Abstract 2373: The RNA-binding protein HuR mediates impaired adipogenesis in pancreatic cancer cachexia
Authors: Worley Beth L. , Pelz Katherine , McCarthy Grace , Mendez Heike , Niro Roberto Di , Chitsazan Alex , Brody Jonathan , Grossberg Aaron 
Published: June 2022

Objective: Cachexia, a wasting condition defined by chronic loss of fat and muscle, is a frequent complication of pancreatic ductal adenocarcinoma (PDAC) that negatively impacts quality of life and confers poor patient survival. Cachectic wasting cannot be abrogated by nutritional supplementation, and the mechanisms underlying this phenotype are unclear. Recent work demonstrates that human antigen R (HuR), an RNA-binding protein that regulates expression of genes involved in key cellular processes such as inflammation, stress response, and apoptosis, is also a major repressor of adipogenesis. Thus, we sought to elucidate the relative contributions of enhanced catabolism and impaired anabolism on fat wasting by investigating adipose tissue response to different nutritional contexts and HuR inhibition in cachectic mice.

Methods: Adult C57BL/6J mice received orthotopic PDAC tumor injections (KrasG12D; p53R172H/+; Pdx1-cre) or sham injections. Mice were fed ad libitum, fasted 24h or fasted and refed 24h at mid-cachexia (9 days after injection). A separate cohort of PDAC mice were treated with the HuR inhibitor KH3 (100 mg/kg) at 6-, 8-, and 10-days post-injection and subjected to the same fast/refeed paradigm. Gross fat pads were weighed to assess anabolism. Adipose tissue mRNA levels were measured using RNAseq and validated with qPCR. Lipolytic rate was quantified as normalized quantity of glycerol released from inguinal (iWAT) and gonadal (gWAT) fat pads ex vivo.

Results: PDAC and control mice exhibited equivalent loss of adipose tissue as a result of food restriction. Fat pads from PDAC mice displayed decreased lipolysis ex vivo and decreased lipase (Atgl & Lipe) mRNA expression. In the fast/refeed model, PDAC mice were unable to restore iWAT or gWAT mass after refeed compared to controls. RNAseq revealed 614 differentially expressed genes between gWAT from PDAC and control mice. Downregulated (n=111) genes were most closely associated with adipogenesis (adj p=5x10-3), and expression of adipogenesis master regulators Pparg and Cebpa were reduced in both iWAT and gWAT from PDAC mice. Inhibition of HuR by KH3 restored lipogenesis in refed animals with a concomitant increase in fat pad mass and associated genes regulating adipogenesis (Pparg, Cebpa, Retn, Adipoq, Fasn).

Conclusion: Adipose tissue wasting during PDAC cachexia can result from impaired anabolism in the absence of excess lipolysis or malabsorption. Adipose anabolism in PDAC mice is mediated by increased HuR activity in adipocytes. Restoring anabolic potential in adipose tissue using the HuR inhibitor KH3 may provide a novel approach to alleviating PDAC cachexia.

Citation Format: Beth L. Worley, Katherine Pelz, Grace McCarthy, Heike Mendez, Roberto Di Niro, Alex Chitsazan, Jonathan Brody, Aaron Grossberg. The RNA-binding protein HuR mediates impaired adipogenesis in pancreatic cancer cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2373.