Identification of YAP/TAZ-regulated non-coding RNAs (ncRNAs) in liver cancer

• Applicant: Professor Dr. Kai Breuhahn
• Subject Area: Pathology
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 412294938

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related deaths with rising incidence in developing and industrialized countries. We and others have shown that the oncogenic Hippo pathway effector YAP (yes-associated protein) represents a promising therapeutic target structure in a subgroup of HCC patients (around 30%). Here YAP induces tumour formation and progression through the induction of gene signatures, which foster chromosomal instability (CIN). Indeed, the inhibition of YAP activity is currently in the focus of many pharmaceutical companies and it is very likely that already existing substances (e.g. verteporfin) or new drugs will be available for the treatment of cancer patients, soon. However, how can patients suitable for a YAP-directed therapy be identified in tumorigenesis?Our preliminary data illustrate that YAP and its paralogue TAZ regulate long non-coding RNAs (lncRNAs) and microRNA (miRNA) in hepatocellular cells. Since both RNA species are detectable in blood and serum of cancer patients, we hypothesize that lncRNA and miRNA may serve as perfect tools for the identification of HCC subgroups with oncogenic YAP/TAZ activation. To generate a comprehensive picture of how YAP/TAZ affect non-coding RNAs (ncRNAs) in hepatocytes and HCC cells and if this knowledge can lead to the identification of meaningful biomarker signatures, we propose a work program that clarifies the following scientific aspects: - Identification of YAP/TAZ-dependent ncRNA/mRNA networks and classifier signatures.- Defining the extent by which lncRNAs and miRNAs mediate the oncogenic properties of YAP and TAZ in vitro and in vivo. - Identification of ncRNA signatures/networks to be used for the classification of HCC patients suitable for a YAP/TAZ-directed therapy.Using techniques from molecular biology, biochemistry, and cell biology we will identify individual lncRNAs and miRNAs as well as complex regulatory ncRNA networks that are specifically regulated by YAP and TAZ in hepatocellular cells. The mode of ncRNA regulation by YAP/TAZ will be analysed as well as their functional relevance in vitro and in innovative in vivo models. Importantly, the confirmation of our findings will be possible through the excellent accessibility to patient material, which will allow us to compare the expression and localization of YAP/TAZ in HCC tissue as well the abundance of mRNA and ncRNA species in tissue and serum samples. In summary, this project will provide comprehensive information of how oncogenic YAP/TAZ is regulating ncRNAs and how this affects tumour initiation and progression. In addition, we will use these results to systematically define individual ncRNAs or ncRNA networks that could serve as serum biomarkers for the identification of patients suitable for YAP/TAZ-directed therapies.

• DFG Programme: Research Grants
• International Connection: Egypt
• Cooperation Partners: Magda Assaf; Gamal Esmat; Imam Waked
• International Co-Applicant: Professor Dr. Ahmed Fahmy