Functional role of Wnt/Ca2+ signaling in triple-negative breast cancer metastasis and chemoresistance - Project Summary/Abstract: Breast cancer poses a significant burden on women's health, being the most commonly diagnosed cancer and a leading cause of cancer-related mortality in the United States. While progress has been made in treating primary breast cancer, the development of metastasis and multi-drug resistance remains a major challenge and accounts for the majority of breast cancer-related deaths. Dysregulation of calcium (Ca2+) homeostasis is prevalent in breast cancer cells, yet the precise role of Ca2+ signaling in breast cancer metastasis, its upstream regulatory mechanisms, and potential therapeutic vulnerabilities remain elusive. This knowledge gap stems largely from the absence of reliable breast cancer models with direct readouts of intracellular Ca2+ dynamics. However, our recent groundbreaking research has uncovered the involvement of noncanonical Wnt signaling and downstream integrin/focal adhesion pathways in regulating the invasion and dissemination of triple-negative breast cancer (TNBC). Noncanonical Wnt signaling is a known inducer of intracellular Ca2+ cascades, which play critical roles in cell adhesion and the cell cycle. In this proposed project, we aim to establish a robust mouse model capable of indicating intracellular Ca2+ levels to unravel the intricate Wnt/Ca2+ signaling pathway in TNBC metastasis and drug resistance. In specific Aim 1, we will employ a highly sensitive, genetically encoded Ca2+ indicator called GCaMP6s to directly measure Wnt-induced Ca2+ mobilization in three-dimensional tumor organoid cultures and genetically engineered mouse models of TNBC. Aim 2 focuses on understanding how Wnt/Ca2+ signaling modulates tumor cell-endothelium adhesion and invasion, thereby enhancing our understanding of tumor intravasation and extravasation processes. In Aim 3, we will explore the molecular mechanisms and therapeutic vulnerabilities associated with Ca2+ inhibition to overcome chemoresistance in TNBC. This comprehensive research proposal will not only shed light on the intricate mechanisms governing Wnt/Ca2+ signaling in TNBC metastasis but also provide novel insights into targeting TNBC progression and overcoming drug resistance from a fresh perspective. My strong background in Ca2+ signaling during my graduate studies at Texas A&M University, combined with my expertise in breast cancer metastasis gained through my postdoctoral training at Baylor College of Medicine, positions me well to undertake this proposed research. This project aligns with the mission of the National Cancer Institute (NCI) to advance scientific knowledge and improve the lives of individuals by leading, conducting, and supporting cancer research nationwide. With the guidance of experts as my mentors and collaborators, as well as access to cutting-edge facilities at Baylor College of Medicine, this proposed project will further enhance my training and contribute to the development of an independent career pathway in metastatic breast cancer research.
