Uncovering Tumor-Promoting Roles of Activin A in Pancreatic Ductal Adenocarcinoma

Seok Yeong Yu, Yi Luan, Siyuan Tang, Amirhossein Abazarikia, Rosemary Dong, Thomas C. Caffrey, Michael A. Hollingsworth, David Oupicky, So Youn Kim

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with high incidence rates of metastasis and cachexia. High circulating activin A, a homodimer of inhibin βA subunits that are encoded by INHBA gene, predicts poor survival among PDAC patients. However, it still raises the question of whether activin A suppression renders favorable PDAC outcomes. Here, the authors demonstrate that activin A is abundantly detected in tumor and stromal cells on PDAC tissue microarray and mouse PDAC sections. In orthotopic male mice, activin A suppression, which is acquired by tumor-targeted Inhba siRNA using cholesterol-modified polymeric nanoparticles, retards tumor growth/metastasis and cachexia and improves survival when compared to scramble siRNA-treated group. Histologically, activin A suppression coincides with decreased expression of proliferation marker Ki67 but increased accumulation of α-SMAhigh fibroblasts and cytotoxic T cells in the tumors. In vitro data demonstrate that activin A promotes KPC cell proliferation and induces the downregulation of α-SMA and upregulation of IL-6 in pancreatic stellate cells (PSC) in the SMAD3-dependent mechanism. Moreover, conditioned media from activin A-stimulated PSC promoted KPC cell growth. Collectively, our data provide a mechanistic basis for tumor-promoting roles of activin A and support therapeutic potentials of tumor activin A suppression for PDAC.

Original languageEnglish (US)
Article number2207010
JournalAdvanced Science
Volume10
Issue number16
DOIs
StatePublished - Jun 2 2023

Keywords

  • activin A
  • cancer-associated fibroblasts
  • cholesterol-modified polymeric nanoparticle
  • orthotopic mice
  • pancreatic ductal adenocarcinoma

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • General Chemical Engineering
  • General Materials Science
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • General Engineering
  • General Physics and Astronomy

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