YAP1 depletion enhances TAZ and its complexation with TEAD4 and AP-1 heterodimer C-JUN/FOSB in gastric cancer progression and metastasis.

Background: Dysregulation of the Hippo signaling pathway, characterized by aberrant activation of the transcriptional coactivators YAP1 and TAZ, drives tumor progression, immunosuppression, and metastasis. Hippo pathway components are emerging therapeutic targets in several solid tumors, however, the expression profiles of Hippo coactivators YAP1, TAZ, and their transcriptional factors TEAD1-4 in gastric cancer peritoneal metastases (GCPMs), and their therapeutic value, are unknown. In this study, we sought to determine the expression status of YAP1, TAZ, and TEAD1-4 in GCPMs and to evaluate whether dual targeting of YAP1 and TAZ provides superior antitumor activity compared with inhibition of either coactivator alone. Methods: Expression of YAP1, TAZ, and TEAD1-4 was examined in GCPMs by single-cell RNA sequencing and co-immunofluorescent staining. Functional studies using genetic knockout and antisense oligonucleotide (ASO) inhibition of YAP1 or TAZ were performed to assess antineoplastic effects Results: YAP1, TAZ, and TEADs1- 4 were highly coexpressed in GCPMs and correlated with poor survival. YAP1 inhibition alone elicited compensatory upregulation of TAZ, while combined inhibition of both coactivators maximally repressed cell proliferation and invasion Conclusions: These findings show that combined YAP1 and TAZ inhibition holds promise for the treatment of GCPM, a highly lethal disease with an urgent need for novel treatment options.