Abstract 5436: A therapeutically targetable dysadherin/YAP axis promotes cancer stem features and tumor aggressiveness in hepatocellular carcinoma

Abstract

Abstract Hepatocellular carcinoma (HCC) remains one of the most challenging tumors to treat. Cancer stem-like cells (CSCs) are believed to be important in HCC development, immune evasion, and treatment resistance. Dysadherin is a cell membrane glycoprotein linked to cancer progression by endowing HCC with CSC features. However, the underlying mechanism of increasing CSC characteristics in refractory advanced HCC is not entirely understood. A comprehensive bioinformatics study revealed that dysadherin-expressing HCC cells were associated with cancer stemness and the YAP signaling activation. Dysadherin knockdown or overexpression in liver cancer cell lines attenuated or increased cancer stemness and aggressiveness via YAP signaling, respectively. Correspondingly, dysadherin deficiency lowered cancer stemness and aggressiveness in the HCC mouse model by blocking the YAP pathway. Mechanistically, dysadherin promoted YAP nuclear localization, which activated stem cell transcription factors such as OCT4, KLF4, and MYC. Of note, our comprehensive gain and loss of function studies in CSCs demonstrated that targeting the dysadherin/YAP axis could boost sorafenib’s therapeutic effect and suppress PD-L1 expression, which helps tumor cells escape from immune surveillance. Thus, our results highlight that the dysadherin/YAP axis drives the aggressive phenotype of HCC, providing a potential therapeutic strategy for HCC. Citation Format: So-El Jeon, Tae-Young Jang, Choong-Jae Lee, Hyeon-Ji Yun, Yeong-Hoon Cho, Da-Ye Lim, Jeong-Seok Nam. A therapeutically targetable dysadherin/YAP axis promotes cancer stem features and tumor aggressiveness in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5436.