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Exploring the functional role of Oct4/Nanog in a non-canonical integrin β3-driven pathway in epithelial carcinomas

Jacob M. Gonzalez

Appointment Period: 2015-2016, Grant Year: [29]

gonzalez

Recent studies have identified cancer stem cells (CSCs) in a variety of epithelial cancers. The molecular mechanisms regulating tumor stemness remain poorly understood, particularly in the context of drug resistance. Our lab previously identified a non-canonical integrin β3-driven pathway that drives tumor stemness under various forms of stress, including nutrient deprivation or exposure to RTK inhibitors such as erlotinib. Preliminary data suggests that integrin β3-mediated reprogramming of epithelial tumor cells to a stem-like fate correlates with the induction of selected transcription factors, such as Oct4 and Nanog, which typically are restricted to embryonic and adult stem cells. The main focus of this project is to address the functional role of Oct4/Nanog in integrin β3-driven tumor stemness of epithelial cancers including pancreatic, lung and breast.

My research proposal will examine mRNA and protein levels of Oct4 and Nanog in a panel of β3- and β3+ breast, pancreas and lung cancer cell lines subjected to nutrient deprivation and erlotinib treatment. The goals will be to determine the mechanism by which β3+ promotes Oct4/Nanog expression (e.g. gene amplification, transcription, epigenetics).

Additionally, I will examine the effect of Oct4/Nanog inhibition on β3-driven-tumor stemness and erlotinib resistance using in vitro and in vivo models of cancer. These studies will confirm the significance of β3/Oct4/Nanog expression in patient biopsies and/or circulating tumor cells.

Lastly, I will undertake identification of the target genes by which Oct4 and Nanog regulates tumor stemness in β3+ CSCs. These experiments will include RNA-seq and qRT-PCR in the presence and absence of Oct4/Nanog. I will also perform ChIP-qPCR to determine which target genes are directly bound by Oct4/Nanog.

PUBLICATIONS (resulting from this training)

Trainee recently appointed to grant: publications are still in progress.