Oncogenic mechanism of Sox2 in Rb-deficient tumors
While Rb is functionally inactivated in nearly every tumor type, its loss is only a causative event in a few tumor types resulting in some pediatric . Many of the cells for which Rb–loss initiates tumors are of neural or neuroendocrine cell types. A commonality of these cell types is that they express the transcription factor Sox2 in their immediate progenitor state. Our work has identified that Rb directly binds to the Sox2 locus and epigenetically represses the Sox2 gene. Indeed we have observed in pituitary cancers that this Rb repression of Sox2 is key to preventing pituitary cancer. We are currently investigating this repression by Rb on Sox2 in other cancer types including lung and pancreatic cancers.
In these Rb-loss initiated cancers, Sox2 become strongly reactivated and our data shows that it is key to the formation of these tumors. Even with the extensive characterization of the genes regulated by Sox2 in embryonic stem cells, the Sox2 network in tumors has not been fully characterized. Using advanced genomics we are investigating the Sox2 network in tumors to elucidate what genes are being directly regulated by Sox2, what is the consequence of Sox2 binding to these genes, and how Sox2 binding might effect the chromatin of bound targets. Already we have identified key oncogenes as targets of Sox2 further expanding our understanding of the gene networks which promote cancer. With a complete description of the Sox2 network in these tumors, we aim to develop novel therapeutics to target Sox2 activity and alleviate the symptoms of patients suffering from cancer.
Kareta, M.S., Gorges, L.L., Hafeez, S., Benayoun, B.A., Marro, M., Zmoos, A.F., Cecchini, M.J., Spacek, D., Batista, L.F.Z., O’Brien, M., Ng, Y.H., Ang, C.E., Vaka, D., Artandi, S.E., Dick, F.A., Brunet, A., Sage, J., Wernig, M. (2015). Inhibition of pluripotency networks by the Rb tumor suppressor restricts reprogramming and tumorigenesis. Cell Stem Cell 16, 39-50.