Novel tumor-specific target for colorectal cancer


Scientists have identified a tumor-specific therapeutic target for colorectal cancers with mutations in the APC gene.

Mutations in APC play a role in the vast majority of colorectal cancer cases. The APC gene is a tumor suppressor gene. Under normal conditions, APC makes a protein that functions as an essential negative regulator of the Wnt signaling pathway. When APC is mutated, the Wnt signaling pathway may become overactive, resulting in cancer development. Overactivation of Wnt signaling has been observed in many different cancers, especially colorectal cancer. Thus, inhibiting Wnt signaling has become a treatment approach. However, since the Wnt signaling pathway is present in many different tissues in the body, targeting it can cause considerable side effects.

In the new study, a group of researchers headed by Dr. Vivian Li of the Francis Crick Institute identified a way to selectively inhibit Wnt signaling in cancer cells while sparing healthy cells. Their findings were described in a paper titled "USP7 Is a Tumor-Specific WNT Activator for APC-Mutated Colorectal Cancer by Mediating β-Catenin Deubiquitination," appearing in the journal Cell Reports this week.

Mutations can occur anywhere in the APC gene, but tend to be clustered in the mutation cluster region (MCR) and result in a truncated protein product. Using the CRISPR/Cas9 technique, the group engineered different APC truncating mutations in human cell lines. They identified a specific region in the APC gene that is critical for regulating Wnt signaling and tumor transformation. The region, known as the β-catenin inhibitory domain (CID), locates right at the MCR.

Further investigation revealed that an enzyme called USP7 is involved in the mechanism by which CID-lacking APC truncation results in Wnt pathway activation. Depletion of USP7 suppressed Wnt activation and the growth of APC-truncated colorectal cancer cells. Notably, USP7 depletion did not affect the growth of normal cells harboring wild-type APC. Collectively, these data indicate that the Wnt-activating role of USP7 is specific to colorectal cancer cells carrying APC mutations.

To confirm the findings, the group injected immunocompromised mice with human APC-mutated colorectal cancer cells and treated the mice with a USP7 inhibitor. The USP7 inhibitor remarkably suppressed tumor growth in vivo. No obvious side effects occurred.

In conclusion, the study identifies USP7 as a tumor-specific therapeutic target for APC-mutated colorectal cancer.
 
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