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The gene encoding the main signaling molecules of the Wnt signaling pathways (the Wnt proteins) was discovered almost four decades ago by Nüsslein-Volhard and Wieschaus. They identified and originally named the gene "wingless" (wg) after a phenotype discovered during their landmark genetic screen in Drosophila for body pattern defects. At around the same time, another researcher named Harold Varmus found that a murine tumor virus activates the mammalian wg homolog, Int-1, which...
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    Area of Science:

    • Oncology
    • Molecular Biology
    • Cancer Therapeutics

    Background:

    • WNT signaling is crucial for intestinal homeostasis but drives colorectal cancer (CRC) when mutated.
    • APC mutations in CRC were thought to cause maximal WNT activation, a concept challenged by this study.

    Purpose of the Study:

    • To identify a therapeutic vulnerability in APC-mutant colorectal cancer.
    • To develop a novel cancer therapy targeting WNT pathway dysregulation.

    Main Methods:

    • Organoid-based screening to identify WNT hyperactivation strategies.
    • Investigating the mechanistic link between WNT hyperactivation and apoptosis in APC-mutant cells.
    • Testing therapeutic efficacy in preclinical models and patient-derived tumors.

    Main Results:

    • APC-mutant cancer cells exist in a "WNT-just-right" zone and undergo apoptosis when WNT signaling is hyperactivated ("over-WNTing").
    • Over-WNTing triggers apoptosis via spillover into non-canonical planar cell polarity signaling, upregulating RHOC and inducing ROCK1/2-mediated cell death.
    • GSK3 inhibition, a method for over-WNTing, demonstrated therapeutic efficacy in adenomas and metastatic CRC models, including patient-derived tumors.

    Conclusions:

    • "Over-WNTing" represents a novel therapeutic strategy selectively targeting cancer cells by exploiting WNT pathway differences.
    • This approach offers a dual benefit: eliminating tumors while enhancing normal tissue function and regeneration.
    • GSK3 inhibition, particularly with nanoparticle formulations, shows promise for treating colorectal cancer across its spectrum.