Coupling of PI3K signaling and actin-based cytoskeletal networks in cancer cell migration and metastasis?.

摘要 转移是大多数癌症死亡的原因，尽管癌症取得了进展 在过去的几十年里一直在治疗。高突变的PI3K信号通路 在各种形式的人类癌症中的频率，已与转移有关 过程，但对细胞机制知之甚少。最新研究表明， 细胞迁移的基本机制为研究细胞如何迁移提供了新的机会 癌细胞迁移和转移。利用网盘基菌和人中性粒细胞作为 模型，首席调查员(PI)已经证明，细胞迁移取决于 可兴奋的RAS-PI3K网络和细胞骨架网络之间的耦合 突起的形成。这项建议的目标是(1)评估 可兴奋的PI3K信号网络和细胞骨架之间的类似耦合程度 网络驱动癌细胞迁移；(2)研究PI3K信号如何改变 活性影响分子网络的动力学，从而改变运动性和 癌细胞的转移行为。为了实现这些目标，PI将使用切割 用于可视化各种信号的时空动力学的边缘成像技术 和细胞骨架活性来了解乳腺癌细胞的特点和功能 这些活动(目标1)。PI3K信号活性将使用遗传或 药理学方法研究信号和细胞骨架活动是如何 以及这些变化如何影响细胞在体外的迁移(目标2)。这个 PI3K基因突变前后不同癌细胞分子网络的动态变化 然后，信号将与它们在小鼠体内转移的能力相关(目标3)。最后， PI3K信号和细胞骨架活性将在原发灶和转移灶进行检测 从乳腺癌患者肿瘤确认临床相关性的实验研究 调查结果(目标4)。这些目标的成功实现将提供宝贵的 发展转移性癌症分子干预措施的信息。少年派有 在他的研究生涯之前接受过临床培训。该奖项将支持PI 获得独立资助所需的初步成果并获得新技能 通过合作，特别是在使用小鼠和患者样本方面。这个 PI的长期目标是将基础细胞生物学应用于新的 癌症的干预措施。

Abstract Metastasis is responsible for the majority of cancer deaths despite progress in cancer treatment over the past decades. The PI3K signaling pathway, which is mutated at high frequencies in various forms of human cancers, has been implicated in the metastatic process, but the cellular mechanism is poorly understood. Recent studies into the fundamental mechanism of cell migration open up new opportunities to investigate how cancer cells migrate and metastasize. Using Dictyostelium and human neutrophils as models, the principle investigator (PI) has demonstrated that cell migration depends on the coupling between an excitable Ras-PI3K network and a cytoskeletal network to drive the formation of protrusions. The objectives of this proposal are (1) to assess to what extent a similar coupling between an excitable PI3K signaling network and a cytoskeletal network drives the migration of cancer cells; (2) to investigate how altered PI3K signaling activity affect the dynamics of the molecular networks to change the motility and metastatic behavior of cancer cells. To achieve these objectives, the PI will use cutting edge imaging techniques to visualize the spatiotemporal dynamics of various signaling and cytoskeletal activities in breast cancer cells to understand the features and functions of these activities (Aim 1). The PI3K signaling activity will be altered using genetic or pharmacological methods to study how the signaling and cytoskeletal activities are affected, and how these changes affect the migration of cells in vitro (Aim 2). The dynamics of the molecular networks in various cancer cells with or without altered Pi3K signaling will then be correlated with their ability to metastasize in mice (Aim 3). Finally, the PI3K signaling and cytoskeletal activities will be examined in primary and metastatic tumors from breast cancer patients to confirm the clinical relevance of experimental findings (Aim 4). The successful completion of these aims will provide valuable information for developing molecular interventions for metastatic cancers. The PI has received clinical training prior to his research career. The award will support the PI to obtain preliminary results required for independent funding and acquire new skills through collaboration, particularly regarding the use of mice and patient samples. The long-term goal of the PI is to apply fundamental cell biology to the development of new interventions for cancers.