Dataset Information

Skeletal Muscle Proteome of Cachectic Pancreatic Cancer Patients

ABSTRACT: Cancer cachexia is a multifactorial condition characterized by skeletal muscle loss that impairs longevity and quality of life of the vast majority of cancer patients. However, the ability to develop therapeutic strategies to counter cachexia is impeded by the limited understanding of the underlying mechanisms of cachexia in human cancer patients. The purpose of this study was therefore to characterize the proteomic signature of skeletal muscle obtained from cachectic pancreatic ductal adenocarcinoma (PDAC) patients, who exhibit one of the highest rates of cachexia. Muscle biopsies (rectus abdominis) were obtained from PDAC patients (n=8; 70Â±10yr; BMI: 26.8Â±5.9kgï½¥m-2) undergoing tumor resection surgery as well as age and sex-matched non-cancer controls (n=6; 66Â±9yr; BMI: 30.8Â±5.2kgï½¥m-2). PDAC patients were cachectic (6 month body weight loss > 5%; mean: 15.7Â±7.9%) and did not undergo neoadjuvant therapy.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Skeletal Muscle

DISEASE(S): Pancreatic Ductal Adenocarcinoma

SUBMITTER: Andrew D'Lugos

LAB HEAD: Andrew R. Judge

PROVIDER: PXD047838 | Pride | 2025-06-23

REPOSITORIES: Pride

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			Action	DRS
	180627_27252_AS_TMT_L1.raw	Raw
	180627_27253_AS_TMT_L2.raw	Raw
	180627_27254_AS_TMT_L3.raw	Raw
	180627_27255_AS_TMT_L4.raw	Raw
	180627_27256_AS_TMT_L5.raw	Raw

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Publications

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

D'Lugos Andrew C AC Ducharme Jeremy B JB Callaway Chandler S CS Trevino Jose G JG Atkinson Carl C Judge Sarah M SM Judge Andrew R AR

The Journal of clinical investigation 20250408 12

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. The ...[more]

PMID: 40198138

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Project description:Background. Pancreatic Ductal AdenoCarcinoma (PDAC), the most frequent pancreatic cancer, is a deadly cancer since often diagnosed late and resistant to current therapies. A high proportion of PDAC patients are affected by cachexia induced by the tumor. This cachexia, characterized by loss of muscle mass and strength, contributes to patient frailty and poor therapeutic response. We showed that mitochondrial metabolism is reprogrammed in PDAC tumor cell and constitutes a vulnerability, opening novel therapeutic avenues. The objective of the present work was to investigate the molecular mechanisms underlying mitochondrial remodeling in PDAC cachectic skeletal muscle. Methods. Our study focused on the gastrocnemius muscle of genetically-engineered mice developing spontaneously a PDAC associated with cachexia (KIC GEMM). We compared KIC mice developing a pancreatic tumor in 9-10 weeks to control littermates. We did an integrative study combining in vivo functional analyses by non-invasive Magnetic Resonance, and ex-vivo histology, Seahorse, RNA-sequencing, and proteomic mass spectrometry and western blotting analyses. Results. The cachectic KIC PDAC mice show a severe sarcopenia with loss of muscle mass and strength associated with a diminution in muscle fiber’s size and induction of protein degradation processes. Mitochondria in PDAC atrophic muscles show decreased respiratory capacities and structural alterations (“hyperfused” mitochondria), associated with deregulation of oxidative phosphorylation and mitochondrial dynamics pathways at the molecular level. Increased expression of multiple reactive oxygen species (ROS) defense genes suggests oxidative stress prone to affect mitochondrial macromolecules and homeostasis. Interestingly, multiple genes and proteins involved in DNA metabolism pathways, such as DNA damage, degradation of DNA, nucleotide synthesis, and folate pathway were found altered in sarcopenic mitochondria. While the number of mitochondria was not changed, the mitochondrial mass was decreased by a factor of 2 and the mitochondrial DNA by a factor of 3, suggesting a defect in mitochondrial genome homeostasis. Conclusions. We unveiled that mitochondrial alterations in skeletal muscle play a central role in PDAC-induced cachexia. Muscle atrophy is associated with strong mitochondrial metabolic defects that are not limited to carbohydrates and protein, but concern also lipids, ROS and nucleic acids. Our data provide a frame to guide towards the most relevant molecular markers that would be affected at the start of tumor development and could be targets in the clinic to limit PDAC-induced cachexia at early stages of the pathology.