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Tcf7l2 is a master regulator of muscle wasting in severe cancer cachexia

ABSTRACT: Hyper-activation of the canonical Wnt signalling pathway drives tumour initiation and cancer progression. Of the four TCF/LEF transcription factors that propagate Wnt signalling, TCF7L2 is believed to be relevant in colorectal cancer because it is essential for adult gut homeostasis. However, this has been challenging to verify because Tcf7l2 germline or adulthood knockouts are lethal. To circumvent lethality and mimic the systemic action of a potential drug, we generated a transgenic mouse strain that allows inducible, tuneable and reversible repression of endogenous Tcf7l2. While >95 % Tcf7l2 repression was lethal, 80 % repression rescued moribund mice from death in the ApcMin/+-DSS colon adenocarcinoma model. Unexpectedly, Tcf7l2 repression did not impact tumour growth but reversed lethal cachexia—a cancer comorbidity characterised by severe weight and muscle loss. During severe cachexia, elevated Tcf7l2 in the gastrocnemius muscle induces atrophy via the ubiquitin proteasome system (UPS) and autophagy lysosome system (ALS). Repressing Tcf7l2 in the gastrocnemius reduces the expression of UPS and ALS genes to non-cachectic levels, thereby preventing atrophy and restoring muscle mass. Therapeutic targeting of TCF7L2 could ameliorate cachexia-induced muscle atrophy. Our mice could be utilised to study conditions that involve muscle atrophy, such as aging, diabetes and neuromuscular diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE212581 | GEO | 2025/09/02

REPOSITORIES: GEO

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Project description:Background: Cancer cachexia (CAC) reduces patient survival and quality of life. Developments of efficient therapeutic strategies are required for the CAC treatments. This long-term process could be shortened by the drug-repositioning approach which exploits old drugs approved for non-cachexia disease. Amiloride, a diuretic drug, is clinically used for treatments of hypertension and edema due to heart failure. Here, we explored the effects of amiloride for ameliorating muscle wasting in murine models of cancer cachexia. Methods: CT26 and LLC tumor cells were subcutaneously injected into mice to induce cancer cachexia. Amiloride was intraperitoneally injected daily once tumors were formed. Cachexia features of the CT26 and LLC models, respectively, were characterized by phenotypic, histopathologic and biochemical analyses. Plasma exosomes and muscle atrophy-related proteins were quantitatively analyzed. Integrative NMR-based metabolomic and transcriptomic analyses were conducted to identify significantly altered metabolic pathways and distinctly changed metabolism-related biological processes in gastrocnemius. Results: The CT26 and LLC models displayed prominent cachexia features including decreases in body weight, skeletal muscle, adipose tissue and muscle strength. The amiloride treatment in tumor-bearing mice distinctly alleviated muscle atrophy and relieved cachexia-related features without affecting tumor growth. The CT26 and LLC cachexia mice showed increased particle density of plasma exosomes which were largely derived from tumors. Significantly, the amiloride treatment inhibited tumor-derived exosome release, which did not obviously affect exosome secretion from non-neoplastic tissues or induce observable systemic toxicities in normal healthy mice. Integrative-omics revealed significant metabolic impairments in cachectic gastrocnemius, including promoted muscular catabolism, inhibited muscular protein synthesis, blocked glycolysis and impeded ketone body oxidation. The amiloride treatment evidently improved the metabolic impairments in cachectic gastrocnemius. Conclusions: Our results demonstrated the efficacy of amiloride in ameliorating cachectic muscle wasting and elucidated the underlying mechanistic rationale for its use as an alternative strategy to improve CAC treatments.

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Tcf7l2 is a master regulator of muscle wasting in severe cancer cachexia

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