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

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）：据美国癌症协会报告，自 1990 年以来，美国乳腺癌死亡率每年下降约 2%。这一令人印象深刻的连胜很大程度上归功于早期检测和治疗的进步。大约 90% 的癌症死亡是由转移形成引起的。了解转移的潜在机制将为生物标志物的发现提供线索，这对于明确诊断和个性化治疗极其重要。极化上皮形态的建立和维持对于正常乳腺结构的发育和抑制肿瘤转移至关重要。细胞与细胞之间的相互作用通常会抑制细胞迁移和癌症转移，而细胞与基质粘附处的整合素信号是迁移和转移所必需的。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，包括上皮极性和细胞运动两个方面。为了实现这一目标，我们一直关注一种名为 PIPKI3 的关键脂质激酶，它通过调节 E-钙粘蛋白介导的细胞间粘附组装或促进细胞基质粘附周转来调节上皮极性和细胞迁移。 PIPKI3 产生磷脂酰肌醇-4,5-二磷酸 (PI4,5P2)，这是通过调节肌动蛋白重组、细胞粘附组装和囊泡运输来实现细胞形态发生的关键脂质第二信使。然而，它是如何监管的尚不清楚。我们观察到，当伤口愈合发生时，PIPKI3在上皮到迁移的转变过程中从细胞-细胞粘附重新分配到细胞-基质粘附，表明该激酶可能在转移发展过程中的相同形态转变中发挥重要作用。在本研究中，我们将研究PIPKI3通过调节PI4、5P2的区域水平参与上皮形态发生和细胞迁移/转移的分子机制。使用一系列互补的方法，我们将定义 PIPKI3 如何调节 E-钙粘蛋白向基底外侧膜的运输、细胞-细胞粘附的成熟，并在重新分布到细胞-基质粘附时促进细胞迁移。对 PIPKI3 多种细胞作用的研究将揭示有助于乳腺上皮形态发生的复杂信号网络，并有助于理解上皮-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新策略，用于检测 PI4、5P2 信号传导未得到适当调节的细胞，以免它们有机会发展成侵袭性转移性肿瘤。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。该项目的成果显然将有利于基础研究和临床患者护理。 公共健康相关性：上皮极化的丧失和迁移表型的获得对于癌症转移的发展至关重要，这是乳腺癌真正致命的方面。该提案旨在了解驱动该过程启动和进展的分子机制。通过探索磷脂信号传导在癌症转移进展中的作用，我们应该获得有价值的信息，以了解转移背后的信号传导网络，并为旨在阻止或逆转转移的癌症治疗确定更有效的靶点。