The Molecular and Genetic Pathogenesis of LAM

摘要 淋巴管肌瘤病(LAM)是一种进行性的女性多系统疾病，其特征是 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800pg/ml是LAM的诊断标志物。这个 大多数LAM细胞携带结节硬化症复合体(TSC)基因的双等位失活突变和 在血液中可以检测到TSC2杂合性缺失的循环LAM细胞。 TSC蛋白复合体通过以下途径抑制雷帕霉素的哺乳动物/机械性靶点(MTORC1) 小分子GTP酶Rheb。MTORC1是一种分子传感器，调节细胞的生长、代谢、自噬、 和microRNA的生物发生。关键的临床试验表明，西罗莫司治疗有临床益处。 (雷帕霉素)或其类似物(雷帕罗)在LAM和TSC。总的来说，这些数据表明雷帕霉素是一种 对LAM有效的抑制治疗。然而，当肺功能下降时，肺功能恢复，肿瘤重新生长。 药物已停止供应。因此，治疗必须是长期的--也许是终生的。这凸显了当务之急 LAM和TSC对消除(而不是抑制)LAM细胞的新治疗策略的需求尚未得到满足， 新的生物标志物允许个体化治疗，并更好地了解 可能有助于预测LAM的严重程度。 这个UO1汇聚了淋巴管肌瘤病(LAM)和结节病领域独特的领导者团队 硬化症复合体(TSC)，以解决具有高度临床影响的关键未解答问题。第一，辨认小说 LAM的生物标志物。LAM的体外和体内模型及人LAM的单细胞RNA测序 肺，系统分析LAM细胞“分泌体”将阐明LAM揭秘小说的发病机制 预后生物标记物。第二，研究通向LAM细胞的新的mTORC1非依赖通路 可作为治疗靶点以诱导LAM细胞死亡的存活。第三，遗传修饰物的分析 LAM和潜在的TSC2基因突变的隐匿性全身性嵌合体来阐明LAM 并帮助识别病情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.