Regulatory mechanisms and role of the PI3K-TSC-mTOR signaling network in tumors

描述（由申请人提供）：复杂信号通路和网络的描述为癌症提供了治疗靶点和策略，极大地提高了我们预测和解释临床结果的能力。涉及脂质激酶PI3K和蛋白激酶mTOR的途径在一个细胞网络中紧密相连，这里称为PI3K- tsc -mTOR网络，该网络由许多致癌基因和肿瘤抑制因子组成。这种信号网络的失调发生在大多数遗传性肿瘤综合征中，如结节性硬化症（TSC）、神经纤维瘤病和考登病，以及所有最常见的癌症形式。在最初的资助下以及在这次更新中继续进行的研究揭示了正常细胞和肿瘤细胞中信号网络的分子连接，并为肿瘤的发生、进展和治疗干预提供了新的见解。进展：在最初的4年拨款的前3.5年的研究中，我们对PI3K-TSC-mTOR网络中的反馈调节和其他关键控制点的理解取得了一些新的突破，这些研究在这段时间内已经在14篇出版物中进行了报道和讨论。对于这一更新来说，特别重要的是关于两个功能不同的mTOR复合物（mTORC1和2）的发现，这为控制mTORC2活性的调控机制提供了一些初步的见解。当前方向：最初拨款的目的是为了了解TSC疾病的信号机制及其在细胞和肿瘤模型中的作用。虽然我们对TSC的浓厚兴趣仍在继续，但在这次更新中，我们也将扩展这些发现，以了解该信号网络在人类恶性肿瘤中的作用。鉴于胶质母细胞瘤中PI3K-TSC-mTOR网络几乎普遍存在缺陷，Aim 3致力于确定导致其失调的机制及其在这些侵袭性肿瘤中的后果。与我们对mTORC1的详细了解相比，我们对mTORC2的调控机制和功能知之甚少。因此，基于我们最近对mTORC2的发现，以及越来越多的证据表明它在促进肿瘤发生中起关键作用，这项更新的目的集中在正常细胞中mTORC2的调节机制和肿瘤中的错误调节。具体目标使用各种细胞和小鼠肿瘤模型以及临床样本，并涉及几个关键合作者。具体目的：1)确定我们最近令人惊讶的发现的机制和后果，即TSC肿瘤抑制因子在抑制mTORC1的同时激活mTORC2。2)确定受体酪氨酸激酶下游mTORC2活化的分子机制。3)确定mTORC2激活及下游信号通路在胶质母细胞瘤中的作用。

DESCRIPTION (provided by applicant): The delineation of complex signaling pathways and networks is providing therapeutic targets and strategies for cancer and greatly enhancing our ability to predict and interpret clinical outcomes. The pathways involving the lipid kinase PI3K and the protein kinase mTOR are intimately linked in a cellular network, referred to here as the PI3K-TSC-mTOR network, that is comprised of numerous oncogenes and tumor suppressors. Dysregulation of this signaling network occurs in the majority of genetic tumor syndromes, such as tuberous sclerosis complex (TSC), neurofibromatosis, and Cowden disease, and all of the most common forms of cancer. Research under the original grant and continued in this renewal is revealing the molecular wiring of this signaling network in normal and tumor cells and providing novel insights into tumor development, progression, and therapeutic intervention. Progress: Research during the first 3.5 years of the original 4-year grant has yielded several new breakthroughs in our understanding of feedback regulation and other critical control points within the PI3K-TSC-mTOR network, and these have been reported and discussed in 14 publications during this time. Of particular significance for this renewal were discoveries regarding the two functionally distinct mTOR complexes (mTORC1 and 2), which provided some of the first insights into the regulatory mechanisms controlling mTORC2 activity. Current Direction: The aims of the original grant were geared toward understanding signaling mechanisms and their effects in cell and tumor models of the TSC disease. While our intense interest in TSC continues, in this renewal we will also expand on these findings to understand the role of this signaling network in human malignancies. Given the nearly universal corruption of the PI3K-TSC-mTOR network in glioblastoma, Aim 3 is dedicated to defining the mechanisms leading to its misregulation and their consequences in these aggressive tumors. In contrast to our detailed understanding of mTORC1, we know very little regarding the regulatory mechanisms and functions of mTORC2. Therefore, building on our recent discoveries with mTORC2 and the increasing evidence that it plays a key role in promoting tumorigenesis, the aims of this renewal are focused on the mechanisms of mTORC2 regulation in normal cells and misregulation in tumors. The specific aims use a variety of cell and mouse tumor models, as well as clinical samples, and involve several key collaborators. Specific Aims: 1) To determine the mechanisms and consequences of our recent surprising finding that the TSC tumor suppressors, while inhibiting mTORC1, activate mTORC2. 2) To determine the molecular mechanisms leading to mTORC2 activation downstream of receptor tyrosine kinases. 3) To determine the role of mTORC2 activation and downstream signaling in glioblastoma.