Cancer invasion: reciprocity between the extracellular matrix and intrinsic ERK signaling

癌细胞侵袭是肺癌发病的主要原因。入侵仍然没有目标，部分原因是 对细胞过程的分子基础的不完全理解。长期的 目的是确定驱动肺腺癌侵袭的机制。这里的总体目标是 探讨Tenascin-C和ERK信号转导机制在LUAD侵袭中的作用。中环 假设ERK和Tenascin-C共同作用诱导LUAD的侵袭。这是基于我们的 初步数据。我们发现Tenascin-C在肿瘤发生后的早期通过激活来表达 ERK途径的上游突变。我们还发现Tenascin-C和ERK都在 肿瘤的侵袭边缘以及Tenascin-C诱导ERK活性和ERK依赖的肿瘤细胞 体外侵袭。中心假设将通过追求三个具体目标来检验：1)确定 LUAD早期Tenascin-C产生的细胞来源和刺激，2)决定其机制 Tenascin-C信号传导到LUAD肿瘤细胞，以及3)确定ERK介导的LUAD侵袭机制。 在第一个目标下，我们将测试成纤维细胞是否会在应变增加时产生Tenascin-C。在AIM 2，我们将确定Tenascin-C信号是否通过激活肿瘤细胞整合素来诱导肿瘤细胞侵袭 还有ERK。在目标3中，我们将测试Lok/Ezrin是否是驱动间充质模式的关键ERK效应器 在LUAD观察到入侵。这将决定肺癌细胞外的机制 基质与致癌的RAS/ERK信号相互作用，驱动侵袭。这项研究中提出的 应用程序是创新的，因为它测试了Tenascin-C诱导的新模型，开发了一种计算 肿瘤在肺内和拉伸下生长的模型，使用器官类型培养，并测试一种新的， 侵袭过程中的可控ERK效应器。这项拟议的研究具有重要意义，因为它 希望通过机械化学的新知识来促进我们对肺癌的理解 间质和癌症之间的信号传递使癌症侵袭。归根结底，这种知识具有 有可能为开发靶向侵袭的新疗法提供强有力的科学依据 并降低肺癌发病率和死亡率。

Cancer cell invasion is the major cause of lung cancer morbidity. Invasion remain untargeted, in part due to an incomplete understanding of the molecular underpinnings of the cellular process. The long-term goal is to identify the mechanisms that drive lung adenocarcinoma invasion. The overall objective here is to elucidate the Tenascin-C and ERK signaling mechanisms that drive LUAD invasion. The central hypothesis is that ERK and Tenascin-C work together to induce LUAD invasion. This is based on our preliminary data. We show that Tenascin-C is expressed early after tumor initiation by activating upstream mutations in the ERK pathway. We also show that Tenascin-C and ERK are both expressed at the invasive edge of tumors, and that Tenascin-C induces ERK activity and ERK-dependent tumor cell invasion in vitro. The central hypothesis will be tested by pursuing three specific aims: 1) Determine the cell source and stimulus for Tenascin-C production in early LUAD, 2) Determine the mechanism by which Tenascin-C signals to LUAD tumor cells, and 3) Identify mechanisms of ERK-mediated LUAD invasion. Under the first aim, we will test if fibroblasts produce Tenascin-C in response to increased strain. In aim 2, we will determine if Tenascin-C signals to induce tumor cell invasion by activating tumor cell integrins and ERK. In aim 3, we will test if LOK/Ezrin are critical ERK effectors that drive the mesenchymal-mode invasion observed in LUAD. This will determine the mechanisms by which the lung cancer extracellular matrix interacts with oncogenic RAS/ERK signaling to drive invasion. The research proposed in this application is innovative, because it tests a new model of Tenascin-C induction, develops a computation model of tumor growth within the lung and under stretch, uses organotypic cultures, and tests a new, druggable ERK effector in the invasion process. The proposed research is significant because it is expected to advance our understanding of lung cancer with new knowledge of how mechanochemical signaling between the stroma and cancer confers cancer invasion. Ultimately, such knowledge has the potential to provide strong scientific justification for the development of new therapies to target invasion and reduce lung cancer morbidity and mortality.