Tumor Etiology and Metastasis

Investigators

Bingcheng Wang, Ph.D.
Khalid Sossey-Alaoui, PhD
Ge Jin, Ph.D.
Shujun Liu, Ph.D.

Bingcheng Wang, PhD

As a member of Eph subfamily receptor tyrosine kinases, EphA2 has been extensively studied in cancer. It is frequently overexpressed in many different types of human cancer, which is often correlated with tumor progression.

While these data suggest EphA2 is an oncogene, strong evidence also exists demonstrating tumor suppressor functions of EphA2. Shedding light on this apparent paradox, we reported recently that EphA2 has diametrically opposite roles in regulating tumor cell migration and invasion. In the presence of ligands called ephrin-As, EphA2 canonical signaling inhibits cell growth, migration and invasion, in part by inactivating 1 integrins, Ras/ERK cascade, and PI3K/Akt pathway. Consistently, genetic deletion of EphA2 in mice leads dramatically increased susceptibility to skin and colon tumorigenesis. 

In contrast, in the absence of ligands EphA2 promoted chemotactic migration and invasion instead. Interestingly the ligand-independent stimulation of cell motility was correlated with phosphorylation of EphA2 on a single serine residue (S897) by Akt and p190RSK. S897A mutation abolished this ligand-independent promotion of cell motility. Preliminary studies show that the activation of EphA2 noncanonical signaling signified by S897 phosphorylation is detected at invasive front of high-grade human prostate cancer and glioblastoma, suggesting pathological relevance of noncanonical signaling. Ongoing studies in the Wang lab examine the molecular basis of EphA2 noncanonical signaling and strategies to target the receptor in invasive and metastatic cancer.

Selected Publications

Miao, H., Wei, B.-R., Peehl, D. M., Li, Q., Burnett, E., Alexandrou, T., Sedor, J. R., Schelling, J. R., and Wang, B. (2001). EphA kinase activation inhibits Ras/MAPK pathway. Nature Cell Biology 3:527-530. PMID: 10655584.

Guo, H., Miao, H., Gerber, L., Singh, J., Denning, M. F., Gilliam, A. C., and Wang, B. (2006) Disruption of EphA2 kinase led to increased susceptibility to skin carcinogenesis. Cancer Research 66:7050-7058. PMID: 16849550.

Miao H, Li D-Q, Mukherjee A, Guo, H., Petty, A. Cutter J, Basilion J, Sedor J, Wu, J., Danielpour, D., Sloan, A. E., Cohen, M., and Wang, B. (2009).    EphA2 Mediates Ligand-Dependent Inhibition and Ligand-Independent Promotion of Cell Migration and Invasion via a Reciprocal Regulatory Loop with Akt, Cancer Cell, 16:9-20, PMID: 19573808.

Volz C, Breid S, Selenz. C, Zaplatina A, Golfmann K, Meder L, Dietlein F, Borchmann S. Chatterjee S, Siobal M, Schottle J, Florin A, Koker K, Nill M, Ozretic L. Uhlenbrock N, Smith S, Buttner R, Miao H, Wang B, and Ullrich R. Inhibition of Tumor VEGFR2 Induces Serine 897 EphA2-Dependent Tumor Cell Invasion and Metastasis in NSCLC. Cell Report. 2020 Apr 28;3:107568. doi: 10.1016/j.celrep.2020.107568. PMID: 32348765

Khalid Sossey-Alaoui, PhD

Identifying and targeting Genes Responsible for Metastatic Ability of Triple-negative Breast Cancer

Amongst individual breast cancer subtypes, those classified as triple-negative breast cancers (TNBCs) are especially lethal due to their highly metastatic behavior and propensity to rapidly recur. As a group, TNBCs lack expression of hormone receptors (ER-α and PR) and ErbB2/HER2.

These molecular deficits have prevented the development of FDA-approved targeted drug therapies to treat this breast cancer subtype. Likewise, recurrent TNBCs quickly acquire resistance to standard-of-care chemotherapeutic agents through mechanisms that remain incompletely understood. Currently, our research focuses on three candidate genes that we identified as drivers of metastatic progression on TNBC tumors WAVE3, Kindlin-2 and YB1). Each of these genes regulates different signaling pathways that activate the metastatic phenotype; i., e., cancer stem cells, EMT,  chemoresistance, TME, and immune evasion, to name a few.   

Information derived from our highly innovative and medically relevant studies will (i) provide valuable information on what drives TNBC development, metastasis, chemoresistance and disease recurrence; and (ii) determine the therapeutic impact of a novel small molecule inhibitors, in combination with chemotherapy to alleviate metastatic TNBCs. Importantly, our findings will significantly impact the treatment of metastatic TNBCs, thereby improving the clinical outcome for patients bearing this deadly disease.

Selected Publications

Rana PS; Wang W; Alkrekshi A; Markovic V;  Khiyami A;  Chan R; Perzynski A; Joseph N and Sossey-Alaoui K. YB1 Is a Major Contributor to Health Disparities in Triple Negative Breast Cancer. Cancers (Basel). 2021 Dec 14;13(24):6262. doi: 10.3390/cancers13246262.

Kansakar U, Wang W, Markovic V, Sossey-Alaoui K. Phosphorylation of the proline-rich domain of WAVE3 drives its oncogenic activity in breast cancer. Sci Rep. 2021 Feb 16;11(1):3868.

Taylor MA, Davuluri G, Parvani JG, Schiemann BJ, Wendt MK, Plow EF, Schiemann WP, Sossey-Alaoui K. Upregulated WAVE3 expression is essential for TGF-β-mediated EMT and metastasis of triple-negative breast cancer cells. Breast Cancer Res Treat. 2013 Nov;142(2):341-53.

Sossey-Alaoui K, Pluskota E, Szpak D, Plow EF. The Kindlin2-p53-SerpinB2 signaling axis is required for cellular senescence in breast cancer. Cell Death Dis. 2019 Jul 15;10(8):539.

Sossey-Alaoui K, Pluskota E, Bialkowska K, Szpak D, Parker Y, Morrison C, Lindner DJ, Schiemann WP, Plow EF. Kindlin-2 regulates the growth of breast cancer tumors by activating CSF-1-mediated macrophage infiltration. Cancer Res. 2017 Sep 15;77(18):5129-5141.

Complete List of Publications

See full list of PubMed Publications