My laboratory uses the nervous system as a paradigm model to gain molecular and mechanistic insights into the coordination of cell growth and differentiation. We use biochemical approaches, mouse genetics and bioinformatics to identify genes and cellular pathways that function in embryonic cells to coordinate cell growth and differentiation and are aberrantly recruited by tumor cells. The main concept is that cancer is a disease of differentiation, which translates in aberrant cell proliferation and survival signals and restoring differentiation mechanisms is a potential strategy to treat human cancer.
We have focused on the role of transcription factors that operate during normal development to preserve the neural stem cell (NSC) state and prevent premature differentiation. We have postulated that these factors will be hijacked during oncogenic transformation to lock cancer cells in an irreversible stem‐like state. The molecules that better helped us to understand this paradigm are the Id (Inhibitor of differentiation) proteins and the N‐myc proto‐oncogene. Our work revealed that Id proteins are master regulators of NSCs, where they operate to coordinate the stem cell state with the anchorage to a specialized niche microenvironment but are recruited by brain tumor cells to initiate and maintain their most aggressive features.
Over the last few years we studied the regulation of N‐Myc in neural stem cells we identified the natural protein complexes engaged by N‐Myc using a state‐of‐the‐art proteomic approach. Among the N‐myc protein partners we identified the ubiquitin ligase Huwe1. Huwe1 targets N‐myc protein for degradation during differentiation and cell cycle arrest in the developing nervous system and neuroblastoma cells. The most exciting novel finding that originated from the identification of the Huwe1‐N‐myc pathway in neural cells is that primary neural tumors in humans carry focal genetic deletions of the Huwe1 gene. These results identify Huwe1 as a new tumor suppressor gene in neural tumors and establish an unprecedented link between neural stem cell renewal and tumor development.
Current areas of research include the mechanism of oncogenic transformation by Id proteins and the identification of novel Id protein targets relevant to the maintenance of stem cell properties using conditional compound knockout mice for the Id genes. We also study novel Huwe1 substrates in neural development and cancer.