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

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 quantitati...

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Bibliographic Details
Published in:The Journal of clinical investigation Vol. 135; no. 12
Main Authors: D’Lugos, Andrew C., Ducharme, Jeremy B., Callaway, Chandler S., Trevino, Jose G., Atkinson, Carl, Judge, Sarah M., Judge, Andrew R.
Format: Journal Article
Language:English
Published: United States American Society for Clinical Investigation 30.06.2025
Subjects:
Animals
Cachexia - etiology
Cachexia - genetics
Cachexia - immunology
Cachexia - metabolism
Cachexia - pathology
Carcinoma, Pancreatic Ductal - complications
Carcinoma, Pancreatic Ductal - genetics
Carcinoma, Pancreatic Ductal - immunology
Carcinoma, Pancreatic Ductal - metabolism
Carcinoma, Pancreatic Ductal - pathology
Causes of
Cell Line, Tumor
Complement Activation
Complement C3 - deficiency
Complement C3 - genetics
Complement C3 - immunology
Complement C3 - metabolism
Female
Health aspects
Humans
Male
Mice
Mice, Knockout
Muscle biology
Muscle diseases
Muscle, Skeletal - immunology
Muscle, Skeletal - metabolism
Muscle, Skeletal - pathology
Muscles
Muscular Atrophy - etiology
Muscular Atrophy - genetics
Muscular Atrophy - immunology
Muscular Atrophy - pathology
Oncology
Pancreatic cancer
Pancreatic Neoplasms - complications
Pancreatic Neoplasms - genetics
Pancreatic Neoplasms - immunology
Pancreatic Neoplasms - metabolism
Pancreatic Neoplasms - pathology
Physiological aspects
United States
Oncology
Muscle
Muscle biology
Proteomics
Cancer
ISSN:1558-8238, 0021-9738, 1558-8238
Online Access:Get full text
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Summary: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.
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Authorship note: SMJ and ARJ are co–senior authors.
ISSN:1558-8238
0021-9738
1558-8238
DOI:10.1172/JCI178806