Novel Mechanisms of Carcinoma Cell Migration

癌细胞迁移的新机制

• 批准号: 8831603
• 负责人: KATHLEEN L. O'CONNOR
• 金额: $ 25.59万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-09 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8831603
• 关键词: A kinase anchoring protein; Adenylate Cyclase; Adhesions; Binding; Biochemical; Biology; Breast Carcinoma; Cancer Biology; Cancer Detection; Cancer Patient; Carcinoma; Cells; Collaborations; Complex; Consensus; Couples; Coupling; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Equilibrium; Generations; Goals; Growth; Growth Factor Receptors; Guanine; Guanine Nucleotide Exchange Factors; Human; Imaging Techniques; Integrins; Invaded; Joints; Macromolecular Complexes; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Methods; Modeling; Molecular; Monomeric GTP-Binding Proteins; Morphology; Neoplasm Metastasis; Operative Surgical Procedures; Output; Pathology; Patients; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphorylation Site; Positioning Attribute; Process; Production; Protein Serine/Threonine Phosphatase; Regulation; Research; Sampling; Signal Pathway; Signal Transduction; Solid; Spatial Distribution; Stress Fibers; Study models; Testing; Therapeutic Intervention; Tumor Cell Invasion; Validation; Work; cancer prevention; cell motility; cellular imaging; effective therapy; improved; in vivo; inorganic phosphate; insight; malignant breast neoplasm; migration; novel; receptor; rho; rhotekin; tissue-factor-pathway inhibitor 2; tumor; tumor progression

DESCRIPTION (provided by applicant): Tumor invasion and metastasis still claim the majority of cancer patients' lives. Although great strides have been made in cancer detection and prevention, the need for a more effective treatment for cancer metastasis remains a central problem. Notably, molecules that control spatial signaling for cell polarization and directed migration contribute to the lethality of cancer through their ability to improve the efficiency of he first steps of metastasis. RhoA contributes to cell polarization during directed cell motility, yet how RhoA is spatially controlled remains unclear. We propose that integrin signaling through cAMP/PKA is instrumental for spatial signaling of RhoA and cell polarization. Importantly, our previous work has shown that ?1 integrins control the generation of PKA activity gradients at the leading edge of migrating carcinoma cells where it controls RhoA function. We provide compelling evidence that these PKA activity gradients exist in breast carcinoma patient samples and in three-dimensional breast carcinoma cultures, which attest to the significance of these gradients in human breast cancer. Integrin??6?4 is upregulated in advanced breast cancers where it is most closely associated with basal-like breast cancers. Importantly, integrin ??6?4 promotes the activation of RhoA by a mechanism that we propose reverses the effect of PKA. Therefore, we suggest that the counter-opposing modes of regulation these integrins have on RhoA permit efficient compartmentalization of RhoA that facilitates breast carcinoma motility, invasion and metastasis. Accordingly, the central hypothesis of this application is that cooperative signaling between ?1 integrins and integrin ?6?4 facilitates the spatial distribution of RhoA activity to promote lamellae formation and directed migration. The long-term goal of our group is to determine how integrins contribute to tumor invasion so that they may be eventually targeted appropriately for therapeutic intervention, with special emphasis on integrin ?6?4. We will test our central hypothesis and achieve our long- term goal through the completion of the following aims: 1) Define the macromolecular complex that couples ?1 integrins to PKA activation thereby limiting RhoA activity at the leading edge, 2) Determine how integrin ?6?4 leads to the activation of RhoA, and 3) Elucidate how RhoA function is altered to promote lamellae formation. We are uniquely suited to perform these studies due to our strong collaborations; our well-characterized models of ?6?4 integrin- and RhoA-dependent invasion and migration; our expertise in integrin biology and Rho signaling, and our solid preliminary data supporting this project. The results obtained from this study will be important as they will go int mechanistic depth regarding how integrins coordinate spatial signaling to achieve polarization, lamellae formation, directed cell migration and, finally, invasion. Ultimately, our study will be significant as it will generate a firmer understanding of signaling pathways that govern leading edge dynamics that will produce successful methods to therapeutically target the early steps in metastasis.

描述（由申请人提供）：肿瘤侵袭和转移仍然声称大多数癌症患者的生命。尽管在癌症检测和预防方面取得了长足的进步，但对癌症转移的更有效治疗的需求仍然是一个核心问题。值得注意的是，控制空间信号传导用于细胞极化和定向迁移的分子通过提高转移的第一步的效率而导致癌症的致死性。 RhoA在定向细胞运动期间有助于细胞极化 RhoA如何在空间控制下仍不清楚。我们提出，通过CAMP/PKA的整联蛋白信号传导对RhoA和细胞极化的空间信号传导有助于。重要的是，我们以前的工作表明，整联蛋白控制着控制RhoA功能的迁移癌细胞前缘的PKA活性梯度的产生。我们提供了令人信服的证据，表明这些PKA活性梯度存在于乳腺癌患者样本和三维乳腺癌培养物中，这些培养物证明了这些梯度在人类乳腺癌中的重要性。整联蛋白?? 6？4在晚期乳腺癌中被上调，它与基底样乳腺癌最紧密相关。重要的是，整联蛋白？4？4通过我们提出的机制促进RhoA的激活，使我们提出逆转PKA的效果。因此，我们建议这些整合素对RhoA允许RhoA有效分室的反对调节模式，从而促进乳腺癌的运动，侵袭和转移。因此，该应用的中心假设是：1整联蛋白和整合素之间的合作信号传导促进RhoA活性的空间分布，以促进薄片形成和定向迁移。我们小组的长期目标是确定整联蛋白如何对肿瘤侵袭做出贡献，以便最终可以适当地针对治疗干预，并特别强调整联蛋白？6？4。 We will test our central hypothesis and achieve our long- term goal through the completion of the following aims: 1) Define the macromolecular complex that couples ?1 integrins to PKA activation thereby limiting RhoA activity at the leading edge, 2) Determine how integrin ?6?4 leads to the activation of RhoA, and 3) Elucidate how RhoA function is altered to promote lamellae formation.由于我们的强大合作，我们非常适合进行这些研究；我们的良好特征模型？我们在整联蛋白生物学和RHO信号传导方面的专业知识，以及支持该项目的可靠初步数据。从这项研究中获得的结果将很重要，因为它们将在整合素坐标如何实现极化，薄片形成，定向细胞迁移以及最后是入侵的方面的空间信号传导方面具有深入的深度。最终，我们的研究将非常重要，因为它将对控制前沿动态的信号通路产生更牢固的了解，该信号通路将产生成功的方法，以治疗方法瞄准转移的早期步骤。