Abstract C062: Lipocalin 2 slows myoblast growth and contributes to pancreatic cancer-associated muscle wasting

Abstract

Abstract Background: Patients with pancreatic cancer (PC) often experience cachexia, a multifactorial syndrome that includes weight loss, malnutrition, appetite suppression, and tissue wasting. Unfortunately, the factors secreted from the pancreas or other tissues that drive cachexia are still poorly defined. Lipocalin 2 (LCN2) is a cytokine involved in innate immunity that we have previously shown to be increased in the pancreas and circulation of patients with PC and mouse models of PC. Recent studies suggest that LCN2 contributes to appetite suppression in cancer cachexia in orthotopic models of PC. However, a reduction in muscle regeneration is also commonly seen in cachexia that is not repaired by increased nutrient intake. In a non-cancer setting, LCN2 has been implicated as an important factor in mediating skeletal muscle repair. Therefore, we hypothesized that elevated LCN2 in PC contributes to cachexia by inhibiting muscle progenitor cell proliferation and differentiation into new muscle fibers. Methods: Muscles from a syngeneic orthotopic mouse model of PC were assessed for muscle RING-finger protein-1 (MuRF1, an E3 ubiquitin ligase highly expressed in muscle during wasting) and LCN2 by qPCR. C2C12 mouse muscle myoblasts were cultured in proliferation or differentiation media with recombinant mouse LCN2. Proliferation across 3 days was assessed by MTS assay. Differentiation was assessed by imaging myotubes and western blotting for myosin heavy chain (MyHC) expression which increases during differentiation. PC genetically engineered mice ± a whole body LCN2 were assessed for pancreatic tumor and gastroc muscle size. One-way and Two-way ANOVAs were used to determine statistical significance. Results: LCN2 and MuRF1 expression are elevated in muscles of mice with PC. C2C12 cells treated with LCN2 decreased proliferation in a dose-dependent manner up to concentrations of LCN2 commonly observed in PC. LCN2 treatments at a physiologic concentration observed in PC delayed differentiation of C2C12 cells into myotubes by reducing myotube diameter and delaying MyHC expression. Deleting LCN2 in a PC genetic mouse model prevented body weight and gastroc weight loss but did not affect pancreas weight. Conclusions: Here, we show a relationship between muscle wasting and LCN2 expression during PC. Elevated circulating LCN2 may be contributing to decreased muscle regeneration observed in PC-associated cachexia by directly inhibiting muscle progenitor cell proliferation and differentiation. Targeting LCN2 in PC may be a viable method of slowing or preventing muscle wasting in PC to improve patient outcomes. Citation Format: Kristyn Gumpper-Fedus, Valentina Pita Grisanti, Ericka Velez Bonet, Martha A. Belury, Christopher Coss, Zobeida Cruz-Monserrate. Lipocalin 2 slows myoblast growth and contributes to pancreatic cancer-associated muscle wasting [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C062.