The lab aims to dissect the genetic control of liver regeneration during the process of tumor formation.
To systematically interrogate the behavior of pre-malignant and malignant cells before and after injury,
we are establishing new genetic and cell biological approaches. First, we have developed gene-editing methods so that we can more efficiently generate mutant hepatocytes in vitro and in vivo. This will allow
us to functionally assess a broader range of mutations identified in cancer genome efforts, both in isolation and in combination.
Second, we are developing regeneration assays with greater cellular resolution. These include competitive transplantation and genetic methods to observe mutant hepatocytes in their wild-type backgrounds before and after chemical or surgical injury. This approach, known as mosaic analysis, is important because it models how cancer really originates, and will allow us to see how pre-malignant clones behave evolutionarily and ecologically in a genetically heterogeneous environment.
Initially, we have directed our efforts toward understanding how WNT, MYC and Lin28/Let-7 pathway alterations affect regeneration. At the same time, we are tackling frequently identified but poorly understood lesions in HCC: chromatin remodeling mutations and ploidy aberrations. By defining the tumor promoting factors that act on regenerating liver cells, we hope to contribute towards earlier diagnostics and preventative measures, as well as a predictive understanding of distinct HCC genetic subtypes.