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Manipulating αvβ3 expression to suppress tumor stemness

Taha Rakhshandehroo

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

Taha Rakhshandehroo  

The Cheresh lab recently reported that integrin αvβ3 is specifically upregulated on a range of histologically distinct epithelial derived cancers that have become resistant to receptor tyrosine kinase inhibitors such as erlotinib. In fact, αvβ3 is necessary and sufficient to drive both erlotinib resistance and stemness by activating a KRAS/RalB/NFκB signaling pathway. In order to further understand stemness in cancer cells, we propose to look at the stem properties of αvβ3 in human embryonic stem cells, which can give insight to the pathways activated in cancer stem cells. Therefore, the two primary goals of this project are to dissect the role of αvβ3 in maintaining stemness in definitive endodermal stem cells and how this pathway relates in cancer stem cells.

My first major goal will be to understand the role of αvβ3 in stemness of the definitive endodermal germ layer. hES cells can differentiate into the endodermal germ layer giving rise to epithelial tissues. We have recently demonstrated the role of β3 in stemness specifically in endoderm-derived epithelial cancers, such as the lung and pancreas. Recent data I acquired indicates β3 is highly upregulated specifically in the endoderm as well as HNF4A, a transcriptional regulator of the ITGΒ3 gene, coding for integrin β3. Recent data from our lab also reveals that β3 drives the expression of OCT4 and NANOG, master regulators of pluripotency, in lung cancer stem cells. Based on these findings, I hypothesize that β3 is necessary and sufficient to drive and maintain the definitive endodermal stem-like state. I will then dissect its downstream effectors.

Second, I will examine the role of αvβ3 in cancer stem cells as a driver of tumor progression. In addition to discovering the impact of integrin αvβ3’s on cancer stem cells, the Cheresh laboratory has recently identified a role for αvβ3 in development of the pregnant mammary gland. This study suggested that β3’s role in cancer may be linked to its normal function during tissue remodeling and or development. Based on this I will test the hypothesis that αvβ3’s role in hES cells (definitive endodermal cells) and its capacity to impact early lineage specification is related to its role as a driver of cancer stemness and the pluripotency of tumors. Accordingly, I will examine how β3-dependent pathways activated during development influences the invasive and metastatic properties of human carcinoma cells both in vitro and in vivo and determine if pathways discovered in our hES studies are utilized by tumor cells during the progression of cancer.

PUBLICATIONS (resulting from this training)

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