the pro-tumorigenic functions of murine breast cancer CAFs both in vitro and in vivo, and identify a STAT3 signature significantly enriched for genes encoding for secreted proteins. Among these, ANGPTL4, MMP13 and STC-1 were functionally validated as STAT3-dependent mediators of CAF pro-tumorigenic functions by different approaches. Both in vitro and in vivo CAFs activities were moreover impaired by MMP13 inhibition, supporting the feasibility of a therapeutic approach based on inhibiting STAT3-induced CAF-secreted proteins. The clinical potential of such an approach is supported by the observation that an equivalent CAF-STAT3 signature in humans is expressed at high levels in breast cancer stromal cells and characterizes patients with a shorter disease specific survival, including those with basal-like disease.
Identifiants
pubmed: 35042959
doi: 10.1038/s41388-021-02172-y
pii: 10.1038/s41388-021-02172-y
doi:
Substances chimiques
Angiopoietin-Like Protein 4
0
Angptl4 protein, mouse
0
Glycoproteins
0
Interleukin-6
0
STAT3 Transcription Factor
0
STAT3 protein, human
0
teleocalcin
76687-96-2
Matrix Metalloproteinase 13
EC 3.4.24.-
Mmp13 protein, mouse
EC 3.4.24.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1456-1467Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.
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