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 2

Skeletal muscle of cachectic PDAC patients exhibits worsened morphology and remodeling of extracellular matrix.

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Skeletal muscle of cachectic PDAC patients exhibits worsened morphology ...
(A) Representative images of rectus abdominis cross sections from CTRL and PDAC stained for myosin heavy chain I (MyHC I; red), MyHC IIa (blue), and laminin (green); scale bars: 200 μm. (B) Relative abundance of fibers positive for each MyHC isoform in CTRL and PDAC. (C) Quantification of overall muscle fiber cross-sectional area (CSA) demonstrates a leftward shift in the proportion of small fibers in PDAC versus CTRL. Significance was assessed through a Gaussian least-squares regression of binned CSA data and calculation of the extra sum-of-squares F test. (D) Fiber type–specific CSA was also quantified. (E) Representative images of skeletal muscle cross sections stained for endothelial cells (Ulex europaeus agglutinin, white), MyHC I (red), and wheat germ agglutinin (WGA; blue); scale bars: 200 μm. (F and G) Capillary density (F) and fiber type–specific capillary contacts (G) were quantified in CTRL and PDAC. (H) Representative images of skeletal muscle cross sections stained for collagen hybridizing peptide (CHP; green), collagen I or IV (red), and DAPI (blue); scale bars: 50 μm. (I–M) Quantification of percentage muscle area positive for collagen I (I), collagen IV (J), and CHP (K), as well as quantitative colocalization analyses on cross sections stained for CHP and collagen I (L) and CHP and collagen IV (M). Data are presented as mean ± SEM, with individual data superimposed. Data are representative of n = 7–8 for CTRL and n = 6–9 for PDAC. Differences were assessed using a 2-way ANOVA with Šidák’s post hoc analysis (D and G), Mann-Whitney U test (F), and Student’s 2-tailed t test (J–L). #P < 0.05 main effect of group, *P < 0.05, **P < 0.01.