Project 1: Mediators of Lung Adenocarcinoma Metastatis

项目1（Massagué）：肺腺癌转移的介导因子 项目摘要 我们在这个项目中的目标是阐明肺腺癌的分子和细胞决定因素 （adenoCa）转移，以提高肺癌复发的防治效果。近一半 早期诊断的（I期和II期）肺腺癌病例尽管进行了手术， 切除原发肿瘤。虽然癌细胞进入血液循环并外渗到远处， 器官是转移级联的重要早期步骤，临床上主要关注的是 预防和治疗由诊断前已扩散的癌细胞引起的复发。 因此，我们的重点是转移定植，包括转移播种，潜伏期， 爆发。基于我们以前和新的脑和多器官转移的小鼠模型， 在目前的资助期内，我们已经确定了转移性潜伏期和免疫逃避的介质， 干细胞样细胞（MetSC）（Malladi et al Cell 2016）和厄洛替尼治疗后残留疾病复发的介质 和克唑替尼治疗肺腺癌（Obenauf et al Nature 2015）。我们还确定了丝氨酸蛋白酶抑制剂介导的 肺MetSC在脑中的存活，并将L1 CAM定义为转移性血管共选择的介质。 生长（Valiente et al Cell 2014）。此外，我们发现，肿瘤-星形胶质细胞间隙连接促进大脑 通过cGAS-STING途径转移和间隙连接的药理学调节的转移是有效的 针对这些模型中已建立的脑病变（Chen et al Nature 2016）。我们的工作转化为两个 临床试验，一项使用间隙连接调节剂甲氨蝶呤，另一项使用抗TNF抗体赛妥珠单抗， IV期肺腺癌患者我们未来的目标1是定义和靶向L1 CAM信号传导的作用， 肺腺癌转移。我们将确定L1 CAM+肺腺Ca MetSC的起源， 生长中的L1 CAM信号传导，以及如何靶向L1 CAM以抑制转移起始和增殖。 目的二是阐明微转移疾病的信号转导机制和免疫逃避状态。 我们将研究三个关键途径-WNT，TGF-β和Hippo-在MetSCs进入和退出过程中的作用。 以及NK和CD 8 + T细胞在通过NKG 2D介导的识别 MetSC中的ULBP配体;最终目标是触发免疫介导的残留疾病清除。我们 目的3是在功能上定义我们最近鉴定的CNS转移介质作为治疗剂 目标的我们将描述连接蛋白43、补体因子3和脂质运载蛋白2作为脑和 软脑膜转移，并将在临床前测试这些目标的药物抑制剂组合 治疗方法由本项目的其他成员开发。通过这项工作，我们 希望为肺癌复发的预防和治疗贡献创新的想法，同时保留我们的 长期专注于发现转移的基本原理。

Project 1 (Massagué): Mediators of lung adenocarcinoma metastasis PROJECT SUMMARY Our goal in this project is to elucidate the molecular and cellular determinants of lung adenocarcinoma (adenoCa) metastasis, in order to improve the prevention and treatment of lung cancer relapse. Nearly half of early-diagnosed (stage I and II) lung adenocarcinoma cases develop local and distant relapse despite surgical resection of the primary tumor. Although cancer cell entry into the circulation and extravasation into distant organs are important early steps in the metastatic cascade, the predominant concern in the clinic is about preventing and treating relapse that is driven by cancer cells that were disseminated since before diagnosis. Therefore, our focus is on metastatic colonization, including the phases of metastatic seeding, latency, and outbreak. Building on our previous and new mouse models of brain and multi-organ metastasis, in the current grant period we have identified mediators of metastatic latency and immune evasion by metastatic stem-like cells (MetSCs) (Malladi et al Cell 2016), and mediators of relapse by residual disease after erlotinib and crizotinib treatment of lung adenoCa (Obenauf et al Nature 2015). We also identified serpin mediators of lung MetSC survival in the brain, and defined L1CAM as a mediator of vascular cooption for metastatic outgrowth (Valiente et al Cell 2014). Moreover, we found that carcinoma-astrocyte gap junctions promote brain metastasis by cGAS-STING pathway transfer and pharmacologic modulation of gap junctions is effective against established brain lesions in these models (Chen et al Nature 2016). Our work translated into two clinical trials, one with gap junction modulator meclofenamate and the other anti-TNF antibody certolizumab, in patients with stage IV lung adenoCa. Our future Aim 1 is to define and target the role of L1CAM signaling in lung adenoCa metastasis. We will determine the origin of L1CAM+ lung adenoCa MetSCs, the role of L1CAM signaling in outgrowth, and how to target L1CAM for inhibition of metastasis initiation and propagation. Aim 2 is to elucidate the signaling dynamics and immune evasive state of micrometastatic disease. We will investigate the role of three key pathways –WNT, TGF-β and Hippo– during MetSCs entry and exit from latency, and the role of NK and CD8+ T cells in enforcing latency by NKG2D-mediated recognition of ULBP ligands in MetSCs; the ultimate goal is to trigger immune-mediated clearance of residual disease. Our Aim 3 is to functionally define our recently identified mediators of CNS metastasis as therapeutic targets. We will characterize connexin 43, complement factor 3, and lipocalin 2 as mediators of brain and leptomeningeal metastasis, and will pre-clinically test pharmacologic inhibitors of these targets in combination with therapeutic approaches being developed by other members of this Program Project. Through this work we hope to contribute innovative ideas for the prevention and treatment of lung cancer relapse while retaining our long-term focus on discovering basic principles of metastasis.