TSC signaling and pulmonary LAM

描述（由申请方提供）：肺部LAM是一种罕见的肺部疾病，主要影响育龄女性，与多发性硬化症（TSC）肿瘤抑制基因突变相关。LAM表现为囊性肺破坏、自发性气胸和肿瘤性LAM细胞生长。尽管LAM细胞生长与mTORC 1活性上调有关，但仍存在关键问题，其中最重要的是：1）LAM细胞肿瘤转化的机制是什么，2）这些变化如何导致LAM特征性肺囊肿形成。我们已经开发了一种新的实验性TSC-无效小鼠LAM模型，其中存在TSC-无效细胞浸润到肺中，并且这些细胞诱导与在人LAM中观察到的高度相似的囊性形态学变化。重要的是，分别用雷帕霉素和辛伐他汀抑制mTORC 1和mTORC 2信号传导，抑制TSC无效肿瘤生长和空域扩大。我们已发表的和新的数据还表明，TSC损失促进LAM细胞侵袭力，激活mTORC 2，增加MMP-9表达，通过上调Rac 1 GTdR活性下调E-钙粘蛋白的膜定位，并诱导细胞转化。这些数据支持我们的中心假设，即：TSC的损失诱导细胞转化mTORC 2依赖性Rac 1激活，下调E-钙粘蛋白的膜定位和上调MMP-9的表达。这又诱导细胞外基质（ECM）的蛋白水解破坏、肺泡细胞凋亡、导致肺实质破坏的炎性细胞浸润、肺泡空间扩大和肺功能丧失。这些观察结果还导致了这样的转化假设，即mTORC 2和mTORC 1信号传导的药理学靶向将在肺LAM中提供组合治疗。这些研究将在LAM中建立TSC损失和肺泡破坏之间的机制联系，并将提供关于治疗LAM的潜在新分子靶点和潜在组合疗法的见解。

DESCRIPTION (provided by applicant): Pulmonary LAM, a rare lung disease affecting predominantly women of childbearing age, is associated with mutations of the Tuberous Sclerosis Complex (TSC) tumor suppressor genes. LAM manifests by cystic lung destruction, spontaneous pneumothoraces and neoplastic LAM cell growth. Although LAM cell growth has been linked to upregulation of the mTORC1 activity that is amenable to rapamycin treatment, key questions remain, among the most important: 1) what is the mechanism of LAM cell neoplastic transformation and 2) how do these changes lead to lung cyst formation characteristic of LAM. We have developed a novel experimental TSC-null murine LAM model in which there is infiltration of TSC-null cells into the lung and these cells induce cystic morphological changes highly similar to those seen in human LAM. Importantly, inhibition of both mTORC1 and mTORC2 signaling with rapamycin and with simvastatin, respectively, inhibits TSC-null tumor growth and airspace enlargement. Our published and new data also show that TSC loss promotes LAM cell invasiveness, activates mTORC2, increases MMP-9 expression, downregulates membrane localization of E-cadherin through upregulation of Rac1 GTPase activity, and induces cell transformation. These data supports our central hypothesis that: loss of TSC induces cell transformation by mTORC2-dependent Rac1 activation that downregulates membrane localization of E-cadherin and upregulates MMP-9 expression. This, in turn, induces proteolytic destruction of extracellular matrix (ECM), alveolar cell apoptosis, an inflammatory cell infiltration leading to destruction of lung parenchyma, alveolar space enlargements and the loss of pulmonary function. These observations also lead to the translational hypothesis that pharmacological targeting of both mTORC2 and mTORC1 signaling will provide combinational therapy in pulmonary LAM. These studies will establish a mechanistic link between loss of TSC and alveolar destruction in LAM, and will provide insights about potential novel molecular targets and potential combinational therapy to treat LAM.