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Molecular Subtypes of Human Skeletal Muscle in Cancer Cachexia

ABSTRACT: Cancer-associated muscle wasting associates with poor clinical outcomes1, but its underlying biology is largely uncharted in humans2. Unbiased RNAome analysis (coding and non-coding RNAs) with unsupervised clustering using Integrative Non-negative Matrix Factorization (intNMF)3 provides an avenue to identify distinct molecular subtypes, here applied to muscle of patients with colorectal or pancreatic cancer. Rectus abdominis biopsies from 84 patients was profiled using high-throughput next generation sequencing. Here we show that intNMF with stringent quality metrics of clustering identifies 2 highly coherent molecular subtypes within muscle of patients with cancer. Patients in Subtype 1 (vs Subtype 2) showed clinical manifestations of cachexia: high-grade weight loss, low muscle mass, atrophy of Type IIA and Type IIX muscle fibres and reduced survival. Based on differential expression between the subtypes, our results indicate biological processes that may contribute to cancer-associated loss of muscle mass and function, including altered post-transcriptional regulation, and perturbation of neuronal systems, cytokine storm/cellular immune response, extracellular matrix, and metabolic abnormalities spanning xenobiotic metabolism, hemostasis, signal transduction, embryonic/pluripotent stem cells, and amino acid metabolism. Differential expression between subtypes indicates involvement of multiple, intertwined higher-order gene regulatory networks, suggesting potential for interacting (hub)lncRNA-miRNA-mRNA interaction networks as targets for future research.

ORGANISM(S): Homo sapiens

PROVIDER: GSE254877 | GEO | 2025/07/17

REPOSITORIES: GEO

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Molecular Subtypes of Human Skeletal Muscle in Cancer Cachexia

Project description:Cancer-associated muscle wasting associates with poor clinical outcomes1, but its underlying biology is largely uncharted in humans2. Unbiased RNAome analysis (coding and non-coding RNAs) with unsupervised clustering using Integrative Non-negative Matrix Factorization (intNMF)3 provides an avenue to identify distinct molecular subtypes, here applied to muscle of patients with colorectal or pancreatic cancer. Rectus abdominis biopsies from 84 patients was profiled using high-throughput next generation sequencing. Here we show that intNMF with stringent quality metrics of clustering identifies 2 highly coherent molecular subtypes within muscle of patients with cancer. Patients in Subtype 1 (vs Subtype 2) showed clinical manifestations of cachexia: high-grade weight loss, low muscle mass, atrophy of Type IIA and Type IIX muscle fibres and reduced survival. Based on differential expression between the subtypes, our results indicate biological processes that may contribute to cancer-associated loss of muscle mass and function, including altered post-transcriptional regulation, and perturbation of neuronal systems, cytokine storm/cellular immune response, extracellular matrix, and metabolic abnormalities spanning xenobiotic metabolism, hemostasis, signal transduction, embryonic/pluripotent stem cells, and amino acid metabolism. Differential expression between subtypes indicates involvement of multiple, intertwined higher-order gene regulatory networks, suggesting potential for interacting (hub)lncRNA-miRNA-mRNA interaction networks as targets for future research.

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Molecular Subtypes of Human Skeletal Muscle in Cancer Cachexia

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Project description:Skeletal muscle wasting is a devastating consequence of cancer that may be responsible for nearly 30% of cancer-related deaths. In addition to muscle atrophy, we have identified significant muscle fiber damage and replacement of muscle with fibrotic tissue in rectus abdominis muscle biopsies from cachectic pancreatic ductal adenocarcinoma (PDAC) patients that associates with poor survival. Transcriptional profiling of muscle harvested from these same patients supported these findings by identifying gene clusters related to wounding, inflammation and cellular response to TGF-B upregulated in cachectic PDAC patients compared with non-cancer controls. In this dataset, we include the expression data obtained from rectus abdominis muscle biopsies fron non-cancer controls patients undergoing abdominal surgery for benign reasons and from PDAC patients undergoing tumor-resection surgery. PDAC patients were further classified as non-cachectic or cachectic. Cachexia was defined as a body weight loss of >5% during the 6 months prior to surgery. The purpose of this study was to identify the broader transcriptional networks changed in cachectic PDAC patients versus non-cancer controls, that may be associated with the histological changes observed in muscle biopsies harvested from these same patients.

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