Repression of the Wnt pathway effector TCF7L2 reverses lethal cachexia in mice with intestinal cancers

Abstract

Hyper-activation of the canonical Wnt signaling pathway drives small intestine and colon tumors. As the major Wnt pathway effector in healthy intestines, TCF7L2 is a suspected oncogene in both cancer types. However, this has been challenging to verify because Tcf7l2 knockout is lethal. To circumvent lethality, we generated a novel transgenic mouse that allows dose-dependent, systemic, inducible and reversible repression of endogenous Tcf7l2 expression. Using this mouse, we demonstrate that TCF7L2 is essential for early adenoma development in the small intestine (ApcMin/+ mouse model) but not colon (DSS-treated ApcMin/+ mouse model). Once established however, neither small intestine nor colon adenomas require TCF7L2 for maintenance. Despite this, Tcf7l2 repression rescues both types of cancer mice from lethal cachexia--a prevalent cancer comorbidity characterized by debilitating weight loss and skeletal muscle atrophy. In colon cancer cachexia, elevated TCF7L2 in the gastrocnemius muscle induces atrophy by activating the transcription of multiple atrophy genes within the ubiquitin-proteasome and autophagy-lysosome systems. Hence, repressing Tcf7l2 normalizes atrophy gene expression back to non-cachectic expression levels and restores muscle mass. The cachexia recovery mechanism in small intestine cancer remains undefined but is independent of the gastrocnemius. This study shows that systemic and partial Tcf7l2 repression is both well-tolerated and effective in rescuing moribund cancer mice from cachexia-induced death. Hence this is a promising treatment strategy for cancer patients suffering from cachexia. Additionally, our transgenic mouse is a valuable tool to study muscle atrophy across other conditions including aging, diabetes and neuromuscular disease.