PROJECT SUMMARY
Glioblastoma (GBM) is an aggressive type of brain cancer that arises de novo and is therapy resistant. A key
contributor to poor outcomes in GBM is a subpopulation of cells called glioma stem-like cells (GSCs) that evade
conventional cytotoxic therapies and repopulate as recurrent tumors. A fuller understanding of the molecular
mechanisms underlying the biology and therapy resistance of GSCs is required. Our group has shown that TAZ,
a transcriptional co-factor is highly expressed in about 70% of GBMs. TAZ and its paralog YAP are oncogenic
drivers of brain tumor progression. GSCs overexpressing TAZ undergo a proneural to mesenchymal subtype
transition. TAZ driven cell fate change is accompanied by aggressive behavior such as increased grade, necrosis
and radio-resistance. Silencing YAP/TAZ ablates tumor growth by activating neurogenic programs, thus making
these proteins attractive therapeutic targets. Although the oncogenic functions of YAP/TAZ are well established
in GBM, the exact molecular mechanisms underlying cell fate transition and their contribution to therapy
resistance are not fully understood. We have now accumulated substantial evidence to pinpoint a direct role for
YAP/TAZ in DNA damage response pathway, a network of proteins that sense and repair DNA lesions in
response to ionizing radiation (IR) treatments. YAP/TAZ also cause by enhancer reprogramming and recruitment
of distinct molecular complexes in proneural and mesenchymal gene enhancers, which offers protection of DNA
damage vulnerable regions of the genome. In this proposal, we will deeply investigate the molecular mechanisms
underlying YAP/TAZ driven control of neurogenic programs and radio-resistance using both conventional and
state-of-the-art molecular, cellular and biochemical approaches. Importantly, we will evaluate the therapeutic
benefit of novel pharmacological inhibitors of the YAP/TAZ in combination with IR using pre-clinical models of
GBM. Successful completion of these studies will not only unravel the mechanistic underpinnings behind
neuronal differentiation and DNA damage repair in GBM, but also inform the development of next generation of
clinical trials for GBM.
