Abstract PO-023: Impaired adipose anabolism drives fat wasting in pancreatic cancer cachexia

Abstract

Abstract Purpose/Objectives: The disease associated wasting condition, cachexia, is a common complication of pancreatic ductal adenocarcinoma (PDAC) that impacts quality of life and portends poor survival. Cachexia remains refractory to nutritional supplementation, but the mechanisms underlying this phenotype are unclear. By examining the adipose response to different nutritional contexts in cachectic mice, we sought to understand the relative contributions of enhanced catabolism and impaired anabolism on adipose tissue wasting. Materials/Methods: Adult C57BL/6J mice received orthotopic PDAC tumor injections (KrasG12D; p53R172H/+; Pdx1-cre) or sham injections. Mice were fasted 24 h or fasted and refed 24 h at mid-cachexia time point, and gross fat pads were weighed to assess anabolic potential. 3T3-L1 cells were treated with PDAC cell conditioned media during or after differentiation to model cachexia in vitro. Lipolytic rate was quantified as normalized quantity of glycerol released from inguinal (iWAT) and gonadal (gWAT) fat pads ex vivo or differentiated 3T3-L1 cells in vitro. Lipogenesis was measured in vitro using Oil-red-O staining. Adipose tissue mRNA levels were measured using bulk RNAseq and confirmed with qPCR. Malabsorption was assessed via fecal protease activity and total fecal protein and lipid content. Results: Adipose tissue in PDAC and control mice were equally sensitive to fasting/food restriction. Both iWAT and gWAT fat pads from PDAC mice showed decreased lipolysis ex vivo, associated with decreased lipase (Atgl & Lipe) mRNA expression. In the fast/refeed paradigm, PDAC mice were unable to restore both iWAT and gWAT mass after refeed, in contrast to control mice. We found no evidence of malabsorption at this timepoint by any measure. RNAseq on gWAT revealed 614 differentially expressed genes between PDAC and control mice. Downregulated (n=111) genes were most closely associated with adipogenesis (adj p<.05), and expression of adipogenesis master regulators Pparg and Cebpa reduced in WAT from PDAC mice. Upregulated genes were associated with increased RELA and NFkB activity (adj p<5 × 10−22) and inflammatory response hallmarks. Treatment of 3T3-L1 cells with PDAC conditioned media phenocopied in vivo model, showing impaired lipolysis and lipogenesis, associated with decreased expression of lipolytic, adipogenic, and lipogenic genes. Conclusions: Adipose tissue wasting in PDAC cachexia can result from impaired anabolism in the absence of enhanced lipolysis or malabsorption. This deficit in adipogenesis is mediated by a cancer cell secreted product and is associated with increased inflammatory signaling in adipocytes, most likely via RELA and NFkB activity. Restoring adipose anabolic potential may provide a novel approach to cachexia treatment in PDAC. Citation Format: Katherine Pelz, Grace McCarthy, Heike Mendez, Samantha Z. Brown, Jonathan R. Brody, Aaron J. Grossberg. Impaired adipose anabolism drives fat wasting in pancreatic cancer cachexia [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-023.