Metastasis is main reason for cancer death and has been shown to be controlled by specific genetic events. The complex nature of metastasis from the primary site to a distant site involves acquisition of many phenotypes which makes the genetics of the process very complex. Individual processes such as cell movement, migration and invasion are central to the process and understanding the multitude of controlling mechanisms in this process is vital to understand metastasis and designing therapies against the process. We have shown that expression of the WAVES gene is a critical facilitator of in vitro and in vivo cell invasion and metastasis in breast cancer cells. In human primary breast cancer, significant up regulation of the WAVES protein is seen in advanced stage tumors compared with low grade tumors. In a mouse model of metastasis using MDA-MB-231 cells, siRNA knockdown of WAVES significantly reduces metastasis potential. Immunocytochemistry shows that loss of WAVES function affects the normal organization of actin structures that are related to cell movement and that this effect is mediated through an interaction with PIS Kinase. Knockdown of WAVES results in a failure of lamellipodia formation which is responsible for the restricted cell movement observed. In model cell systems, WAVES appears to control the invasion phenotype through the regulation of MMP production through the p38 pathway. Our preliminary data demonstrating the mechanism of how WAVES controls cellular invasion and migration has provided important clues to another key regulator of these phenotypes which impact on metastasis in vivo. To understand the function of WAVES more fully it will be important therefore to determine the regulator controls of this gene and the pathways it is involved in, since this will likely provide new insights into the regulation of cellular invasion. In this application we propose a series of proteomics approaches to identify the proteins that interact with WAVES to obtain a better understanding of the pathways it is involved in. We also propose a series of experiments using siRNA and somatic cell knockout to eliminate WAVES function in specific cells to evaluate the importance of specific protein-protein interactions. Finally we have designed a series of experiments to probe more deeply into the mechanisms of WAVES function. Since expression of WAVES promotes invasion, it is an attractive potential target for therapy against metastasis, which after all is the lethal phase of cancer progression in most cases. A better understanding of the intracellular regulatory pathways governing the function of WAVES, therefore, may provide new opportunities for therapeutic intervention.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Tumor Progression and Metastasis Study Section (TPM)
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Snyderwine, Elizabeth G
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Georgia Regents University
Schools of Medicine
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Teng, Yong; Ngoka, Lambert; Cowell, John K (2017) Promotion of invasion by mutant RAS is dependent on activation of the WASF3 metastasis promoter gene. Genes Chromosomes Cancer 56:493-500
Teng, Yong; Bahassan, Abdulaziz; Dong, Dayong et al. (2016) Targeting the WASF3-CYFIP1 Complex Using Stapled Peptides Suppresses Cancer Cell Invasion. Cancer Res 76:965-73
Teng, Y; Ren, X; Li, H et al. (2016) Mitochondrial ATAD3A combines with GRP78 to regulate the WASF3 metastasis-promoting protein. Oncogene 35:333-43
Teng, Y; Pi, W; Wang, Y et al. (2016) WASF3 provides the conduit to facilitate invasion and metastasis in breast cancer cells through HER2/HER3 signaling. Oncogene 35:4633-40
Teng, Yong; Qin, Haiyan; Bahassan, Abdulaziz et al. (2016) The WASF3-NCKAP1-CYFIP1 Complex Is Essential for Breast Cancer Metastasis. Cancer Res 76:5133-42
Teng, Y; Mei, Y; Hawthorn, L et al. (2014) WASF3 regulates miR-200 inactivation by ZEB1 through suppression of KISS1 leading to increased invasiveness in breast cancer cells. Oncogene 33:203-11
Teng, Yong; Xie, Xiayang; Walker, Steven et al. (2013) Evaluating human cancer cell metastasis in zebrafish. BMC Cancer 13:453
Teng, Yong; Ghoshal, Pushpankur; Ngoka, Lambert et al. (2013) Critical role of the WASF3 gene in JAK2/STAT3 regulation of cancer cell motility. Carcinogenesis 34:1994-9
Teng, Yong; Ngoka, Lambert; Mei, Yun et al. (2012) HSP90 and HSP70 proteins are essential for stabilization and activation of WASF3 metastasis-promoting protein. J Biol Chem 287:10051-9
Ghoshal, Pushpankur; Teng, Yong; Lesoon, Leslie Ann et al. (2012) HIF1A induces expression of the WASF3 metastasis-associated gene under hypoxic conditions. Int J Cancer 131:E905-15

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