Claudia Benavente, Ph.D.
Understanding epigenetic deregulation in pediatric cancer tumorigenesis
The Benavente Lab research interests focus on elucidating the molecular and cellular mechanisms that drive tumor progression. Our research is specifically focus on the genetic and epigenetic changes that occur following tumor initiation. Two independent discoveries have set the stage for this research. First, we found that tumor progression in human retinoblastoma (pediatric eye cancer) is driven by epigenetics. This challenges the current thinking that tumor progression in retinoblastoma is driven by genome instability following inactivation of the retinoblastoma-susceptibility gene (RB1). Second, we found that loss of the E2F1 or E2F3 members of the E2F family of transcription factors is sufficient to prevent tumorigenesis in laboratory models of retinoblastoma. These discoveries suggest that activator E2Fs (aE2Fs) regulate recruitment and/or expression of the epigenetic machinery required for tumor formation in the absence of the Rb family. The goals of our research are directed toward identifying the downstream genes or pathways that are regulated by the retinoblastoma protein (Rb) and have the potential to become alternative therapeutic targets for the treatment of cancer.
Furthermore, while functional loss of RB1 is sufficient for the retinal cell of origin to form retinoblastoma, osteoblasts require additional inactivation of the TP53 tumor suppressor for osteosarcoma (bone cancer) formation. Through the study of the epigenetic landscape of retinoblastoma and osteosarcoma, we hope to determine why some cell types are more susceptible to tumor formation than other cell types, in particular following RB1 inactivation. This has been an unanswered question in the field of cancer biology since the cloning of the first tumor suppressor gene (RB1) and progress in this area is needed to better target cancer therapy in the future.
• Benavente CA, Dyer MA. (2015). Genetically engineered mouse and orthotopic human tumor xenograft models of retinoblastoma. In Methods in Molecular Biology. (pp. 307-17). New York: Springer Science+Business Media.
• Benavente CA, Dyer MA. (2015). Genetics and Epigenetics of Human Retinoblastoma. Annual Reviews of Pathology: Mechanisms of Disease,(10), 547-562.
• Steward E, Goshorn R, Bradley C, Griffiths LM, Benavente C, Twarog NR, Caufield W, Freeman BB 3rd, Bahrami A, Pappo A, Wu J, Loh A, Karlström Å, Calabrese C, Gordon B, Tsurkan L, Hatfield MJ, Potter PM, Snyder SE, Thiagarajan S, Shirinifard A, Sablauer A, Shelat AA, Dyer MA (2014) Targeting the DNA repair pathway in Ewing sarcoma. Cell Reports, 9(3):829-41.
• Benavente CA, Finkelstein D, Johnson DA, Marine JC, Ashery-Padan R, Dyer MA (2014). Chromatin remodelers HELLS and UHRF1 mediate the epigenetic deregulation of genes that drive retinoblastoma tumor progression. Oncotarget, 5(20), 9594-608.
• Benavente CA, McEvoy JD, Finkelstein D, Wei L, Kang G, Wang YD, Neale G, Ragsdale S, Valentine V, Bahrami A, Temirov J, Pounds S, Zhang J, Dyer MA. (2013). Cross-species genomic and epigenomic landscape of retinoblastoma. Oncotarget, 4(6), 844-59.
• Zhang J*, Benavente CA*, McEvoy J*, Flores-Otero J*, Ding L, Chen X, Ulyanov A, Wu G, Wilson M, Wang J, Brennan R, Rusch M, Manning AL, Ma J, Easton J, Shurtleff S, Mullighan C, Pounds S, Mukatira S, Gupta P, Neale G, Zhao D, Lu C, Fulton RS, Fulton LL, Hong X, Dooling DJ, Ochoa K, Naeve C, Dyson NJ, Mardis ER, Bahrami A, Ellison D, Wilson RK, Downing JR, Dyer MA. (2012). A novel retinoblastoma therapy from genomic and epigenetic analyses. Nature, 481(7381), 329-34. 0028-0836. *Authors contributed equally to this manuscript. Faculty of 1000 (F1000)
• Benavente CA, Schnell SA, Jacobson EL. (2012). Effects of niacin restriction on sirtuin and PARP responses to photodamage in human skin. PloS ONE, 7(7), e42276.
• Bermudez Y, Benavente CA, Meyer RG, Coyle WR, Jacobson MK, Jacobson EL. (2011). Nicotinic acid receptor abnormalities in human skin cancer: implications for a role in epidermal differentiation. PloS ONE, 6(5), e20487.
• Benavente CA, Jacobson MK, Jacobson EL. (2009). NAD in skin: therapeutic approaches for niacin. Current pharmaceutical design, 15(1), 29-38. 1381-6128.
• Benavente CA, Jacobson EL. (2008). Niacin restriction upregulates NADPH oxidase and reactive oxygen species (ROS) in human keratinocytes. Free radical biology & medicine, 44(4), 527-37. 0891-5849.
• Benavente CA, Sierralta WD, Conget PA, Minguell JJ. (2003). Subcellular distribution and mitogenic effect of basic fibroblast growth factor in mesenchymal uncommitted stem cells. Growth factors, 21(2), 87-94. 0897-7194.