Complement pathway activation mediates pancreatic cancer–induced muscle wasting and pathological remodeling
Andrew C. D’Lugos, Jeremy B. Ducharme, Chandler S. Callaway, Jose G. Trevino, Carl Atkinson, Sarah M. Judge, Andrew R. Judge
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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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 4

Orthotopic KPC model of PDAC-associated cachexia recapitulates skeletal muscle complement activation observed in cachectic PDAC patients.

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Orthotopic KPC model of PDAC-associated cachexia recapitulates skeletal ...
(A and B) Representative images (A) and quantification (B) of costal diaphragm stained for complement component C3 (green) and DAPI (blue); scale bars: 100 μm. (C) Correlation between complement C3 deposition in diaphragm and body weight loss. (D and E) Representative images (D) and quantification (E) of costal diaphragm stained for terminal complement complex C5b-9 (membrane attack complex, green) and wheat germ agglutinin (red); scale bars: 50 μm. (F) Correlation between complement C3 deposition and C5b-9 formation in costal diaphragm. (G and H) Representative images (G) and quantification (H) of TA stained for complement component C3 (green) and DAPI (blue); scale bars: 100 μm. (I and J) Representative images (I) and quantification (J) of TA stained for terminal complement complex C5b-9 (membrane attack complex, green); scale bars: 100 μm. (K) Heatmap depicting changes in the expression level of complement transcripts in the diaphragm muscles of mice with orthotopic KPC tumors during cachexia progression relative to control mice, extracted from previously published RNA-Seq data by Neyroud et al. (32). (L) Quantitative reverse transcriptase PCR analysis of complement C3 mRNA expression from liver of sham and KPC tumor–bearing mice. Data are presented as mean ± SEM, with individual data superimposed. Data are representative of n = 5–9 mice per group. Differences were assessed using Student’s 2-tailed t test (B, E, and L) and linear regression analysis (C and F). *P < 0.05, **P < 0.01.