Signal Transduction by PI3K/mTOR

项目概要： 我们研究的总体目标是揭示mTOR在细胞内表达的分子和细胞机制。 信号转导是空间调节的，并阐明亚细胞mTORC 1信号转导对 肿瘤发生和癌症治疗抗性。由磷脂酰肌醇3- 激酶（PI 3 K）和雷帕霉素的机制靶点（mTOR）调节许多关键过程 细胞生理学，因此经常在疾病中失调，包括癌症。特别是， PI 3 K/mTOR信号通路的激活是口腔粘膜中最常见的失调信号机制， 鳞状细胞癌（OSCC）是一种每年导致全球约300，000人死亡的疾病， 生存率估计约为60%，尽管积极的多模态治疗。空间 PI 3 K/mTOR的区室化不仅对于增强信号传导特异性至关重要，而且还 这是通道正常运作所必需的。然而，空间调控的机制， PI 3 K/mTOR信号传导仍然知之甚少，并且不清楚哪些亚细胞池的信号传导 分子有助于肿瘤发生和治疗抗性。我们聚集了一个强大的跨学科 团队拥有互补的专业知识，包括化学生物学和激酶专家张金博士 Silvio Gutkind博士是一位著名的癌症生物学家，他的实验室专注于研究致癌基因。 信号通路驱动OSCC的发生和发展。在我们以前的研究中，我们创造了新的 用于研究mTOR信号传导的空间调节的工具，包括用于跟踪的荧光生物传感器 活细胞中的mTOR复合物1（mTORC 1）活性和用于实现mTOR复合物1的亚细胞抑制的方法。 激酶信号利用这些工具，我们发现了核调控的新机制， mTORC 1。在OSCC的背景下，我们已经表明，mTOR抑制剂在一个肿瘤细胞中发挥了有效的抗肿瘤活性。 大量的遗传定义和化学诱导的OSCC模型和良好的临床反应， 最近完成的II期临床试验（NCT 01195922）。目前的建议将开发新的分子 研究活细胞中mTORC 1信号传导的时空调控的工具，阐明调控机制， 核mTORC 1信号传导机制，并确定亚细胞mTORC 1的功能作用 信号转导在肿瘤发生和西妥昔单抗耐药的OSCC。揭示的功能和调节 亚细胞mTORC 1信号转导应该提供一条途径，选择性靶向通路组分， 降低毒性和耐药性的疗法。

Project summary: The overall goal of our research is to uncover the molecular and cellular mechanisms by which mTOR signaling is spatially regulated and to elucidate the contribution of subcellular mTORC1 signaling to tumorigenesis and cancer therapy resistance. The signaling pathway regulated by phosphatidylinositol 3- kinase (PI3K) and mechanistic target of rapamycin (mTOR) regulates a number of processes that are critical to cell physiology, and therefore is often dysregulated in diseases, including cancer. In particular, persistent activation of the PI3K/mTOR signaling circuitry is the most frequent dysregulated signaling mechanism in oral squamous cell carcinoma (OSCC), a disease that results in ~300,000 deaths each year worldwide, with 5-year survival estimates of approximately 60%, despite aggressive multimodality therapies. Spatial compartmentalization of PI3K/mTOR is not only critical for enhancing the signaling specificity, but also required for proper functioning of the pathway. However, the mechanisms underlying spatial regulation of PI3K/mTOR signaling remain poorly understood and it is not clear which subcellular pools of the signaling molecules contribute to tumorigenesis and therapy resistance. We have assembled a strong interdisciplinary team with complementary expertise, including Dr. Jin Zhang, an expert in chemical biology and kinase signaling, Dr. J. Silvio Gutkind, a renowned cancer biologist whose lab has focused on the study of oncogenic signaling pathways driving OSCC initiation and progression. In our previous studies, we have created novel tools for studying the spatial regulation of mTOR signaling, including a fluorescent biosensor for tracking mTOR Complex 1 (mTORC1) activity in living cells and an approach for achieving subcellular inhibition of kinase signaling. Using these tools, we discovered novel mechanisms underlying regulation of nuclear mTORC1. In the context of OSCC, we have shown that mTOR inhibition exerts potent antitumor activity in a large series of genetically-defined and chemically-induced OSCC models and favorable clinical responses in a recently completed clinical phase II trial (NCT01195922). The current proposal will develop new molecular tools to interrogate the spatiotemporal regulation of mTORC1 signaling in living cells, elucidate the regulatory mechanisms of nuclear mTORC1 signaling, and determine the functional roles of subcellular mTORC1 signaling in tumorigenesis and Cetuximab resistance in OSCC. Unravelling the function and regulation of subcellular mTORC1 signaling should offer a path toward selective targeting of pathway components and yield therapies with reduced toxicity and resistance.