Complement pathway activation mediates pancreatic cancer–induced muscle wasting and pathological remodeling
Andrew C. D’Lugos, … , Sarah M. Judge, Andrew R. Judge
Andrew C. D’Lugos, … , Sarah M. Judge, Andrew R. Judge
Published April 8, 2025
Citation Information: J Clin Invest. 2025;135(12):e178806. https://doi.org/10.1172/JCI178806.
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Research Article Muscle biology Oncology

Complement pathway activation mediates pancreatic cancer–induced muscle wasting and pathological remodeling

Abstract

Cancer cachexia is a multifactorial condition characterized by skeletal muscle wasting that impairs quality of life and longevity for many cancer patients. A greater understanding of the molecular etiology of this condition is needed for effective therapies to be developed. We performed a quantitative proteomic analysis of skeletal muscle from cachectic pancreatic ductal adenocarcinoma (PDAC) patients and non-cancer controls, followed by immunohistochemical analyses of muscle cross sections. These data provide evidence of a local inflammatory response in muscles of cachectic PDAC patients, including an accumulation of plasma proteins and recruitment of immune cells into muscle that may promote the pathological remodeling of muscle. Our data further support the complement system as a potential mediator of these processes, which we tested by injecting murine pancreatic cancer cells into wild-type mice and mice with genetic deletion of the central complement component 3 (C3–/– mice). Compared with wild-type mice, C3–/– mice showed attenuated tumor-induced muscle wasting and dysfunction and reduced immune cell recruitment and fibrotic remodeling of muscle. These studies demonstrate that complement activation contributes to the skeletal muscle pathology and dysfunction in PDAC, suggesting that the complement system may possess therapeutic potential in preserving skeletal muscle mass and function.

Authors

Andrew C. D’Lugos, Jeremy B. Ducharme, Chandler S. Callaway, Jose G. Trevino, Carl Atkinson, Sarah M. Judge, Andrew R. Judge

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Figure 5

Deletion of C3 attenuates ascites and fat wasting in murine model of PDAC-associated cachexia.

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Deletion of C3 attenuates ascites and fat wasting in murine model of PDA...
C57BL/6J wild-type (WT) mice and complement C3–null C57BL/6J mice (C3–/–) underwent orthotopic surgeries in which either PBS (sham) or KPC tumor cells were implanted into the pancreas. (A) Body mass was monitored over the course of tumor burden until IACUC-mandated endpoint (day 14). (B) At endpoint, tumor-free body mass was reduced in KPC tumor–bearing mice (squares) versus sham (circles). (C–F) Tumor mass (C), ascites mass (D), and fat mass (E and F) on day 14 after surgery. (F) Tumor-induced fat wasting relative to sham controls was determined within each genotype (WT, C3–/–). Data are presented as mean ± SEM, with individual data superimposed. Data are representative of n = 8–12 mice per group. Differences were assessed using a 2-way ANOVA with Šidák’s post hoc analysis (B and E), Mann-Whitney U test (D), and Student’s 2-tailed t test (F). **P < 0.01, ****P < 0.0001.