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Adrenergic-mediated increases in INHBA drive CAF phenotype and collagens
Journal article   Open access   Peer reviewed

Adrenergic-mediated increases in INHBA drive CAF phenotype and collagens

Archana S Nagaraja, Robert L Dood, Guillermo Armaiz-Pena, Sherry Y Wu, Yu Kang, Julie K Allen, Nicholas B Jennings, Lingegowda S Mangala, Sunila Pradeep, Yasmin Lyons, …
JCI insight, Vol.2(16), e93076
08/17/2017
DOI: 10.1172/jci.insight.93076
PMCID: PMC5621917
PMID: 28814667
url
https://doi.org/10.1172/jci.insight.93076View
Published (Version of record) Open Access

Abstract

Adrenergic signaling is known to promote tumor growth and metastasis, but the effects on tumor stroma are not well understood. An unbiased bioinformatics approach analyzing tumor samples from patients with known biobehavioral profiles identified a prominent stromal signature associated with cancer-associated fibroblasts (CAFs) in those with a high biobehavioral risk profile (high Center for Epidemiologic Studies Depression Scale [CES-D] score and low social support). In several models of epithelial ovarian cancer, daily restraint stress resulted in significantly increased CAF activation and was abrogated by a nonspecific β-blocker. Adrenergic signaling-induced CAFs had significantly higher levels of collagen and extracellular matrix components than control tumors. Using a systems-based approach, we found INHBA production by cancer cells to induce CAFs. Ablating inhibin β A decreased CAF phenotype both in vitro and in vivo. In preclinical models of breast and colon cancers, there were increased CAFs and collagens following daily restraint stress. In an independent data set of renal cell carcinoma patients, there was an association between high depression (CES-D) scores and elevated expression of ACTA2, collagens, and inhibin β A. Collectively, our findings implicate adrenergic influences on tumor stroma as important drivers of CAFs and establish inhibin β A as an important regulator of the CAF phenotype in ovarian cancer.

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