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Updated: Sep 17, 2025
The Colon-26 Carcinoma Tumor-bearing Mouse as a Model for the Study of Cancer Cachexia
Published on: November 30, 2016
The TWEAK/Fn14 signaling mediates skeletal muscle wasting during cancer cachexia
Meiricris Tomaz da Silva1,2, Anirban Roy1,2, Anh Tuan Vuong1,2
1Institute of Muscle Biology and Cachexia, University of Houston College of Pharmacy, Houston, TX, USA.
Abstract:
Cancer cachexia is a multifactorial syndrome characterized by progressive skeletal muscle wasting. The TWEAK-Fn14 system regulates muscle mass in diverse conditions. However, its role in the regulation of muscle mass during cancer cachexia remains less understood. Here, we demonstrate that the levels of Fn14 are induced in skeletal muscle of multiple mouse models of cancer cachexia. Muscle-specific deletion of Fn14 reduces myofiber atrophy in mouse models of pancreatic and lung cancer cachexia. Silencing of Fn14 in KPC pancreatic cancer cells prior to their implantation in mice attenuates tumor growth without affecting myofiber size. Muscle-specific deletion of Fn14 reduces the gene expression of various components of the PERK and IRE1α arms of the unfolded protein response during KPC tumor growth. The inhibition of PERK improves protein synthesis and average myotube diameter in TWEAK-treated cultures. Altogether, our study suggests that the inhibition of TWEAK/Fn14 signaling can attenuate tumor growth and muscle wasting during cancer cachexia.
Insights
Targeting the TWEAK/Fn14 signaling pathway can reduce muscle wasting and tumor growth in cancer cachexia. Inhibiting Fn14 in skeletal muscle mitigates muscle atrophy, offering a potential therapeutic strategy for this debilitating condition.
Area of Science:
- Biomedical Science
- Molecular Biology
- Oncology
Background:
- Cancer cachexia involves progressive skeletal muscle wasting.
- The TWEAK-Fn14 system influences muscle mass.
- The role of TWEAK-Fn14 in cancer cachexia is not fully understood.
Purpose of the Study:
- To investigate the role of the TWEAK-Fn14 system in cancer cachexia.
- To determine if targeting TWEAK-Fn14 signaling can ameliorate muscle wasting and tumor progression.
Main Methods:
- Utilized mouse models of pancreatic and lung cancer cachexia.
- Performed muscle-specific deletion of Fn14.
- Assessed myofiber atrophy and tumor growth.
- Analyzed gene expression related to the unfolded protein response (UPR).
- Investigated the effect of PERK inhibition in vitro.
Main Results:
- Fn14 levels were elevated in skeletal muscle during cancer cachexia.
- Muscle-specific Fn14 deletion reduced myofiber atrophy in cancer models.
- Silencing Fn14 in cancer cells attenuated tumor growth.
- Fn14 deletion modulated UPR components (PERK, IRE1α).
- PERK inhibition improved protein synthesis and myotube diameter in TWEAK-treated cells.
Conclusions:
- The TWEAK-Fn14 pathway is implicated in cancer cachexia-associated muscle wasting.
- Inhibiting TWEAK/Fn14 signaling shows potential for treating cancer cachexia.
- Targeting this pathway may reduce both tumor growth and muscle loss.
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