Cancers are thought to result from genetic changes that deregulate cell signaling and provoke abnormal cell proliferation. However, the oncogenic changes do not acton their own, but collaborate with the underlying circuitry of the cells from which the tumors arise. The influence of cell type-specific circuitry is especially clear in pediatric cancers, as inherited oncogenic changes typically initiate tumorigenesis in only a limited number of cell types. Our research aims to determine how cell type- specific circuitry sensitizes to oncogenic mutations during the development of pediatric malignancies.
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 develops in response to mutations in the retinoblastoma gene (RB1), but the cell of origin and cellular features that sensitize to RB1 mutations have been unclear. We recently found that retinoblastoma cells have properties of cone photoreceptor precursors, that normal cone precursors as well as cone-like retinoblastoma cells express high levels of the cancer-related MDM2 and N-Myc (Figure 1), and that retinoblastoma cells require cone-related circuitry for their MDM2 and N-Myc expression, proliferation, and survival [PubMed Abstract]. These findings imply that that the cell type-specific circuitry that drives MDM2 and N-Myc expression during retinal development cooperates with RB1 mutations during retinoblastoma tumorigenesis. Notably, the underlying circuitry may be specific to the human retina, which is uniquely sensitive to the oncogenic effects of RB1 loss.
Ongoing studies aim to further define the role of cone-related signaling circuitry in retinoblastoma and to assess its contributions to other cancers. For example, we’re evaluating the role of Rb in human cones versus other retinal cells, and using mouse models to assess whether the human pattern of MDM2 and N-Myc expression underlies the tendency to develop cone-like tumors. We’re also examining pathways through which cone-related factors influence proliferative signaling, by defining pathways that sustain Skp2 expression [PubMed Abstract] and that cooperate with RB1 mutations in other Rb-deficient cancers. These studies are expected to identify cell-intrinsic contextual features that contribute to a broad subset of human malignancies.
In addition to our retinoblastoma studies, we work with Dr. Nai-Kong Cheung to study neuroblastoma biology, including mechanisms of tumor evolution, relapse, and metastasis. Neuroblastoma is the most common solid tumor in children, and has unacceptably poor survival due to the tendency of tumors to relapse or metastasize in a therapy resistant form. Unlike retinoblastoma, the originating mutations in most neuroblastomas have not been defined, and mechanisms of tumor evolution and relapse are obscure. Our ongoing efforts aim to provide insight into these processes through comprehensive genomic analyses of an extensive and unique bank of matched primary and relapsed samples from patients with neuroblastoma, in conjunction with functional analyses of patient-matched neuroblastoma cell lines accrued by the Cheung laboratory over the past 25 years. While the studies are still in their early phases, they suggest that relapses often derive from distant ancestral cells, and hint at pathways that are recurrently involved in CNS metastases. Efforts to define ancestral and relapse-specific mutations are expected to provide novel insights into neuroblastoma biology and to yield novel approaches for neuroblastoma therapy.
Our studies of retinoblastoma and neuroblastoma biology complement the therapeutic initiatives led by Dr. Nai-Kong Cheung. Qualified applicants are invited to apply to join these efforts, learn more on our Career Opportunities page.
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]
Xu, XL, TC Lee, N Offer, C Cheng, A Liu, Y.Fang, SC Jhanwar, DH Abramson, and D Cobrinik. 2010 Tumor-associated retinal astrocytes promote retinoblastoma cell proliferation through production of IGFBP-5. Am J Pathol 177: 424-35. [PubMed Abstract]
