Abstract IA-17: Mechanisms of pancreatic cancer-induced cachexia

Cachexia is a debilitating syndrome that results in severe, involuntary weight loss due to the depletion of skeletal muscle mass. Currently, no effective therapy exists to combat this malignant disorder. For pancreatic cancer, 85% of patients lose on average 14% of their pre-illness weight, and cachexia dramatically limits their ability to tolerate surgery, chemo- or radiotherapy. New therapies will likely evolve from an enhanced understanding of the mechanisms leading to muscle wasting and tumor development. Our laboratory has been examining the role of the NF-κB signaling pathway in tumorigenesis for several decades and that interest led us to discover the connection between NF-κB and muscle wasting in cancer cachexia and more recently in pancreatic cancer. We view the pathway as playing two separate functions in pancreatic cancer-induced cachexia. The first occurs at the level of skeletal muscle, or more preciously in skeletal muscle stem cells. We have found that during cancer progression, skeletal muscle undergoes a type of injury response leading to the activation of resident stem cells to engage in a regeneration program. NF-κB is activated in these stem cells and functions to inhibit regeneration, which contributes to the overall wasting process in cachexia. New data reveal that NF-κB activity in progenitor cells also regulates a local muscle inflammatory environment that might also contribute to skeletal muscle catabolism. The mechanism of this regulation will be discussed in more details. The second function of NF-κB signaling that we are pursuing focuses in the tumor microenvironment of pancreatic cancer. Using orthotopic mouse models of pancreatic cancer, we showed that NF-κB plays a critical role in protecting tumor cells from the surveillance property of anti-tumor macrophages. This occurs through the direct transcriptional regulation of the immunosuppressive cytokine, GDF15. Interestingly, circulating levels of GDF15 are elevated in cachectic patients and recent studies indicate that this cytokine might be an attractive therapeutic target in cancer cachexia. Together, we speculate that NF-κB functions in cancer cachexia by acting in muscle stem cells to block muscle repair, as well as promoting pancreatic cancer through the production of immunosuppressive genes such as GDF15. Citation Format: Benjamin Pryce, Nivedita Ratnam, Erin E. Talbert, Mary Dilhoff, Carl R. Schmidt, David J. Wang, Denis C. Guttridge. Mechanisms of pancreatic cancer-induced cachexia [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr IA-17.