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Adrenergic-mediated increases in INHBA drive CAF phenotype and collagens

Archana S. Nagaraja, Robert L. Dood, Guillermo Armaiz-Pena, Yu Kang, Sherry Y. Wu, Julie K. Allen, Nicholas B. Jennings, Lingegowda S. Mangala, Sunila Pradeep, Yasmin Lyons, Monika Haemmerle, Kshipra M. Gharpure, Nouara C. Sadaoui, Cristian Rodriguez-Aguayo, Cristina Ivan, Ying Wang, Keith Baggerly, Prahlad Ram, Gabriel Lopez-Berestein, Jinsong Liu, Samuel C. Mok, Lorenzo Cohen, Susan K. Lutgendorf, Steve W. Cole, and Anil K. Sood

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Published April 1, 2021 - More info

Published in Volume 6, Issue 7 on April 8, 2021
JCI Insight. 2021;6(7):e149895. https://doi.org/10.1172/jci.insight.149895.
© 2021 phenotype et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published April 1, 2021 - Version history
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Related article:

Adrenergic-mediated increases in INHBA drive CAF phenotype and collagens
Archana S. Nagaraja, … , Steve W. Cole, Anil K. Sood
Archana S. Nagaraja, … , Steve W. Cole, Anil K. Sood
Chronic adrenergic signaling promotes a cancer-associated fibroblast phenotype characterized by increased collagen deposition driven by Inhibin beta A production by cancer cells.
Research Article Cell biology Oncology

Adrenergic-mediated increases in INHBA drive CAF phenotype and collagens

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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.

Authors

Archana S. Nagaraja, Robert L. Dood, Guillermo Armaiz-Pena, Yu Kang, Sherry Y. Wu, Julie K. Allen, Nicholas B. Jennings, Lingegowda S. Mangala, Sunila Pradeep, Yasmin Lyons, Monika Haemmerle, Kshipra M. Gharpure, Nouara C. Sadaoui, Cristian Rodriguez-Aguayo, Cristina Ivan, Ying Wang, Keith Baggerly, Prahlad Ram, Gabriel Lopez-Berestein, Jinsong Liu, Samuel C. Mok, Lorenzo Cohen, Susan K. Lutgendorf, Steve W. Cole, Anil K. Sood

×

Original citation: JCI Insight. 2017;2(16):e93076. https://doi.org/10.1172/jci.insight.93076

Citation for this corrigendum: JCI Insight. 2021;6(7):e149895. https://doi.org/10.1172/jci.insight.149895

The Editors previously posted an Expression of Concern for this article regarding images in Figure 5E that appeared to be the same (siControl Stress and siNHBA Control). An institutional review committee concluded that the error in Figure 5E was inadvertent and recommended correction. The authors provided the correct image for the siControl Stress sample from the original study. The correct version of Figure 5E appears below.

Figure 5

The authors regret the error.

Footnotes

See the related article at Adrenergic-mediated increases in INHBA drive CAF phenotype and collagens.

Version history
  • Version 1 (April 8, 2021): Electronic publication
  • Version 2 (May 19, 2021): Electronic publication.
  • Version 2 (April 8, 2021): In-Press Preview

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