We are interested in identifying and understanding genes that drive tumorigenesis. Our lab uses genomic analyses of primary tumors and mouse modeling to gain insights into how specific gene mutations contribute to tumor initiation, progression and metastasis.
We focus on tumors with frequent mutation in the RB tumor suppressor gene. One such tumor type is retinoblastoma, a pediatric tumor of the retina. Children who inherit a mutant copy of RB develop retinoblastoma at extremely high frequency. We generated some of the first mouse models of retinoblastoma. These models make use of retina-specific mutation of RB in concert with additional inactivation of one of the two additional RB family members, p107 or p130. These models mimic many aspects of human retinoblastoma progression.
One of our aims is to better understand mutational events that cooperate with inactivation of RB in cancer. We have used genomic approaches to identify regions of chromosomal deletion or amplification in human and murine retinoblastoma. We have found a number of alterations that are common to murine and human retinoblastoma, such as N-Myc amplification, suggesting that the pathways to transformation in human retinoblastomas and mouse models are similar.
We recently found that the miR-17~92 cluster of microRNAs is amplified in a subset of murine retinoblastoma samples and is highly expressed in human retinoblastomas. We demonstrated that miR-17~92 overexpression in the retina alone has little consequence but miR-17~92 synergizes with deletion of RB family members to promote rapid tumorigenesis. miR-17~92 extended the proliferative capacity of cells lacking RB family members to drive tumorigenesis.We are particularly interested in identifying and understanding new cancer genes that synergize broadly with RB inactivation beyond retinoblastoma and have expanded our genomic and mouse genetic analyses towards other RB-deleted tumor types.