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

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.

Lef1 restricts ectopic crypt formation and tumor cell growth in intestinal adenomas

“…Although Apc- mutant adenomas are independent of Wnt ligands ( 15 , 58 ), we found that several Wnt antagonists were decreased after Apc ; Lef1 deletion. This observation may be functionally significant, as a recent study showed that the secreted Wnt antagonist Notum produced by the Apc -mutant adenomas inhibits Wnt signaling in the neighboring WT ISCs ( 59 , 60 ).…”

“…APC and CTNNB1 mutations lead to constitutive activation of the Wnt pathway, in which the tumors progress in a Wnt ligand–independent manner ( 15 ). CRC can also develop through an alternative serrated trajectory that involves distinct genetic alterations, such as truncating Ring finger protein 43 ( RNF43 ) mutations or R-spondin ( RSPO ) fusions ( 16 , 17 ).…”

Genetic and immune landscape evolution defines subtypes of MMR deficient colorectal cancer

“…Mutual exclusivity was observed for disrupting APC and RNF43 aberrations in the WNT-pathway. This allowed further validation of our algorithm for the identification of drivers in TS genes as AXIN2 RNA overexpression is an established marker of ligand-independent WNT activation (described to occur through APC inactivation or CTNNB1 hm) versus ligand dependent WNT activation (through RNF43 inactivation) (Kleeman and Leedham, 2020). Six tumors that harbored two truncal dm in APC showed significantly higher AXIN2 expression than tumors with truncal RNF43 drivers ( Fig.2D ), and similar expression to those with truncal APC dm/LOH or CTNNB1 hm.…”

Pilot Nanostring PanCancer pathway analysis of colon adenocarcinoma in a tertiary healthcare centre in Kerala, India

“…It is interesting to note that, ETV4, RNF43 and AXIN2 are highly correlated with tumour cell purity ( Figure 4b ). RNF43 and AXIN2 are negative regulators of the Wnt-ligand dependent type of CRC [ 27 , 28 ] and their downregulation in MSI samples might suggest an association of Wnt ligand dependent pathogenesis in a subset of tumours.…”