Abstract 6084: Wave3 tyrosine phosphorylation activates the invasion-metastasis cascade of triple negative breast cancer tumors through the maintenance of the cancer stem cell niche
Authors: Wei Wang, Urna Kansakar, Vesna Markovic, Khalid Sossey-Alaoui
Journal: Cancer Research (2020)

Abstract The acquisition of metastatic phenotypes is responsible for the death of ~90% of breast cancer (BC) patients. In fact, metastatic BC is the 2nd leading cause of cancer-related deaths in women in the United States, annually accounting for more than 40,100 deaths and 266,000 new cases of invasive BC. Typically, metastases are incurable and result in a median survival of only 1.5 to 3 years for BC patients. Clinically, ~30% of BC patients diagnosed with early-stage, noninvasive disease will ultimately progress to late-stage, metastatic disease, an event that severely limits treatment options and associates with dismal clinical outcomes. This problem is exacerbated by the fact the BCs are heterogeneous and comprised of at least 5 genetically distinct subtypes. Amongst individual BC subtypes, those classified as TNBCs are especially lethal due to their highly metastatic behavior and propensity to recur rapidly. As a group, TNBCs lack expression of hormone receptors (ER-α and PR) and ErbB2/HER2, which has prevented the development of FDA-approved targeted drug therapies effective against this BC subtype. Likewise, recurrent TNBCs frequently acquire resistance to standard-of-care chemotherapeutic agents (e.g., doxorubicin, cyclophosphamides, and taxanes) through mechanisms that remain incompletely understood. We established Wiskott-Aldrich Syndrome Protein-3 (WAVE3) as a novel promoter of TNBC development and metastatic progression. Our previously published studies have shown that phosphorylation of WAVE3 at specific tyrosine residues by c-Abl non-receptor tyrosine kinase is required for cancer cell migration and invasion. In this study, we show that WAVE3 phosphorylation is required for the activation of the invasion-metastasis cascade of TNBCs, both in vitro and in in vivo mouse models. Genetic inactivation of WAVE3 via CRISPR/Cas9 gene editing suppressed migration, invasion and the formation of 3D tumorspheres of TNBC cells, in vitro, as well as tumor growth and metastasis in vivo. While re-expression of phospho-active WAVE3 in the WAVE3-deficient TNBC cells restored the oncogenic activity of WAVE3, re-expression of phospho-mutant WAVE3 or the pharmacologic inhibition of WAVE3 phosphorylation did not. Further studies revealed that phosphorylation of WAVE3 was required for the activation of several hallmarks of cancer through the upregulation of survival signaling pathways. Blocking WAVE3 expression or phosphorylation inhibited epithelial-mesenchymal transition (EMT) as well as disrupted the breast cancer stem cell (BCSC) niche by inhibiting expression of BCSC-specific markers. Finally, loss of WAVE3 phosphorylation was sufficient to resensitize TNBC cells to standard of care chemotherapy-induced apoptosis and cell death through the targeting of the BCSCs. Together, our data support the targeting of WAVE3 as a novel therapeutic strategy to treat metastasis in patients with TNBC tumors by specifically targeting BCSCs. Citation Format: Wei Wang, Urna Kansakar, Vesna Markovic, Khalid Sossey-Alaoui. Wave3 tyrosine phosphorylation activates the invasion-metastasis cascade of triple negative breast cancer tumors through the maintenance of the cancer stem cell niche [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6084.