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High circulating activin A, a homodimer of inhibin \u03b2A 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\u2010targeted Inhba siRNA using cholesterol\u2010modified polymeric nanoparticles, retards tumor growth\/metastasis and cachexia and improves survival when compared to scramble siRNA\u2010treated group. Histologically, activin A suppression coincides with decreased expression of proliferation marker Ki67 but increased accumulation of \u03b1\u2010SMA<jats:sup>high<\/jats:sup> fibroblasts and cytotoxic T cells in the tumors. In vitro data demonstrate that activin A promotes KPC cell proliferation and induces the downregulation of \u03b1\u2010SMA and upregulation of IL\u20106 in pancreatic stellate cells (PSC) in the SMAD3\u2010dependent mechanism. Moreover, conditioned media from activin A\u2010stimulated PSC promoted KPC cell growth. Collectively, our data provide a mechanistic basis for tumor\u2010promoting roles of activin A and support therapeutic potentials of tumor activin A suppression for PDAC.<\/jats:p>","DOI":"10.1002\/advs.202207010","type":"journal-article","created":{"date-parts":[[2023,4,21]],"date-time":"2023-04-21T07:50:37Z","timestamp":1682063437000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Uncovering Tumor\u2010Promoting Roles of Activin A in Pancreatic Ductal Adenocarcinoma"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4091-761X","authenticated-orcid":false,"given":"Seok\u2010Yeong","family":"Yu","sequence":"first","affiliation":[{"name":"Olson Center for Women's Health Department of Obstetrics and Gynecology College of Medicine University of Nebraska Medical Center  Omaha NE USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Luan","sequence":"additional","affiliation":[{"name":"Olson Center for Women's Health Department of Obstetrics and Gynecology College of Medicine University of Nebraska Medical Center  Omaha NE USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyuan","family":"Tang","sequence":"additional","affiliation":[{"name":"Center for Drug Delivery and Nanomedicine Department of Pharmaceutical Sciences College of Pharmacy University of Nebraska Medical Center  Omaha NE USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amirhossein","family":"Abazarikia","sequence":"additional","affiliation":[{"name":"Olson Center for Women's Health Department of Obstetrics and Gynecology College of Medicine University of Nebraska Medical Center  Omaha NE USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosemary","family":"Dong","sequence":"additional","affiliation":[{"name":"Olson Center for Women's Health Department of Obstetrics and Gynecology College of Medicine University of Nebraska Medical Center  Omaha NE USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas C.","family":"Caffrey","sequence":"additional","affiliation":[{"name":"Eppley Institute for Research in Cancer and Allied Diseases University of Nebraska Medical Center  Omaha NE 68198 USA"},{"name":"Fred &amp; 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