Repression of the Wnt pathway effector TCF7L2 reverses lethal cachexia in mice with intestinal cancers
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eLife Assessment
In this valuable study, the authors demonstrate that TCF7L2 plays a role in the pathogenesis of cachexia in a mouse model of GI cancer. The results are solid, although future studies will need further mechanistic analyses. These data will be interesting to cancer biologists, especially those trying to understand late-stage complications such as cachexia and wasting, a major cause of cancer morbidity and mortality.
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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 ( Apc Min/+ mouse model) but not colon (DSS-treated Apc Min/+ 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.
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eLife Assessment
In this valuable study, the authors demonstrate that TCF7L2 plays a role in the pathogenesis of cachexia in a mouse model of GI cancer. The results are solid, although future studies will need further mechanistic analyses. These data will be interesting to cancer biologists, especially those trying to understand late-stage complications such as cachexia and wasting, a major cause of cancer morbidity and mortality.
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Reviewer #1 (Public review):
Summary:
Systemic and partial Tcf7l2 repression is effective in protecting cancer mice from cachexia-induced death. Hence, this is a promising treatment strategy for cancer patients suffering from cachexia.
Strengths:
The method is well-designed and clearly explained.
Weaknesses:
(1) Abbreviations should be mentioned in full terms for the first time.
(2) Relatively old or even very old references in the Introduction and Discussion.
(3) The result section contains discussion with references, as well.
(4) The number of mice in individual groups is relatively small (3 mice in some groups).
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Reviewer #2 (Public review):
Summary:
This study by Leong and colleagues examines the role of the TCF7L2 transcription factor in the Wnt signaling pathway as a regulator of colon/small intestinal cancers and cachexia. Investigators utilize a Tet off repressor genetic system in mice under Dox regulation to silence TCF7L2. Results show DSS-treated APCMin/+ mice lose body weight that can be rapidly rescued by Dox treatment and suppression of TCF7L2 expression. Reduction of TCF7L2 rescues features of cachexia, including body weight, gastrocnemius muscle and adipose mass, as well as molecular markers of cachexia such as the E3 Ub ligases, MuRF1, and Atrogin-1. The most significant finding in the study is that loss of TCF7L2 reduces but does not eliminate tumor progression, as tumors go from adenomas to adenocarcinomas over time while mice …
Reviewer #2 (Public review):
Summary:
This study by Leong and colleagues examines the role of the TCF7L2 transcription factor in the Wnt signaling pathway as a regulator of colon/small intestinal cancers and cachexia. Investigators utilize a Tet off repressor genetic system in mice under Dox regulation to silence TCF7L2. Results show DSS-treated APCMin/+ mice lose body weight that can be rapidly rescued by Dox treatment and suppression of TCF7L2 expression. Reduction of TCF7L2 rescues features of cachexia, including body weight, gastrocnemius muscle and adipose mass, as well as molecular markers of cachexia such as the E3 Ub ligases, MuRF1, and Atrogin-1. The most significant finding in the study is that loss of TCF7L2 reduces but does not eliminate tumor progression, as tumors go from adenomas to adenocarcinomas over time while mice are treated with Dox, yet cachexia persists. This implies that TCF7L2 has a direct effect on cachexia. Overall, the study provides insight into the role of TCFL2 in the development of intestinal cancers and muscle atrophy in cachexia.
Strengths:
The study uses an elegant genetic mouse model to provide significant new insight into the role of TCFL2 in colon and small intestinal cancers. In addition, the authors describe the role of TCF7L2 as a regulator of muscle wasting in cachexia. This, too, can be viewed as a new finding for the cachexia field.
Weaknesses:
However, in its current form, the study lacks sufficient data to support the authors' claim regarding the relevance of TCF7L2 as a regulator of cachexia.
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