Project 1: Mediators of Lung Adenocarcinoma Metastatis

项目1(Massagué)：肺腺癌转移的介体 项目总结 我们这个项目的目标是阐明肺腺癌的分子和细胞决定因素。 (腺钙)转移，以提高肺癌复发防治。近一半的人 早期诊断(I期和II期)的肺腺癌患者尽管进行了手术，但仍出现局部和远处复发 切除原发肿瘤。虽然癌细胞进入血液循环并向远处渗出 器官是转移级联过程中重要的早期步骤，临床上主要关注的是 预防和治疗由癌细胞驱动的复发，这些癌细胞在确诊前就已经扩散。 因此，我们的重点是转移定植，包括转移播种、潜伏期、 然后爆发。在我们以前和新的小鼠脑和多器官转移模型的基础上，在 目前的授权期我们已经确定了转移潜伏期和转移免疫逃避的介体 干细胞样细胞(MetSCs)(Malladi等人细胞2016)，以及厄洛替尼治疗后残留疾病复发的介体 和Crizotinib治疗肺腺钙(Obenauf等人，《自然》，2015)。我们还确定了蛇毒蛋白的中介体 肺金属间充质干细胞在脑内的存活，并将L1CAM定义为转移的血管共选的介质 OutGrowth(Valiente等人细胞，2014)。此外，我们发现癌细胞和星形胶质细胞的缝隙连接促进了大脑 通过cGAS-STING通路转移和缝隙连接的药物调节转移是有效的 针对这些模型中已建立的脑损伤(Chen等人《自然》2016)。我们的工作被翻译成两个 临床试验，一项是缝隙连接调节剂甲氯芬酸酯，另一项是抗肿瘤坏死因子抗体Certolizumab， 在IV期肺腺癌患者中。我们未来的目标1是定义和定位L1CAM信号的作用 在肺腺钙转移中。我们将确定L1CAM肺腺钙间充质干细胞的来源、作用 L1CAM在生长过程中的信号转导，以及如何靶向L1CAM以抑制肿瘤转移的启动和扩散。 目的2阐明微转移疾病的信号动力学和免疫逃避状态。 我们将研究三个关键途径-WNT，转化生长因子-β和HIPPO-在大肠干细胞进入和退出过程中的作用 从潜伏期开始，以及NK和CD8 T细胞在NKG2D介导的识别潜伏期中的作用 骨髓间充质干细胞中的ULBP配体；最终目标是触发免疫介导的残留疾病清除。我们的 目标3是从功能上将我们最近发现的中枢神经系统转移的介质定义为治疗性的 目标。我们将把连接蛋白43、补体因子3和脂粘蛋白2表征为脑和 软脑膜转移，并将在临床前联合测试这些靶点的药物抑制剂 该计划项目的其他成员正在开发治疗方法。通过这项工作，我们 希望为肺癌复发的防治贡献创新的思路，同时保持我们的 长期致力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.