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David Cobrinik
David Cobrinik, MD, PhD
Visiting Investigator

Cancers are thought to result from genetic changes that deregulate cell signaling and provoke abnormal cell proliferation. However, these oncogenic changes do not act entirely on their own, but collaborate with the underlying circuitry of the cells from which the tumors arise. The influence of cell type-specific signaling circuitry is quite clear in pediatric cancers, as specific oncogenic changes initiate tumorigenesis only in specific cell types. Thus, our research aims to determine how cell type-specific circuitry sensitizes specific cells to specific oncogenic mutations during the development of pediatric malignancies.

Figure 1
Figure 1
MDM2 (green) in cone photoreceptor precursors (arrow) in the human retina.

To address this issue, we have focused on a pediatric eye cancer called retinoblastoma. This cancer is known to develop in response to mutations in the so-called retinoblastoma gene (RB1), but the cells from which the tumors arise and the cellular features that sensitize to RB1 mutations have been unclear. In collaboration with other Memorial Sloan-Kettering Cancer Center investigators, we found that retinoblastoma cells have properties cone photoreceptors, which are the retinal cells that are normally used for color vision. We also found that immature cone precursors normally express exceptionally high levels of the cancer-causing proteins MDM2 and N-Myc (Figure 1), that retinoblastoma cells must also express high levels of MDM2 and N-Myc for their abnormal proliferation, and that cone-specific signaling circuitry promotes MDM2 and N-Myc expression within the retinoblastoma cells [PubMed Abstract]. These findings imply that that the normal cone circuitry that drives MDM2 and N-Myc expression cooperates with RB1 mutations during retinoblastoma tumorigenesis.

Our ongoing studies aim to further define the role of the cone circuitry in retinoblastoma and to assess its contributions to other cancers. For example, we're using mouse models to determine whether the human-specific pattern of MDM2 and N-Myc expression underlies the uniquely human tendency to develop cone-like retinoblastoma tumors. In addition, we are determining whether the normal high-level expression of MDM2 is important in other pediatric cancers, and whether MDM2-specific antagonists can be used to treat pediatric cancers, regardless of whether there has been an MDM2 genetic alteration. These studies aim to apply our understanding of the basic mechanisms of tumorigenesis in order to improve cancer therapy.

Publications

Cobrinik, D. 2005. Pocket proteins and cell cycle control. Oncogene 24: 2796-809. [PubMed Abstract]

Lee, TC, D Almeida, N Claros, DH Abramson, and D Cobrinik. 2006. Cell cycle-specific and cell type-specific expression of Rb in the developing human retina. Invest Ophthal Vis Sci 47: 5590-98. [PubMed Abstract]

Xu, XL, Y Fang, TC Lee, D Forrest, C Gregory-Evans, D Almeida, A Liu, SC Jhanwar, DH Abramson, and D Cobrinik. 2009. Retinoblastoma has properties of a cone precursor tumor and depends upon cone-specific MDM2 signaling. Cell 137: 1018-31. [PubMed Abstract]

Wang H, Bauzon F, Ji P, Xu X, Sun D, Locker J, Sellers RS, Nakayama K, Nakayama KI, Cobrinik D, Zhu L.  2010. Skp2 is required for survival of aberrantly proliferating Rb1-deficient cells and for tumorigenesis in Rb1+/- mice. Nat Genet 42: 83-8. [PubMed Abstract]

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