Since 1990, the breast cancer death rate in the United States has decreased by ~2% per year, as reported by the American Cancer Society. This impressive winning streak was made possible in large part by advances in early detection and treatment. Approximately 90% of all cancer deaths arise from metastasis formation. Understanding the underlying mechanisms of metastasis will provide clues for biomarker discovery, which could be extremely important for definitive diagnosis and personalized treatment. Establishment and maintenance of the polarized epithelial morphology is essential for the development of normal breast structure and suppression of tumor metastasis. Cell-cell interactions generally inhibit cell migration and cancer metastasis, whereas integrin signals at cell-matrix adhesions are required for migration and metastasis. Our long-term goal is to understand the molecules and mechanisms that control the morphogenesis of epithelial cells including two aspects: epithelial polarity and cell motility. Towards this aim, we have been focusing on a critical lipid kinase, named PIPKI3, that regulates both epithelial polarity and cell migration via modulating E- cadherin mediated intercellular adhesion assembly or facilitating cell-matrix adhesion turnover. PIPKI3 generates phosphatidylinositol-4,5-bisphosphate (PI4,5P2), a critical lipid second messenger for cell morphogenesis by regulating actin reorganization, cell adhesion assembly, and vesicular trafficking. However, how it is regulated is not known. We observed that PIPKI3 was re-distributed from cell-cell adhesion to cell- matrix adhesion during the epithelial-to-migratory transition when wound healing occurs, indicating this kinase may have an important role in the same morphogenic transformation during the development of metastasis. In this proposal, we will investigate the molecular mechanisms by which PIPKI3 participates in epithelial morphogenesis and cell migration/metastasis via regulating the regional levels of PI4,5P2. Using a series of complementary approaches, we will define how PIPKI3 modulates the transport of E-cadherin to the basolateral membrane, maturation of cell-cell adhesion, and facilitates cell migration when re-distributed to the cell-matrix adhesions. Investigation of the diverse cellular roles of PIPKI3 will shed light on the complicated signaling networks that contribute to breast epithelial morphogenesis and will aid in the understanding of the mechanisms of the epithelial-to-migratory morphogenic transformation and tumorigenesis. Ultimately, we hope to translate this knowledge into new strategies for detecting cells where PI4,5P2 signaling is not appropriately regulated, before they have the opportunity to develop into aggressive metastatic tumors. Furthermore, these studies will provide potent candidates for new biomarkers and cancer drug targets. The outcomes of this project will clearly benefit both basic research and clinical patient care.
The loss of epithelial polarization and acquisition of migratory phenotype is essential for the development of cancer metastasis, the real lethal aspect of breast cancers. This proposal is designed to understand the molecular mechanism driving the initiation and the progression of this process. By exploring the role of phospholipid signaling in the progression of cancer metastasis, we should get valuable information toward understanding the signaling networks underlying metastasis, as well as define more potent targets for cancer therapies that aim to stop or reverse metastasis.
|Chen, C; Wang, X; Xiong, X et al. (2015) Targeting type I? phosphatidylinositol phosphate kinase inhibits breast cancer metastasis. Oncogene 34:4635-46|
|Xu, Qingwen; Zhang, Yuxia; Xiong, Xunhao et al. (2014) PIPKI? targets to the centrosome and restrains centriole duplication. J Cell Sci 127:1293-305|
|Zhang, Qing; Hu, Jinghua; Ling, Kun (2013) Molecular views of Arf-like small GTPases in cilia and ciliopathies. Exp Cell Res 319:2316-22|
|Wei, Qing; Xu, Qingwen; Zhang, Yuxia et al. (2013) Transition fibre protein FBF1 is required for the ciliary entry of assembled intraflagellar transport complexes. Nat Commun 4:2750|
|Xiong, Xunhao; Xu, Qingwen; Huang, Yan et al. (2012) An association between type Iýý PI4P 5-kinase and Exo70 directs E-cadherin clustering and epithelial polarization. Mol Biol Cell 23:87-98|