The WNT/β-catenin signaling pathway plays a major role in normal development and is aberrantly active in cancer. In normal homeostasis, the destruction complex phosphorylates serine residues in β-catenin leading to its degradation by the proteasome. Upon binding of the WNT ligand to the FZD/LRP receptor the destruction complex is inactivated leading to accumulation and nuclear translocation of β-catenin. In the nucleus β-catenin binds to transcription regulators that drive the expression of genes that promote cell proliferation and differentiation (Fig. 1).
Genomic alterations leading to aberrant β-catenin activity are found in the majority of colon cancers and suffice to drive tumor growth. Specifically, inactivating mutations in the tumor suppressor APC are found in ~80% of colon cancers, and we have recently reported that the remaining 20% of colon cancers harbor loss of function mutation in RNF43, a negative regulator of the WNT/β-catenin signaling pathway, suggesting that deregulation of β-catenin activity is required in nearly all colon cancers. Furthermore, studies in animal models and cultured cell lines demonstrate that β-catenin activity is required for tumor progression even in advanced cancers. However, despite the indisputable evidence demonstrating the requirement of this pathway for colon cancer pathogenesis we still lack strategies for direct targeting of β-catenin.
Loss of function screens identify genes required for proliferation of β-catenin driven cancers.
Using loss of function proliferation screens we are able to identify all the genes that are required for proliferation of a particular cancer cell lines. Using an RNAi based approach we have identified genes that that are essential in 216 cancer cell lines. By β-catenin active and inactive cell lines we find genes that are essential for proliferation only in the context of aberrant β-catenin activity
YAP1, β-catenin and cancer
Our previous observations using genome scale RNAi loss of function screening in 84 cancer cell lines identified the transcription factor YAP1 as a gene essential for survival of cell lines with aberrant β-catenin activity (Rosenbluh et al. Cell, 2012). Further mechanistic studies revealed that YAP1 and β-catenin form a transcription complex that drives the transcription of cell survival genes such as BCL2L1 and BIRC5. Furthermore, we found that the YES1, a member of the tyrosine kinase family, regulates the activity of this complex and that small molecule inhibitors of YES1 modulate the activity of this complex. Research in the lab will focus on identifying new YAP1 inhibitors and on further charecterization of YAP1 activity in β-catenin driven cancers.
Rosenbluh et al.