Therapeutic Strategy for LAM (Lymphangioleiomyomatosis)

结节性硬化症是一种常染色体显性遗传病，由结节性硬化症复合体1(TSC1)或TSC2突变引起。TSC的特征是各种组织中的肿瘤、癫痫、智力低下、自闭症和器官衰竭。淋巴管肌瘤病(LAM)是一种进行性囊性肺疾病，影响35%的女性TSC，其特征是肺内异常和潜在转移性的非典型平滑肌样LAM细胞生长。由于TSC2基因的体细胞突变，无TSC的女性可发生散发性LAM。有研究表明，LAM细胞经历了上皮间充质转化(EMT)。SRC激酶是细胞增殖、运动、侵袭和EMT的关键调节因子。这一建议的中心假设是在LAM细胞中激活了Src，并且Src激活的增加有助于下调E-cadherin的表达，并提高这些细胞的致癌能力。因此，抑制Src是一种潜在的治疗策略，可以上调LAM细胞中的E-钙粘蛋白，抑制EMT，降低其致癌和转移潜能。TSC2缺陷细胞中Src活性的增加可能是由于抑制了与mTOR高激活相关的自噬。自噬已被证明是导致活性Src降解的原因。我们建议探索Src抑制剂在LAM中的应用。

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in tuberous sclerosis complex 1 (TSC1) or TSC2. TSC is characterized by tumors in wide range of tissues, seizures, mental retardation, autism, and organ failure. Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease affecting 35% of women with TSC and is characterized by growth of abnormal and potentially metastatic atypical smooth muscle-like LAM cells within the lungs. Sporadic LAM can develop in women without TSC, owing to somatic mutations in TSC2 gene. It has been suggested that LAM cells undergo epithelial-mesenchymal transition (EMT). Src kinases are key regulators of cellular proliferation, motility, invasiveness and EMT. The central hypothesis of this proposal is that ¿Src is activated in LAM cells and that increased Src activation contributes to down-regulation of E-cadherin and raises the oncogenic abilities of these cells. Thus, Src inhibition represents a potential therapeutic strategy to up-regulate E-cadherin in LAM cells, suppress EMT and reduce their oncogenic and metastatic potential.¿ The increased Src activity in TSC2-deficient cells is likely caused by inhibition of autophagy associated with hyper-activation of mTOR. Autophagy has been shown to be responsible for degradation of active Src. We propose to explore the use of Src inhibitors in LAM.