{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T17:17:13Z","timestamp":1772039833546,"version":"3.50.1"},"reference-count":41,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T00:00:00Z","timestamp":1760054400000},"content-version":"vor","delay-in-days":9,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HD096042"],"award-info":[{"award-number":["R01HD096042"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Cancer\u2010associated cachexia (CAC) is a severe metabolic disorder characterized by involuntary weight loss, skeletal muscle atrophy and adipose tissue depletion. It is a major contributor to morbidity and mortality in the advanced stages of various cancers. However, the impact of CAC on the pancreas remains largely unexplored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We used mice with constitutively active\n                      <jats:italic>PI3K<\/jats:italic>\n                      in oocytes, generated through a Cre\u2010inducible\n                      <jats:italic>Pik3ca*<\/jats:italic>\n                      knock\u2010in allele driven by\n                      <jats:italic>Gdf9<\/jats:italic>\n                      \u2010icre and performed histological and molecular analyses of the pancreas during cachexia development. Additionally, we examined pancreatic changes following ovariectomy and administration of Follistatin 288 (FST288).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Mice that developed cachexia symptoms associated with granulosa cell tumour (GCT) growth exhibited significant pancreatic atrophy compared to controls (Cre+ vs. Cre\u2212 at PD83,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001), including reduced size of individual acinar cells (102.99\u2009\u00b1\u200912.19\u2009\u03bcm\n                      <jats:sup>2<\/jats:sup>\n                      vs. 207.94\u2009\u00b1\u200924.85\u2009\u03bcm\n                      <jats:sup>2<\/jats:sup>\n                      at PD83,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001) and acinar units (346.41\u2009\u00b1\u2009169.22\u2009\u03bcm\n                      <jats:sup>2<\/jats:sup>\n                      vs. 1193.59\u2009\u00b1\u2009136.01\u2009\u03bcm\n                      <jats:sup>2<\/jats:sup>\n                      at PD83,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001), despite comparable food intake between groups. Acinar cells exhibited a decrease in zymogen granules, reduced amylase expression and diminished amylase activity in both serum (0.29\u2009\u00b1\u20090.08 vs. 1.41\u2009\u00b1\u20090.40,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001) and tissue (0.37\u2009\u00b1\u20090.14 vs. 1.05\u2009\u00b1\u20090.29,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01). In contrast, pancreatic islets remained intact, as evidenced by histological analysis and preserved insulin expression. The pancreas of PD83 Cre+ mice also developed fibrosis and acinar cell death, characterized by elevated expression of collagen IV and \u03b1\u2010SMA, and TUNEL\u2010positive signals in acinar cells, respectively. Ovariectomy preserved body weight (2.66\u2009\u00b1\u20091.30\u2009g for Cre+\/OVX vs. 1.60\u2009\u00b1\u20090.97\u2009g for Cre\u2212) compared to Cre+ mice (\u22123.66\u2009g) and maintained pancreatic function, suggesting that tumour\u2010derived factors from GCT contribute to the severity of cachexia. Acinar cells showed high expression of ACVR2B, leading to activation of downstream p\u2010SMAD3 signalling. Accordingly, activin A directly induced acinar cell atrophy in both ex\u00a0vivo cultured pancreas (79.27\u2009\u00b1\u200919.03\u2009\u03bcm\n                      <jats:sup>2<\/jats:sup>\n                      vs. 171.14\u2009\u00b1\u200927.01\u2009\u03bcm\n                      <jats:sup>2<\/jats:sup>\n                      ,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001) and 266\u20106 acinar cells, as evidenced by reduced acinar cell size and decreased amylase production. Injection of FST288, an activin A inhibitor, rescued pancreatic acinar atrophy (252.95\u2009\u00b1\u200911.59\u2009\u03bcm\n                      <jats:sup>2<\/jats:sup>\n                      in Cre+\/FST288 vs. 97.25\u2009\u00b1\u200912.37\u2009\u03bcm\n                      <jats:sup>2<\/jats:sup>\n                      in Cre+,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001) without affecting GCT tumour size. Ex\u00a0vivo culture of pancreas and 266\u20106 acinar cells exposed to activin A confirmed that activin A directly induces pancreatic damage.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings demonstrate pancreatic damage occurs during CAC development and highlight the critical role of activin A in this process. Targeting activin A signalling may represent a promising therapeutic strategy to mitigate cachexia in cancer patients and preserve pancreatic function.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.70096","type":"journal-article","created":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:53:33Z","timestamp":1760108013000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Pancreatic Damage in Ovarian Cancer\u2013Associated Cachexia Is Driven by Activin A Signalling"],"prefix":"10.1002","volume":"16","author":[{"given":"Amirhossein","family":"Abazarikia","sequence":"first","affiliation":[{"name":"Olson Center for Women's Health, Department of Obstetrics and Gynecology, College of Medicine University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wonmi","family":"So","sequence":"additional","affiliation":[{"name":"Olson Center for 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USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1013-6852","authenticated-orcid":false,"given":"So\u2010Youn","family":"Kim","sequence":"additional","affiliation":[{"name":"Olson Center for Women's Health, Department of Obstetrics and Gynecology, College of Medicine University of Nebraska Medical Center  Omaha Nebraska USA"},{"name":"Fred and Pamela Buffett Cancer Center University of Nebraska Medical Center  Omaha Nebraska 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