This proposal will examine the novel hypothesis that VEGF/Neuropilin-2 (NRP2) signaling cooperates with oncogenic stimuli to drive the formation of mammary cancers, especially triple-negative tumors, by potentiating the function of tumor-initiating cells. The mechanism proposed is that VEGF/NRP2 signaling promotes integrin ?6?1/focal adhesion kinase (FAK)-mediated induction of the Hedgehog effector Gli1, which contributes to the function of tumor initiating cells by promoting the transcriptional activation o Bmi-1 and other target genes. To validate this mechanism, three specific aims are proposed.
The first aim will define the role of NRP2 in the formation, maintenance and therapy of triple-negative tumors, and address the hypothesis that VEGF/NRP2 signaling enhances the function of tumor initiating cells.
This aim will involve transgenic and orthotopic mouse models, as well as tumor cells isolated from freshly resected tumors.
The second aim i s based on the finding that NRP2 interacts specifically with the ?6?1 integrin (CD49f), which is a functional marker of tumor initiating cells.
This aim will examine the hypothesis that VEGF/NRP2 signaling contributes to the regulation of Bmi-1, a polycomb group transcriptional repressor important for the function of tumor stem cells, by a FAK- dependent mechanism.
The third aim will establish that VEGF/NRP2 signaling promotes activation of the Hedgehog pathway in tumor initiating cells, and that the contribution of VEGF/NRP2 to tumorigenesis is dependent on Gli1. More specifically, the hypothesis will be evaluated that VEGF/NRP2 signaling induces Gli1 and Gli1-mediated Bmi-1 expression in tumor initiating cells and that loss of NRP2 can be compensated for by Gli1 expression. The proposed work will provide an integrated mechanism for how VEGF/NRP2 signaling, integrin ?6?1 and FAK interface with the Hedgehog pathway to regulate the function of tumor initiating cells. At a translational level, these studies will highlight the feasibility of targeting NRP2 on tumor cells for therapy of aggressive breast cancers. This issue is timely because the FDA has recommended discontinuing the use of Avastin (bevacizumab), which does not inhibit the VEGF/NRP2 interaction, for treating breast cancer because it has not been shown to be effective. These findings strengthen the rationale for targeting NRP2 directly especially given the preferential expression and critical function of NRP2 in tumor-initiating cell.
This proposal seeks to understand mechanisms that contribute to the formation and growth of breast cancers. We propose to investigate a network of molecules that cooperate with oncogenes to initiate the formation of breast tumors, and evaluate whether these molecules are potential targets for the treatment of these tumors.
|Goel, Hira Lal; Pursell, Bryan; Shultz, Leonard D et al. (2016) P-Rex1 Promotes Resistance to VEGF/VEGFR-Targeted Therapy in Prostate Cancer. Cell Rep 14:2193-2208|
|Yoshii, Tatsuyuki; Geng, Yingying; Peyton, Shelly et al. (2016) Biochemical and biomechanical drivers of cancer cell metastasis, drug response and nanomedicine. Drug Discov Today 21:1489-1494|
|Samanta, S; Sun, H; Goel, H L et al. (2016) IMP3 promotes stem-like properties in triple-negative breast cancer by regulating SLUG. Oncogene 35:1111-21|
|Chang, Cheng; Goel, Hira Lal; Gao, Huijie et al. (2015) A laminin 511 matrix is regulated by TAZ and functions as the ligand for the ?6B?1 integrin to sustain breast cancer stem cells. Genes Dev 29:1-6|
|Parker, Matthew W; Linkugel, Andrew D; Goel, Hira Lal et al. (2015) Structural basis for VEGF-C binding to neuropilin-2 and sequestration by a soluble splice form. Structure 23:677-87|
|Barney, L E; Dandley, E C; Jansen, L E et al. (2015) A cell-ECM screening method to predict breast cancer metastasis. Integr Biol (Camb) 7:198-212|
|Li, Jiarong; Sun, Huayan; Feltri, M Laura et al. (2015) Integrin ?4 regulation of PTHrP underlies its contribution to mammary gland development. Dev Biol 407:313-20|
|Goel, Hira Lal; Gritsko, Tatiana; Pursell, Bryan et al. (2014) Regulated splicing of the ?6 integrin cytoplasmic domain determines the fate of breast cancer stem cells. Cell Rep 7:747-61|
|Chang, Cheng; Yang, Xiaofang; Pursell, Bryan et al. (2013) Id2 complexes with the SNAG domain of Snai1 inhibiting Snai1-mediated repression of integrin ?4. Mol Cell Biol 33:3795-804|
|Samanta, Sanjoy; Pursell, Bryan; Mercurio, Arthur M (2013) IMP3 protein promotes chemoresistance in breast cancer cells by regulating breast cancer resistance protein (ABCG2) expression. J Biol Chem 288:12569-73|
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