The transcriptional coactivator TAZ has an opposite impact on progression-free survival of metastatic colorectal cancer patients depending on Colorectal Cancer Assigner subtypes

Background. The Hippo pathway is a highly conserved signalling, and, in the majority of cancers, its alteration and the consequent activation of YAP and TAZ are oncogenic stimuli. However, the role of this pathway is not always straightforward as in the case of colorectal cancer (CRC). Herein, we sought to understand the impact of Hippo disruption on the response to chemotherapy of CRC patients also in the light of molecular subtypes, which highlight peculiar biological features. Methods. The expression levels of 74 genes belonging to the expanded Hippo pathway and four genes encoding for immune checkpoint molecules were evaluated in 94 synchronous RAS-mutated metastatic CRC included in the arm B of TRIBE2 study. These patients were treated with fluorouracil, oxaliplatin and irinotecan plus bevacizumab. Results. The expression levels of YAP, TAZ and their targets were greatly variable among molecular subtypes especially Colorectal Cancer Assigner (CRCA). In particular, stem-like tumors expressed the highest levels of these genes, whereas goblet-like had the lowest expression level. TAZ and YAP/TAZ target levels positively correlated with those of checkpoint molecules such as CTLA-4 and VISTA. Finally, TAZ levels had a significant interaction with CRCA subtypes in progression-free survival (PFS); specifically, high TAZ levels predict a worse PFS in inflammatory, mixed and stem-like tumors, whereas they are associated with a better outcome in enterocyte, goblet-like and transit amplifying. Conclusion. The role of TAZ depends on the CRCA subtypes. Stem-like tumors might be the most addicted to this signalling, whereas in differentiated tumors, such as enterocyte and goblet-like, TAZ might have an opposite role. The inhibition of this signalling is an appealing strategy in CRC, but CRCA should be considered to understand which tumors can benefit from this approach.