PMON230 Pancreatic Exocrine Cells are Altered during the Progression of Ovarian Cancer-Driven Cachexia in Female Mice

Abstract

Abstract Cancer-associated cachexia (CAC) is a progressive debilitating syndrome that frequently complicates metabolic function in body vital organs and subsequently causes a high mortality rate in cancer patients. However, the underlying mechanisms and the functional consequences of organs dysfunction during CAC are not fully elucidated. Recently, we have developed a preclinical model characterized by oocyte-specific knockin for constitutively active Pi3k (Pik3ca*) which induces ovarian granulosa cell tumor (GCT) and mimics the stagewise progression of CAC in humans. Here, we aim to characterize the pathophysiological effect of cachexia on pancreatic dysfunction and investigate the potential role of the pancreas in the development and complication of cachexia in transgenic female mice with ovarian cancer. Notably, we found that cachectic mice showed a drastic loss in the pancreatic volume (PV) before death. Histological and morphometric assays revealed that exocrine pancreatic acinar atrophy (PAA) is drastic in the pancreas of cachectic PIK3CA* mice. The pancreas appeared to have an increased number of pancreatic stellate-shaped cells between acini. No significant changes were observed in the morphology of endocrine islets. Immunohistochemical assay confirmed a high level of TNF-a in atrophied pancreatic tissue and decreased intensity of pancreatic amylase in the cytoplasm of atrophied pancreatic acinar cells. Additionally, moderate fibrosis was also observed in the wall of pancreatic ducts and blood vessels, but not between the pancreatic acini. Masson trichrome and histochemical staining confirmed expression of extracellular matrix proteins including collagen I, II, IV, and a -smooth muscle actin in ducts and vessel walls. Overall, our preliminary findings in this novel CAC mouse model strongly suggest potential signs of exhausted exocrine pancreatic cells during the progression of ovarian cancer-driven cachexia. This mouse line could be an ideal preclinical model to aid in clarifying molecular mediators of pancreatic pathophysiology and metabolic dysfunction during CAC. Keywords: Ovarian cancer-driven cachexia, pancreas, atrophy, amylase. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.