Wnt Planar Cell Polarity Signaling In Breast Cancer Cell Migration And Invasiveness

Download or read book Wnt/Planar Cell Polarity Signaling in Breast Cancer Cell Migration and Invasiveness written by Kacey Michelle VanderVorst and published by . This book was released on 2019 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Metastasis is a complex, multi-step process whereby cancer cells migrate and invade into surrounding tissues, traverse the vasculature, and colonize metastatic lesions. Cell migration is critical to metastatic dissemination, and aberrant reactivation of developmental migratory pathways is a common theme in cancer biology. Wnt/planar cell polarity (Wnt/PCP) signaling is a non-canonical Wnt signaling pathway that mediates cell migratory events critical to proper embryonic development. Wnt/PCP signaling components are frequently dysregulated in solid tumors, and aberrant pathway activation contributes to tumor cell migratory properties. This dissertation focuses on two distinct observations: (1) that Wnt/PCP signaling mediates carcinoma collective cell migration and invasion, a migratory mode with an emerging role in breast cancer metastasis, and (2) that Wnt/PCP signaling may mediate cell migratory events driven by epithelial-to-mesenchymal transition (EMT), another significant driver of metastatic dissemination. Discussion of each finding is preceded by a review of the literature highlighting recent advances in the contribution of Wnt/PCP signaling to cancer migration and metastasis. Cell migratory modes may be generally classified into two major subtypes: single cell migration or collective cell migration. Importantly, both modes of invasion have been demonstrated to contribute to metastasis, and it is possible that individual tumors invade through one or both mechanisms. Collective migration and invasion have been most extensively studied in breast cancer, where analysis of both mouse and human samples suggest that clusters of primary tumor cells may significantly contribute to critical steps of metastatic dissemination. Here, the contribution of Wnt/Planar cell polarity signaling to breast carcinoma collective cell migration and invasion is described. Components of this pathway are dysregulated in breast cancer, and activating ligand Wnt5a mediates collective cell migration in a Vangl-dependent manner. Wnt5a or Vangl overexpression drives the collective invasion of tumor cells mediated by Keratin14-positive cells at the tips of invading multicellular strands in ex vivo organoid assays. Visualization of Wnt/PCP components and active RhoA GTPase at the leading edge of actively migrating breast cancer cells suggest a model where Wnt/PCP signaling component localization to the leading edge of migrating breast cancer cells regulates the spatio-temporal activity of actin cytoskeletal effectors to govern protrusive membrane activity that drives cellular migration. Epithelial-mesenchymal transition (EMT) has long been considered critical for metastatic dissemination. During EMT, epithelial cells acquire mesenchymal phenotypes characterized by reduced cell-cell adhesion, loss of polarity, and increased migratory and invasive phenotypes. The molecular mechanisms underlying EMT-driven migration and invasion have not been fully characterized. Here, the contribution of Wnt/PCP signaling to EMT-driven migration is described. Activation of the EMT program transcriptionally induces Wnt/PCP signaling components Wnt5a and Fzd7, while simultaneously suppressing Nrdp1, a negative regulator of Wnt/PCP signaling. Suppression of Wnt/PCP signaling impairs EMT-driven cell migration, raising the possibility that Wnt/PCP signaling may be a candidate clinical target for intervention in patients with metastatic disease.