The Molecular and Genetic Pathogenesis of LAM

摘要 淋巴管平滑肌瘤病（LAM）是一种进行性多系统疾病的妇女，其特征在于 囊性肺破坏、肾血管平滑肌脂肪瘤和乳糜性胸腔积液。淋巴管生成突出 在肺LAM结节中，血清VEGF-D水平高于800 pg/ml是LAM的诊断生物标志物。的 大多数LAM细胞在结节性硬化症（TSC）基因中携带双等位基因失活突变， 可以在血液中检测到具有TSC 2杂合性缺失的循环LAM细胞。 TSC蛋白复合物通过免疫抑制剂抑制雷帕霉素的哺乳动物/机制靶标（mTORC 1）。 小GTtagh Rheb。mTORC 1作为一种分子传感器，调节细胞生长、代谢、自噬， 和microRNA的生物合成。初步临床试验已经证明西罗莫司治疗的临床获益 （雷帕霉素）或其类似物（雷帕霉素类似物）。总的来说，这些数据表明雷帕霉素是一种抗肿瘤药物。 有效的LAM抑制治疗。然而，肺功能下降恢复，肿瘤再生时， 药物停止。因此，治疗必须长期使用-也许是终身使用。这突出表明， 对LAM和TSC中消除（而不是抑制）LAM细胞的新型治疗策略的未满足需求， 新的生物标志物允许个性化治疗，并更好地了解遗传和临床因素， 可能有助于预测LAM的严重程度。 这个UO 1汇集了一个独特的领导团队，在淋巴管平滑肌瘤病（LAM）和结节性 硬化症（TSC），以解决具有高度临床影响的关键未回答的问题。第一，识别新的 LAM的生物标志物。使用LAM的体外和体内模型和来自人LAM的单细胞RNA测序 肺，系统分析LAM细胞的“分泌组”，将阐明LAM的发病机制，揭示新的 预后生物标志物。第二，研究新的mTORC 1非依赖性途径导致LAM细胞 存活可以在治疗上靶向诱导LAM细胞死亡。第三，基因修饰物分析， LAM和TSC 2基因突变的潜在隐性广义体细胞嵌合体，以阐明LAM 发病机制并帮助识别进展风险最高的患者。

Abstract Lymphangioleiomyomatosis (LAM) is a progressive multi-system disease of women characterized by cystic lung destruction, renal angiomyolipomas, and chylous pleural effusions. Lymphangiogenesis is prominent in pulmonary LAM nodules and serum VEGF-D levels above 800 pg/ml are a diagnostic biomarker of LAM. The majority of LAM cells carry bi-allelic inactivating mutations in the tuberous sclerosis complex (TSC) genes and circulating LAM cells with TSC2 loss of heterozygosity can be detected in the blood. The TSC protein complex inhibits the mammalian/mechanistic target of rapamycin (mTORC1) via the small GTPase Rheb. mTORC1 acts as a molecular sensor that regulates cell growth, metabolism, autophagy, and microRNA biogenesis. Pivotal clinical trials have demonstrated clinical benefit from treatment with sirolimus (Rapamycin) or its analogs (Rapalogs) in LAM and TSC. Collectively these data indicate that Rapamycin is an effective suppressive therapy for LAM. However, lung function decline resumes, and tumors regrow when the drug is discontinued. Therefore, therapy must be used chronically – perhaps lifelong. This highlights the urgent unmet need for novel therapeutic strategies in LAM and TSC to eliminate (rather than suppress) LAM cells, for novel biomarkers allowing personalization of therapy and to better understand genetic and clinical factors that may help to predict the severity of LAM. This UO1 brings together a unique team of leaders in lymphangioleiomyomatosis (LAM) and tuberous sclerosis complex (TSC) to address key unanswered questions with high clinical impact. First, identifying novel biomarkers of LAM. Using in vitro and in vivo models of LAM and single cell RNA sequencing from human LAM lungs, systematic analysis of the LAM cell “secretome” will elucidate the pathogenesis of LAM revealing novel prognostic biomarkers. Second, investigating novel mTORC1-independent pathways leading to LAM cell survival that could be therapeutically targeted to induce LAM cell death. Third, analysis of genetic modifiers of LAM and of potential cryptic generalized somatic mosaicism for TSC2 gene mutations to elucidate LAM pathogenesis and help identify patients at highest risk of progression.