The accumulation of genetic and epigenetic alterations transforms normal cells into cancer cells. But how does cancer initiate? In the hierarchy from stem cells to terminally differentiated cells present in adult tissues, what cell types have the potential to act as target cells for cancer? And how do these mutant cells become cancer stem cells? Key issues in the cancer field are to identify the target cells for cancer initiation and to determine the nature and consequences of cancer-initiating lesions.

To address these basic questions, we study the mechanisms of action of the retinoblastoma (RB) tumor suppressor gene. RB was cloned from families in which patients inherit one mutant allele of RB from one parent, and develop childhood retinal malignancy upon loss of the second allele. RB is also mutated in a broad range of human sporadic tumors, such as carcinomas of the lung, breast, liver, bladder, and prostate. RB has been implicated in the control of multiple cellular processes, including cell cycle progression, senescence, cell death, chromatin structure, chromosomal stability and cellular differentiation. A major focus of the lab is to identify the cell of origins of various cancers and to determine what function(s) of RB and its two family members p107 and p130 are critical for tumor suppression. In particular, we investigate the consequences of altering the function of RB family members in embryonic and adult stem cells, both in mice and in humans.

The RB family may prevent cancer by controlling cellular differentiation and the fate of stem cells, and by preventing cell cycle re-entry of post-mitotic cells. Identifying potential target cells for cancer and understanding cancer initiation may provide invaluable tools to detect and treat human cancer. In the future, the ability to activate compensatory mechanisms by p107 and p130 after loss of RB mutant human cancers may also have important therapeutic implications.