To understand and suppress liver cancer cell plasticity and evolution

The incidence of liver cancer is increasing worldwide and current therapies are ineffective. This is mainly because liver tumors are highly heterogeneous, allowing the evolution of therapy resistant sub-clones. Thus, the objective of this project is to understand and control cancer cell plasticity in liver cancer. We will first characterize the spectrum of the cellular heterogeneity present in liver cancer and then identify molecular mechanisms that drive this heterogeneity. We will use an integrated approach that combines analyses of human and mouse cancers with state of the art single cell biology methodologies (RNA-seq, ATAC-seq) and sophisticated methods for somatic genome engineering in mouse models of liver cancer. This will allow us to determine the molecular spectrum of liver cancer cell phenotypes from patients with different types of liver cancer (HCC, CCA, and mixed CCA-HCC). We will then determine the role of the Hippo pathway as a driver of cancer cell plasticity and heterogeneity to identify the mechanism by which liver cancer cells switch into an aggressive phenotype. Altogether, our experiments will provide a comprehensive understanding of how epigenetic signals orchestrate liver cancer cell fate decisions and drive liver cancer heterogeneity.

Keywords:Single cell sequencing, Tumor heterogeneity, Genetic mouse models, Liver Cancer, Hippo signaling, YAP, TAZ

Disciplines:Cancer biology, Vertebrate biology, Animal cell and molecular biology, Cell growth and development, Cell signalling, Hepatology