Skeletal muscle fibrosis in pancreatic Cancer patients with respect to survival
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Abstract Background Cancer cachexia is a catabolic condition characterized by skeletal muscle wasting, consequent to tumor burden, which negatively impacts tolerance to cancer therapies and contributes to increased mortality. Partly because of the limited knowledge of the underlying mechanisms of cancer cachexia derived from human studies, however, the ability to therapeutically intervene remains elusive. The purpose of the current study was therefore to better define the phenotype of skeletal muscle obtained from patients with pancreatic ductal adenocarcinoma (PDAC), which has one of the highest rates of cachexia. Methods Morphological analyses were performed on rectus abdominis muscle biopsies obtained from resectable PDAC patients undergoing tumor resection surgery (N = 20) and from weight-stable non-cancer control subjects undergoing benign abdominal surgery (N = 16). PDAC patients with a body weight loss of greater than 5% during the previous 6 months were considered cachectic (N = 15). Statistical tests were two sided. Results Skeletal muscle from cachectic PDAC patients had increased collagen content compared with non-cancer control subjects (1.43% vs 9.66%, P = .0004, Dunn test). Across all PDAC patients, collagen content positively correlated with body weight loss (P = .0016, r = 0.672), was increased in patients with lymph node metastasis (P = .007, Mann-Whitney U test), and was associated with survival on univariate (HR = 1.08, 95% confidence interval [CI] = 1.02 to 1.04, P = .008) and multivariable analyses (HR = 1.08, 95% CI = 1.00 to 1.17, P = .038). Cachectic PDAC patients also displayed increased lipid deposition (2.63% vs 5.72%, P = .042), infiltration of CD68+ macrophages (63.6 cells/mm2 vs 233.8 cells/mm2, P = .0238), calcium deposition (0.21% vs 2.51%, P = .030), and evidence of deficient cellular quality control mechanisms (Mann-Whitney U test). Transcriptional profiling of all patients supported these findings by identifying gene clusters related to wounding, inflammation, and cellular response to TGF-β upregulated in cachectic PDAC patients compared with non-cancer control subjects. Conclusions To our knowledge, this work is the first to demonstrate increased collagen content in cachectic PDAC patients that is associated with poor survival.
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With aging and chronic disease, senescent FAPs and endothelial cells may accumulate as witnessed in similar cell types of other organs.
“with aging and chronic disease, senescent FAPs and endothelial cells may accumulate as witnessed in similar cell types of other organs”
From Skeletal muscle aging, cellular senescence, and senotherapeutics: current knowledge and future directions (2021) · cites this paper as Judge et al., 2018
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Cardaci, T. D., VanderVeen, B. N., Bullard, B. M., McDonald, S. J., Unger, C. A., Enos, R. T., Fan, D., Velázquez, K. T., Frizzell, N., Spangenburg, E. E., et al. (2023) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.13391 · Cited by 27 · see citing works
Lin, Y., Hou, Y., Wang, H., & Shan, Y. (2023) · Theranostics · doi:10.7150/thno.82911 · Cited by 26 · see citing works
Activated mast cells in skeletal muscle can be a potential mediator for cancer‐associated cachexia
Widner, D. B., Liu, C., Zhao, Q., Sharp, S., Eber, M. R., Park, S. H., Files, D. C., & Shiozawa, Y. (2021) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.12714 · Cited by 25 · see citing works
Kunz, H., Dorschner, J. M., Berent, T. E., Meyer, T., Wang, X., Jatoi, A., Kumar, R., & Lanza, I. R. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.014884 · Cited by 23 · see citing works
Lu, Z., Wang, L., Huo, Z., Li, N., Tong, N., Chong, F., Liu, J., Zhang, Y., & Xu, H. (2024) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.13544 · Cited by 20 · see citing works
Cameron, M. E., Underwood, P. W., Williams, I. E., George, T. J., Judge, S. M., Yarrow, J. F., Trevino, J. G., & Judge, A. R. (2021) · Cancer Medicine · doi:10.1002/cam4.4416 · Cited by 20 · see citing works
Neyroud, D., D’Lugos, A. C., Trevino, E. J., Callaway, C. S., Lamm, J. H., Laitano, O., Poole, B., Deyhle, M. R., Brantley, J., Le, L., et al. (2025) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.13668 · Cited by 19 · see citing works
Exploring heterogeneity: a dive into preclinical models of cancer cachexia
da Silva, F. M., Cabrera, A. R., & Greene, N. P. (2024) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00317.2024 · Cited by 20 · see citing works
Skeletal muscle omics signatures in cancer cachexia: perspectives and opportunities
Gilmore, L. A., Parry, T. L., Thomas, G. A., & Khamoui, A. V. (2023) · JNCI Monographs · doi:10.1093/jncimonographs/lgad006 · Cited by 17 · see citing works
Mitochondrial fusion and altered beta-oxidation drive muscle wasting in a Drosophila cachexia model
Dark, C., Ali, N., Golenkina, S., Dhyani, V., Blazev, R., Parker, B. L., Murphy, K. T., Lynch, G. S., Senapati, T., Millard, S. S., et al. (2024) · EMBO Reports · doi:10.1038/s44319-024-00102-z · Cited by 16 · see citing works
Melchor, S. J., Hatter, J. A., Castillo, É. A. L., Saunders, C. M., Byrnes, K. A., Sanders, I., Abebayehu, D., Barker, T. H., & Ewald, S. E. (2020) · Scientific Reports · doi:10.1038/s41598-020-72767-0 · Cited by 15 · see citing works
Development of skeletal muscle fibrosis in a rodent model of cancer cachexia
Washington, T. A., Schrems, E. R., Haynie, W. S., Rosa‐Caldwell, M. E., Brown, J. L., Saling, L. W., Lim, S., Perry, R. A., Brown, L. A., Lee, D. E., et al. (2023) · Cell Biochemistry and Function · doi:10.1002/cbf.3797 · Cited by 14 · see citing works
Park, M. A., Whelan, C. J., Ahmed, S., Boeringer, T., Brown, J. S., Carson, T., Crowder, S. L., Gage, K. L., Gregg, C. J., Jeong, D. K., et al. (2024) · Cancers · doi:10.3390/cancers16132364 · Cited by 12 · see citing works
Cole, C. L., Bachman, J. F., Ye, J., Murphy, J. D., Gerber, S. A., Beck, C. A., Boyce, B. F., Muthukrishnan, G., Chakkalakal, J. V., Schwarz, E. M., et al. (2021) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.12699 · Cited by 12 · see citing works
Molecular mechanisms of skeletal muscle fibrosis and potential targeted therapeutic strategies
Gong, J., Xu, J., Zhang, J., Shen, Y., Sun, H., & Chen, B. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1714238 · Cited by 11 · see citing works
Platelet status in cancer cachexia progression in ApcMin/+ mice
Cunningham, P., Unger, C. A., Patton, E. A., Aiken, A., Browne, A., James, E., Al-Adhami, A., Hope, M. C., VanderVeen, B. N., Cardaci, T. D., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1253587 · Cited by 9 · see citing works
Cancer-induced FOXP1 disrupts and reprograms skeletal-muscle circadian transcription in cachexia
Ducharme, J. B., Neyroud, D., Schonk, M. M., Gutierrez‐Monreal, M. A., Huo, Z., Tucker, H. O., Esser, K. A., Judge, S. M., & Judge, A. R. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115689 · Cited by 9 · see citing works
D’Lugos, A. C., Ducharme, J. B., Callaway, C. S., Trevino, J. G., Atkinson, C., Judge, S. M., & Judge, A. R. (2025) · Journal of Clinical Investigation · doi:10.1172/jci178806 · Cited by 8 · see citing works
Ducharme, J. B., Carelock, M. E., Schonk, M. M., Al‐Zaeed, N., Zhang, W., Judge, S. M., & Judge, A. R. (2025) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00816.2024 · Cited by 7 · see citing works
Hildebrandt, W., Keck, J., Schmich, S. K. P., Bonaterra, G. A., Wilhelm, B., Schwarzbach, H., Eva, A., Bertoune, M., Slater, E. P., Fendrich, V., et al. (2022) · Cells · doi:10.3390/cells11101607 · Cited by 7 · see citing works
Cameron, M. E., Ayzengart, A., Oduntan, O., Judge, S. M., Judge, A. R., & Awad, Z. T. (2023) · Journal of the American College of Surgeons · doi:10.1097/xcs.0000000000000535 · Cited by 7 · see citing works
Brown, A., Collao, N., Saleh, A., Strong, N., Lisio, M. D., & Wiper‐Bergeron, N. (2026) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.70260 · Cited by 5 · see citing works
Khamoui, A. V., Tokmina‐Roszyk, D., Feresin, R. G., Fields, G. B., & Visavadiya, N. P. (2022) · Proteomics · doi:10.1002/pmic.202100157 · Cited by 4 · see citing works
CXCL5 neutralization mitigates cancer cachexia by disrupting CAF-cancer cell crosstalk
Kim, H., Kim, S.-W., Kim, J.-H., Lee, S. H., Joo, K.-H., Lee, S., Lee, H., Min, J., Cho, S., Jung, D., et al. (2025) · Journal of Biomedical Science · doi:10.1186/s12929-025-01192-0 · Cited by 4 · see citing works
Proteomic profiling of the extracellular matrix in skeletal muscle
Swandulla, D., & Ohlendieck, K. (2025) · Advances in clinical chemistry · doi:10.1016/bs.acc.2025.06.008 · Cited by 3 · see citing works
Haug, M., Schwappacher, R., Pollmann, C., Ritter, P. D., Michael, M., Hermann, H. J., Grützmann, R., Mittelstädt, A., Neurath, M. F., Zopf, Y., et al. (2024) · Cancers · doi:10.3390/cancers16081608 · Cited by 3 · see citing works
Gait speed is a biomarker of cancer-associated cachexia decline and recoveryPreprint
Roy, I., Binder‐Markey, B. I., Sychowski, D., Willbanks, A. R., Phipps, T., McAllister, D. M., Bhakta, A., Marquez, E., D’Andrea, D., Franz, C. K., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.11.13.566852 · Cited by 3 · see citing works
The effects of tissue inflammation on cancer cachexia
Pryce, B. R., & Kerr, H. L. (2025) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2025.168144 · Cited by 2 · see citing works
Michael, M., Kovbasyuk, L. A., Ritter, P. D., Reid, M. B., Friedrich, O., & Haug, M. (2022) · Cells · doi:10.3390/cells11233715 · Cited by 2 · see citing works
Roy, I., Binder‐Markey, B. I., Willbanks, A. R., Sychowski, D., Phipps, T., Barber, A., McAllister, D. M., D’Andrea, D., Franz, C. K., Pichika, R., et al. (2024) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00173.2024 · Cited by 2 · see citing works
Puppa, M., & Carson, J. A. (2025) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-88361-3_12 · Cited by 2 · see citing works
Mitochondrial fusion and altered beta-oxidation drive muscle wasting in a Drosophila cachexia modelPreprint
Dark, C., Ali, N., Golenkina, S., Blazev, R., Parker, B. L., Murphy, K., Lynch, G. S., Senapati, T., Millard, S. S., Judge, S. M., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.06.23.546217 · Cited by 2 · see citing works
van de Haterd, B., Hendriks, M., Houben, B., Weijzen, M. E. G., Vandenabeele, F., Verboven, K., & Agten, A. (2025) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00533.2025 · Cited by 1 · see citing works
Concurrent PIK3CA mutant promotes cachexia through inflammatory signaling in EGFR mutant lung cancer
Yue, M., Qin, Z., Tang, S., Cai, X., Zhao, Y., Yang, C., Chen, L., Chen, L., & Ji, H. (2025) · Nature Communications · doi:10.1038/s41467-025-67345-9 · Cited by 1 · see citing works
Tumor-Secreted ADAMTSL4 Activates Latent TGFβ1 to Drive Cancer Cachexia
Machado, J., Karthikaisamy, V., Mohr, H., Kaltenecker, D., Benedikt, P., Morigny, P., Mhamane, A., Geppert, J., Fumo, A. R., Haase, K., et al. (2026) · Cancer Discovery · doi:10.1158/2159-8290.cd-26-0045 · Cited by 1 · see citing works
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Pathophysiological remodeling of the skeletal muscle microenvironment in patients with lung cancerPreprint
Battey, E., Irazoki, A., Wang, J., Sørensen, J., Modvig, J. L., Themsen, S. S. B., Voldstedlund, C. T., Knos, C., Andersen, N. R., Frank, E., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.11.19.689342 · Cited by 1 · see citing works
Ji, L. L. (2021) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.738789048.793582075
Biological Sex Differences of Fibrosis During the Development of Cancer CachexiaPreprint
Washington, T. A., Schrems, E. R., Haynie, W. S., Rosa‐Caldwell, M. E., Brown, J. L., Saling, L. W., Lim, S., Perry, R. A., Brown, L. A., Lee, D. J., et al. (2023) · doi:10.22541/au.167285880.01226764/v1
Judge, S. M., Deyhle, M. R., Neyroud, D., Nosacka, R. L., D’Lugos, A. C., Cameron, M. E., Vohra, R., Smuder, A. J., Roberts, B. M., Callaway, C. S., et al. (2023) · doi:10.1158/0008-5472.22424191
Judge, S. M., Deyhle, M. R., Neyroud, D., Nosacka, R. L., D’Lugos, A. C., Cameron, M. E., Vohra, R., Smuder, A. J., Roberts, B. M., Callaway, C. S., et al. (2023) · doi:10.1158/0008-5472.22424191.v1
SKELETAL MUSCLE SENSITIVITY TO WASTING INDUCED BY UROTHELIAL CARCINOMA
Esteves, M., Duarte, M., Oliveira, P. A., da Costa, R. M. G., Monteiro, M. P., & Duarte, J. A. (2023) · Experimental Oncology · doi:10.15407/exp-oncology.2023.01.107
CXCL5 Neutralization Mitigates Cancer Cachexia by Disrupting CAF-Cancer Cell CrosstalkPreprint
Kim, S.-W., Kim, H., Kim, J.-H., Lee, S. H., Lee, S., Lee, H., Min, J., Cho, S., Jung, D., & Williams, D. R. (2024) · SSRN Electronic Journal · doi:10.2139/ssrn.4835836
Exploiting the tumor microenvironment and tumor mechanobiology for the treatment of cancer cachexia
Papavassiliou, K. A., & Papavassiliou, A. G. (2024) · Annals of Oncology · doi:10.1016/j.annonc.2024.07.721
Multisymptom Burden in Cancer Survivors: Benefits of Physical Activity
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Parry, T. L., Gilmore, L. A., & Khamoui, A. V. (2025) · Functional & Integrative Genomics · doi:10.1007/s10142-024-01524-7
Concurrent PIK3CA mutant drives cachexia through inflammatory signaling in EGFR mutant lung cancerPreprint
Yue, M., Qin, Z., Tang, S., Cai, X., Zhao, Y., Chen, L., Chen, L., & Ji, H. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.01.17.633515
Counts, B. R., Jean, S., Gaafer, O. U., Ota, S., Inabathini, I., Guo, T., D, D. C. G., Ostrowski, M. C., Koniaris, L. G., Cao, S., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.09.01.673500
Li, X., van der Ende, M., Moonen, H. P. F. X., Plas, R. L. C., Lotstra, S., Poland, M., Keijer, J., Witkamp, R. F., van Heek, N. T., Grefte, S., et al. (2025) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.70117
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Sex-divergent skeletal muscle remodeling emerges early in cancer cachexia
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Duckett, S. M., Ducharme, J. B., Schonk, M. M., Neyroud, D., Judge, S. M., & Judge, A. R. (2026) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00390.2026
Pancreatic Cancer Disrupts Circadian Patterns of Gene Expression in Cardiorespiratory Muscles
Ducharme, J. B., Schonk, M. M., Gutierrez‐Monreal, M. A., Ferreira, L. F., Esser, K. A., Judge, A. R., & Judge, S. M. (2026) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.70383
- Authors
- Judge, S. M., Nosacka, R. L., Delitto, D., Gerber, M. H., Cameron, M. E., Trevino, J. G., & Judge, A. R.
- Affiliations
- University of Florida (US)
- University of Florida Health (US)
- Corresponding author
- Judge, Sarah M
- Judge, Andrew R
- ORCID
- Venue
- JNCI Cancer Spectrum
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-07-01
- Volume
- 2
- Issue
- 3
- Pages
- pky043-pky043
- ISSN
- 2515-5091 (ISSN-L)
- PMC
- PMC6322478
- OpenAlex
- W2909386160
- Cited by
- 91
- References
- 52
- Citations by year
- 2026: 9 · 2025: 17 · 2024: 11 · 2023: 19 · 2022: 8 · 2021: 11 · 2020: 12 · 2019: 4
- FWCI
- 4.63
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- JNCI Cancer Spectrum (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- National Institute of Arthritis, Musculoskeletal and Skin Diseases (R01AR060209)
- National Cancer Institute (R21CA194118)
- National Institutes of Health (UL1TR001427)
- V Foundation for Cancer Research (V2015-021)
- National Institute of Child Health and Human Development (T32-HD-043730)
- Clinical and Translational Science Award (UL1-TR001430)
- Topics
- Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Keywords
- cancer cachexia, skeletal muscle fibrosis, pancreatic ductal adenocarcinoma, collagen deposition, weight loss, survival, CD68+ macrophages, lipid accumulation, calcium deposition, cell quality control, TGF-beta, inflammation, lymph node metastasis, gene expression profiling, cachexia therapy
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