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| Status |
Public on Mar 10, 2020 |
| Title |
Mouse limb and respiratory muscle show distinct cachexia profiles in response to human pancreatic tumors II |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
Background: Cancer 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. Almost all 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. Methods: To create the four cohorts of PDX mice evaluated in this study, tumors resected from four pancreatic ductal adenocarcinoma (PDAC) patients were portioned and attached to the pancreas of immunodeficient NSG mice. Results: Body 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 tumor-burden on their morphology. Subsequent genome-wide microarray analysis on TA and DIA revealed key differences between their transcriptomes in response to cancer as well. Indeed, upregulated genes in the diaphragm were enriched for extracellular matrix (ECM) protein-encoding genes and genes related to the inflammatory response, and downregulated genes were enriched for mitochondria related protein-encoding genes. Conversely, the TA showed upregulation of canonical atrophy-associated pathways such as ubiquitin-mediated protein degradation and apoptosis and enrichment of downregulated genes encoding ECM proteins. Conclusions: These data suggest that distinct biological processes account for wasting in different skeletal muscles in response to the same tumor burden. Further investigation into these differences will be critical for the future development of effective clinical strategies to counter cancer cachexia.
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| Overall design |
Four cohorts of PDX mice were evaluated in this study: tumors resected from four pancreatic ductal adenocarcinoma (PDAC) patients were portioned and attached to the pancreas of immunodeficient NSG mice which developed cachexia in response to tumor growth (sham mice underwent surgery with no tumor implantation). RNA was extracted from the tibialis anterior (TA) and diaphragm (DIA) of sham and PDAC-PDX mice. Subsequent microarray analysis was performed with multiple samples from both muscles of mice from each of the four cohorts.
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| Contributor(s) |
Nosacka R, Judge A |
| Citation(s) |
32039571 |
| |
| Submission date |
Sep 25, 2019 |
| Last update date |
Mar 12, 2020 |
| Contact name |
Boston University Microarray and Sequencing Resource |
| E-mail(s) |
msrdata@bu.edu
|
| Organization name |
Boston University
|
| Department |
Microarray and Sequencing Resource
|
| Street address |
72 East Concord Street, E631
|
| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02118 |
| Country |
USA |
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| Platforms (1) |
| GPL17791 |
[MoGene-2_0-st] Affymetrix Mouse Gene 2.0 ST Array [mogene20st_Mm_ENTREZG_17.1.0] |
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| Samples (58)
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| This SubSeries is part of SuperSeries: |
| GSE137985 |
Mouse limb and respiratory muscle show distinct cachexia profiles in response to human pancreatic tumors |
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| Relations |
| BioProject |
PRJNA574102 |
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