Abstract 365: Targeting FGF21 inhibits tumor growth and attenuates cachexia in experimental colorectal cancer

Abstract

Abstract Background: Colorectal cancer (CRC) is frequently accompanied by cachexia, an uncured multi-organ wasting syndrome, debilitating musculoskeletal health, physical function, and overall survival. Fibroblast growth factor 21 (FGF21) is a modulator of musculoskeletal health and metabolism and has been associated with CRC risk and progression. Here, we investigated the effects of tumor derived FGF21 on musculoskeletal health in CRC. Methods: Plasma from CRC patients and preclinical models of CRC (C26, MC38) were assessed for circulating FGF21 levels, and CRC cell lines (C26, MC38, HCT116) were screened for FGF21 expression. Using CRISPR/Cas9 technology, FGF21 was deleted from MC38 cells (KO-MC38). 8-week-old male C57BL/6J mice were subcutaneously injected (1.0x106) with wild-type (WT-MC38) or FGF21-/- (KO-MC38) MC38 tumor cells, while experimental control animals received saline (n = 10-13/group). Animals underwent electrophysiological testing to obtain motor unit number estimation (MUNE) 48 hours prior to euthanasia and were assessed for maximum plantarflexion torque 24 hours prior to euthanasia. At the time of euthanasia, plasma was collected for assessment of systemic FGF21, while tumors and skeletal muscles (gastrocnemius, quadriceps, and tibialis anterior) were excised and weighed. Femur bones were processed for microcomputed tomography (µCT) imaging and analysis. Results: CRC patients and MC38 tumor hosts demonstrated elevated circulating plasma FGF21 (p<0.05) compared to controls. Gene expression of CRC cells revealed an 11-fold increase of FGF21 in MC38 compared to C26 and HCT116 cells. WT-MC38 tumor hosts had elevated plasma FGF21 (4-fold; p<0.05) compared to control, which was unchanged in KO-MC38 hosts. In line with the development of cachexia, WT-MC38 hosts displayed reductions in muscle mass (gastrocnemius: -5%; p<0.05, quadriceps: -10%; p<0.01, tibialis anterior: -8%; p<0.01), MUNE (-31%; p<0.01), and plantarflexion torque (-10%; p<0.05). Meanwhile, µCT of femur bones demonstrated reductions in trabecular bone volume fraction (BV/TV: -30%; p<0.05) and cortical cross-sectional thickness (Cs.Th: -14%; p<0.05) in WT-MC38 hosts compared to experimental controls. Conversely, when compared to WT-MC38, KO-MC38 hosts had preserved skeletal muscle mass (gastrocnemius: +7%; p<0.01, quadriceps: +13%; p<0.001, tibialis anterior: +8%; p<0.001), MUNE (+47%; p<0.01), plantarflexion torque (+8%; p<0.05), and bone mass (BV/TV: +69%; p<0.001, Cs.Th: +23%; p<0.001). Strikingly, the mass of KO-MC38 tumors was reduced 75% (p<0.01) compared to WT-MC38 tumors. Conclusion: Our data suggest that targeting CRC-derived FGF21 halts tumor growth, resulting in preservation of musculoskeletal health and function. Thus, counteracting tumor-derived FGF21 may serve as a therapeutic intervention against the progression of cancer and cancer-associated cachexia. Citation Format: Fabrizio Pin, Anika Shimonty, Joshua Robert Huot. Targeting FGF21 inhibits tumor growth and attenuates cachexia in experimental colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 365.