Dataset Information

Profiling of Adipose and Skeletal Muscle in Human Pancreatic Cancer Cachexia Reveals Distinct Gene Profiles with Convergent Pathways.

ABSTRACT: The vast majority of patients with pancreatic ductal adenocarcinoma (PDAC) suffer cachexia. Although cachexia results from concurrent loss of adipose and muscle tissue, most studies focus on muscle alone. Emerging data demonstrate the prognostic value of fat loss in cachexia. Here we sought to identify the muscle and adipose gene profiles and pathways regulated in cachexia. Matched rectus abdominis muscle and subcutaneous adipose tissue were obtained at surgery from patients with benign conditions (n = 11) and patients with PDAC (n = 24). Self-reported weight loss and body composition measurements defined cachexia status. Gene profiling was done using ion proton sequencing. Results were queried against external datasets for validation. 961 DE genes were identified from muscle and 2000 from adipose tissue, demonstrating greater response of adipose than muscle. In addition to known cachexia genes such as FOXO1, novel genes from muscle, including PPP1R8 and AEN correlated with cancer weight loss. All the adipose correlated genes including SCGN and EDR17 are novel for PDAC cachexia. Pathway analysis demonstrated shared pathways but largely non-overlapping genes in both tissues. Age related muscle loss predominantly had a distinct gene profiles compared to cachexia. This analysis of matched, externally validate gene expression points to novel targets in cachexia.

SUBMITTER: Narasimhan A

PROVIDER: S-EPMC8073275 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Profiling of Adipose and Skeletal Muscle in Human Pancreatic Cancer Cachexia Reveals Distinct Gene Profiles with Convergent Pathways.

Narasimhan Ashok A Zhong Xiaoling X Au Ernie P EP Ceppa Eugene P EP Nakeeb Atilla A House Michael G MG Zyromski Nicholas J NJ Schmidt C Max CM Schloss Katheryn N H KNH Schloss Daniel E I DEI Liu Yunlong Y Jiang Guanglong G Hancock Bradley A BA Radovich Milan M Kays Joshua K JK Shahda Safi S Couch Marion E ME Koniaris Leonidas G LG Zimmers Teresa A TA

Cancers 20210420 8

The vast majority of patients with pancreatic ductal adenocarcinoma (PDAC) suffer cachexia. Although cachexia results from concurrent loss of adipose and muscle tissue, most studies focus on muscle alone. Emerging data demonstrate the prognostic value of fat loss in cachexia. Here we sought to identify the muscle and adipose gene profiles and pathways regulated in cachexia. Matched rectus abdominis muscle and subcutaneous adipose tissue were obtained at surgery from patients with benign conditio ...[more]

PMID: 33923976

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Project description:BackgroundCancer cachexia is a life-threatening metabolic syndrome that causes significant loss of skeletal muscle mass and significantly increases mortality in cancer patients. Currently, there is an urgent need for better understanding of the molecular pathophysiology of this disease so that effective therapies can be developed. The majority of pre-clinical studies evaluating skeletal muscle's response to cancer have focused on one or two pre-clinical models, and almost all have focused specifically on limb muscles. In the current study, we reveal key differences in the histology and transcriptomic signatures of a limb muscle and a respiratory muscle in orthotopic pancreatic cancer patient-derived xenograft (PDX) mice.MethodsTo create four cohorts of PDX mice evaluated in this study, tumours resected from four pancreatic ductal adenocarcinoma patients were portioned and attached to the pancreas of immunodeficient NSG mice.ResultsBody weight, muscle mass, and fat mass were significantly decreased in each PDX line. Histological assessment of cryosections taken from the tibialis anterior (TA) and diaphragm (DIA) revealed differential effects of tumour burden on their morphology. Subsequent genome-wide microarray analysis on TA and DIA also revealed key differences between their transcriptomes in response to cancer. Genes up-regulated in the DIA were enriched for extracellular matrix protein-encoding genes and genes related to the inflammatory response, while down-regulated genes were enriched for mitochondria related protein-encoding genes. Conversely, the TA showed up-regulation of canonical atrophy-associated pathways such as ubiquitin-mediated protein degradation and apoptosis, and down-regulation of genes encoding extracellular matrix proteins.ConclusionsThese data suggest that distinct biological processes may account for wasting in different skeletal muscles in response to the same tumour burden. Further investigation into these differences will be critical for the future development of effective clinical strategies to counter cancer cachexia.

Project description:Energetically inefficient inter-organ substrate shuttles are proposed contributors to cachexia-related weight loss. Here, we examined glycolytic pathway metabolites, enzyme activity and transport proteins in skeletal muscle, liver and tumours of mice with cachexia-related weight loss induced by colon-26 cancer cells. Skeletal muscle of cachexic mice had increased [L-lactate]/[pyruvate], LDH activity and lactate transporter MCT1. Cachexic livers also showed increased MCT1. This is consistent with the proposal that the rate of muscle-derived lactate shuttling to liver for use in gluconeogenesis is increased, that is, an increased Cori cycle flux in weight-losing cachexic mice. A second shuttle between liver and tumour may also contribute to disrupted energy balance and weight loss. We found increased high-affinity glucose transporter GLUT1 in tumours, suggesting active glucose uptake, tumour MCT1 detection and decreased intratumour [L-lactate]/[pyruvate], implying increased lactate efflux and/or intratumour lactate oxidation. Last, high [L-lactate]/[pyruvate] and MCT1 in cachexic muscle provides a potential muscle-derived lactate supply for the tumour (a 'reverse Warburg effect'), supporting tumour growth and consequent cachexia. Our findings suggest several substrate shuttles among liver, skeletal muscle and tumour contribute to metabolic disruption and weight loss. Therapies that aim to normalize dysregulated substrate shuttling among energy-regulating tissues may alleviate unintended weight loss in cancer cachexia. SIGNIFICANCE OF THE STUDY: Cachexia is a serious complication of cancer characterized by severe weight loss, muscle atrophy and frailty. Cachexia occurs in roughly half of all cancer patients, and in up to 80% of patients with advanced disease. Cachexia independently worsens patient prognosis, lowers treatment efficacy, increases hospitalization cost and length of stay, and accounts for 20-30% of cancer-related deaths. There are no effective treatments. Our findings suggest several substrate shuttles among liver, skeletal muscle and tumour contribute to metabolic disruption and weight loss in cancer cachexia. Identifying therapies that normalize dysregulated substrate shuttling among energy-regulating tissues may protect against cachexia-related weight loss.

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.

Dataset Information

Profiling of Adipose and Skeletal Muscle in Human Pancreatic Cancer Cachexia Reveals Distinct Gene Profiles with Convergent Pathways.

Publications

Profiling of Adipose and Skeletal Muscle in Human Pancreatic Cancer Cachexia Reveals Distinct Gene Profiles with Convergent Pathways.

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