Abstract B002: Tumor-secreted PTHrP facilitates pancreatic cancer cachexia by regulation of de novo lipogenesis pathway

Abstract Pancreatic cancer is associated with one of the highest and most severe forms of cancer- associated cachexia amongst solid tumors. In an effort to further our understanding of the molecular etiology of pancreatic cancer-associated cachexia, we have developed mouse models to study adipose tissue wasting during Pancreatic Ductal Adenocarcinoma (PDAC) progression. In these pursuits, we have identified a pro-cachectic factor, PTHrP, that is produced and secreted by PDAC tumor cells and directly signals to adipocytes to facilitate wasting. Genetic deletion and pharmacological inhibition of PTHrP significantly extended the survival of tumor-bearing animals and dramatically reduced cachectic phenotypes in these animals, manifesting as decreased adipose and muscle tissue wasting. Mechanistic studies have shown crosstalk between tumor-cell derived PTHrP and adipose tissue PTH1R that drives the cachectic phenotype. Finally, bulk RNA sequencing analysis in PTHrP-driven cachectic models point towards a role for reduced de novo lipogenesis and adipogenesis in cachectic adipose depots, suggesting potential rewiring of the metabolic profile of white adipose tissue in tumor-bearing mice with higher PTHrP expression. Citation Format: Nikita Bhalerao, Jessica Peura, Yamini Ogoti, Calvin Johnson, Qingbo Chen, Ekaterina Korobkina, Faith Keller, Maximillan Wengyn, Robert Norgard, Richard Kremmer, Emma Watson, Marcus Ruscetti, David Guertin, Jason R Pitarresi. Tumor-secreted PTHrP facilitates pancreatic cancer cachexia by regulation of de novo lipogenesis pathway abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84 (17 Suppl₂): Abstract nr B002.