Abstract IA21: The Hippo pathway in cancer

Abstract

Abstract The Hippo pathway plays a critical role in organ size control in development. Deregulation of the Hippo pathway leads to drastic enlargement of organs due to increased cell proliferation, inhibition of apoptosis, and dedifferentiation of differentiated cells. Interestingly, deregulation of the Hippo pathway also plays a critical role in tumorigenesis. However, precise roles of the Hippo pathway in tumorigenesis are unclear. By generating genetically defined liver tumor-initiating cells (TICs) with Hippo pathway inactivation or YAP activation, we found that the Hippo pathway unexpectedly mediates a crosstalk between TICs and the immune system. Via cytokines induced by YAP, TICs actively recruit M2 macrophages from as early as the single-cell stage. Elimination of TIC-associated macrophages (TICAMs) abolishes tumorigenesis in a manner dependent on the immune system. Furthermore, YAP activation has been observed in TICs induced by pathologically relevant oncogenes in murine livers and in human hepatocellular carcinoma (HCC) precancerous lesions. These results demonstrate for the first time that macrophages play a decisive role in the survival of single TIC in vivo and provide a proof of principle for TIC elimination by targeting YAP or M2 macrophages. Furthermore, we found that YAP induces leukocyte-specific integrin β2 (ITGB2) expression in cancer cells, thereby promoting cell invasion through the endothelium in a manner mimicking leukocytes. Through independent biochemical purification and a functional screen, we further identified PR/SET domain 4 (PRDM4) as a transcription factor interacting with the WW domains of YAP to mediate ITGB2 expression and cell invasion. Consistently, ITGB2 and PRDM4 mRNA levels are significantly increased in metastatic prostate cancer. In addition, PRDM4 contributes to YAP-induced tumorigenesis, possibly via mediating the expression of other YAP target genes. Our results demonstrate that YAP promotes cell invasion by inducing leukocyte-specific integrin expression and identify PRDM4 as a novel transcription factor for YAP targets. Citation Format: Xiaocan Guo, Huan Liu, Xiaolei Cao, Bin Zhao. The Hippo pathway in cancer [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr IA21.