Not All Wnt Activation Is Equal: Ligand-Dependent versus Ligand-Independent Wnt Activation in Colorectal Cancer

Cancers
Sam O Kleeman, Simon J Leedham

Abstract

Wnt signaling is ubiquitously activated in colorectal tumors and driver mutations are identified in genes such as APC, CTNNB1, RNF43 and R-spondin (RSPO2/3). Adenomatous polyposis coli (APC) and CTNNB1 mutations lead to downstream constitutive activation (ligand-independent), while RNF43 and RSPO mutations require exogenous Wnt ligand to activate signaling (ligand-dependent). Here, we present evidence that these mutations are not equivalent and that ligand-dependent and ligand-independent tumors differ in terms of underlying Wnt biology, molecular pathogenesis, morphology and prognosis. These non-overlapping characteristics can be harnessed to develop biomarkers and targeted treatments for ligand-dependent tumors, including porcupine inhibitors, anti-RSPO3 antibodies and asparaginase. There is emerging evidence that these therapies may synergize with immunotherapy in ligand-dependent tumors. In summary, we propose that ligand-dependent tumors are an underappreciated separate disease entity in colorectal cancer.

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Citations

Jul 13, 2021·Drug Discovery Today·Avradip ChatterjeeManash K Paul
Nov 18, 2021·Science Advances·Sarika HeinoKari Alitalo

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Methods Mentioned

BETA
transfection
biopsy
xenografts
xenograft
ubiquitination

Clinical Trials Mentioned

NCT01351103
NCT03447470
NCT03507998
NCT02521844
NCT02675946

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