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

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. Overall design: 6 samples were analysed, comprising of colon tumours from cachectic APC-WT mice under doxycycline treatment for 10 days (n = 3) and recovered APC-KI mice under doxycycline treatmnet for 6 weeks (n = 3). Doxycycline treatment repressed endogenous Tcf7l2 expression in a systemic manner, but only APC-KI and not APC-WT mice.