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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Vydáno v:	The Journal of clinical investigation Ročník 135; číslo 12
Hlavní autoři:	D’Lugos, Andrew C., Ducharme, Jeremy B., Callaway, Chandler S., Trevino, Jose G., Atkinson, Carl, Judge, Sarah M., Judge, Andrew R.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States American Society for Clinical Investigation 30.06.2025
Témata:	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
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Authorship note: SMJ and ARJ are co–senior authors.
ISSN:	1558-8238 0021-9738 1558-8238
DOI:	10.1172/JCI178806