Phosphoinsitide signaling in Breast Epithelial Morphogenesis and Metastasis

乳腺上皮形态发生和转移中的磷酸肌醇信号传导

• 批准号: 8121660
• 负责人: Kun Ling
• 金额: $ 31.74万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8121660
• 关键词: Actins; Adherens Junction; Adhesions; American Cancer Society; Antineoplastic Agents; Automobile Driving; Basic Science; Binding; Biogenesis; Biological Markers; Breast; Breast Cancer Cell; Cancer Death Rates; Cancer Patient; Cell Adhesion; Cell Communication; Cell-Cell Adhesion; Cell-Matrix Junction; Cells; Cellular Morphology; Cessation of life; Characteristics; Clinical; Complex; Data; Development; Diagnosis; Down-Regulation; Drug Delivery Systems; E-Cadherin; Early Diagnosis; Early treatment; Epithelial; Epithelial Cells; Event; Focal Adhesions; Goals; Immigration; Integrins; Investigation; Knowledge; Lateral; Light; Lipids; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mammary Neoplasms; Mediating; Membrane; Molecular; Morphogenesis; Morphology; Names; Neoplasm Metastasis; Outcome; Patient Care; Phenotype; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositol Phosphates; Phospholipids; Phosphorylation; Phosphotransferases; Physiological; Play; Process; Publishing; Recruitment Activity; Reporting; Role; Second Messenger Systems; Series; Signal Transduction; Structure; Talin; Testing; Translating; Tumor Suppression; United States; Up-Regulation; Vesicle; Vinculin; Wound Healing; basolateral membrane; cancer cell; cancer therapy; cell motility; design; malignant breast neoplasm; migration; myosin VI; outcome forecast; public health relevance; research study; second messenger; spatiotemporal; trafficking; tumorigenesis; Actins; Adherens Junction; Adhesions; American Cancer Society; Antineoplastic Agents; Automobile Driving; Basic Science; Binding; Biogenesis; Biological Markers; Breast; Breast Cancer Cell; Cancer Death Rates; Cancer Patient; Cell Adhesion; Cell Communication; Cell-Cell Adhesion; Cell-Matrix Junction; Cells; Cellular Morphology; Cessation of life; Characteristics; Clinical; Complex; Data; Development; Diagnosis; Down-Regulation; Drug Delivery Systems; E-Cadherin; Early Diagnosis; Early treatment; Epithelial; Epithelial Cells; Event; Focal Adhesions; Goals; Immigration; Integrins; Investigation; Knowledge; Lateral; Light; Lipids; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mammary Neoplasms; Mediating; Membrane; Molecular; Morphogenesis; Morphology; Names; Neoplasm Metastasis; Outcome; Patient Care; Phenotype; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositol Phosphates; Phospholipids; Phosphorylation; Phosphotransferases; Physiological; Play; Process; Publishing; Recruitment Activity; Reporting; Role; Second Messenger Systems; Series; Signal Transduction; Structure; Talin; Testing; Translating; Tumor Suppression; United States; Up-Regulation; Vesicle; Vinculin; Wound Healing; basolateral membrane; cancer cell; cancer therapy; cell motility; design; malignant breast neoplasm; migration; myosin VI; outcome forecast; public health relevance; research study; second messenger; spatiotemporal; trafficking; tumorigenesis

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请人提供）：自1990年以来，美国的乳腺癌死亡率每年降低约2％，据美国癌症协会报道。这种令人印象深刻的连胜纪录在很大程度上是由于早期发现和治疗的进步。所有癌症死亡中约有90％来自转移的形成。了解转移的潜在机制将为生物标志物发现提供线索，这对于确定性诊断和个性化治疗可能非常重要。极化上皮形态的建立和维持对于正常乳腺结构和抑制肿瘤转移至关重要。细胞 - 细胞相互作用通常会抑制细胞迁移和癌症转移，而细胞基质粘附处的整联蛋白信号则需要迁移和转移。我们的长期目标是了解控制上皮细胞形态发生的分子和机制，包括两个方面：上皮极性和细胞运动。为了实现这一目标，我们一直专注于一种名为PIPKI3的临界脂质激酶，该激酶通过调节e-钙粘蛋白介导的细胞间粘附组件或促进细胞 - 矩阵粘附的转换来调节上皮极性和细胞迁移。 PIPKI3通过调节肌动蛋白的重组，细胞粘附组装和囊泡运输，生成磷脂酰肌醇-4,5-双磷酸（PI4,5P2），用于细胞形态发生的关键脂质第二信使。但是，如何调节它是不清楚的。我们观察到，当伤口愈合发生时，在上皮到迁移过渡期间，将PIPKI3从细胞细胞粘附到细胞基质粘附，表明该激酶在转移过程中在相同的形态发生转化中可能具有重要作用。在此提案中，我们将通过调节PI4,5P2的区域水平来研究PIPKI3参与上皮形态发生和细胞迁移/转移的分子机制。使用一系列互补方法，我们将定义PIPKI3如何调节电子钙粘蛋白向基底外侧膜的运输，细胞 - 细胞粘附的成熟，并促进将细胞迁移重新分布到细胞 - 矩阵粘附。对PIPKI3的各种细胞作用的研究将揭示出有助于乳腺上皮形态发生的复杂信号网络，并将有助于理解上皮到迁移形态发生转化和肿瘤发生的机制。最终，我们希望将这些知识转化为检测PI4,5P2信号传导的细胞的新策略，然后才有机会发展为侵袭性转移性肿瘤。此外，这些研究将为新的生物标志物和癌症药物靶标提供有效的候选者。该项目的结果显然会受益于基础研究和临床患者护理。 公共卫生相关性：上皮两极化和迁移表型的获取的丧失对于癌症转移的发展至关重要，癌症转移是乳腺癌的真正致命方面。该建议旨在了解推动该过程的启动和进展的分子机制。通过探索磷脂信号在癌症转移进展中的作用，我们应该获得有价值的信息，以了解转移的基础信号网络，并为旨在停止或反向转移的癌症疗法定义了更有效的靶标。