Control of lung cancer invasion and metastasis by vimentin

描述（由申请人提供）：肺癌是世界上最致命的恶性癌症，在美国每年导致超过15万人死亡。特别是占所有肺癌近80%的非小细胞肺癌（NSCLC），其5年生存率仅为15-25%。大量报道表明，中间丝蛋白vimentin在侵袭性人类肿瘤中过表达，但在非侵袭性、静止性肿瘤中几乎检测不到。在非小细胞肺癌中，vimentin表达与生存率低、转移性疾病增加和分化差相关。然而，波形蛋白在非小细胞肺癌中的机制作用尚不清楚。我们发现STRAD1-LKB1肺癌肿瘤抑制通路在30%的NSCLC患者中发生突变，是NSCLC中第三高的突变通路，在肺癌运动过程中调节波形蛋白功能。因此，我们将vimentin与一个强大的非小细胞肺癌肿瘤抑制通路联系起来。我们将验证在肺癌侵袭过程中，波形蛋白受到STRAD1-LKB1的监督，并参与维持方向性持久性的正反馈循环。我们的目标是确定STRAD1-LKB1如何监督vimentin功能，vimentin如何继续调节NSCLC运动，以及NSCLC患者中vimentin表达的分子和临床后果。重要的是，我们已经发表了STRAD1-LKB1与典型细胞极性和运动蛋白cdc42-PAK1相互作用。我们基于这些数据来确定STRAD1-LKB1是否通过cdc42-PAK1调节vimentin。此外，我们提出vimentin随后通过包含cdc42和cdc42鸟嘌呤交换因子（GEF） VAV2的正反馈回路继续调节NSCLC的方向性持久性。我们采用创新和全面的机制方法，结合最先进的细胞和分子生物学，体内异种移植模型和基于患者组织的方法来充分转化这些发现。通过了解STRAD1-LKB1如何调控vimentin以及vimentin表达如何促进NSCLC转移，我们可以影响我们对LKB1突变体（约5万例患者）和vimentin过表达NSCLC患者的生物学理解。因此，这一提议可以为非小细胞肺癌中vimentin的功能建立一个新的范式，并表明vimentin在肺癌转移性侵袭的调节中发挥着重要作用。

DESCRIPTION (provided by applicant): Lung cancer is the most lethal malignant cancer worldwide and results in over 150,000 deaths per year in the United States. In particular, non-small cell lung cancer (NSCLC), which accounts for nearly 80% of all lung cancers, has a 5-year survival rate ranging from only 15-25%. Numerous reports show that the intermediate filament protein vimentin is overexpressed in invasive human tumors but is nearly undetectable in non- invasive, stationary tumors. In NSCLC, vimentin expression correlates with poor survival, increased metastatic disease, and poor differentiation. Nevertheless, the mechanistic role of vimentin in NSCLC is unexplored. Here we show that the STRAD1-LKB1 lung cancer tumor suppressor pathway, which is mutated in 30% of NSCLC patients and is the 3rd highest mutated pathway in NSCLC, regulates vimentin function during lung cancer motility. Thus, we link vimentin to a robust NSCLC tumor suppressor pathway. We will test the central hypothesis that during lung cancer invasion, vimentin is overseen by STRAD1-LKB1 and participates in a positive feedback loop that maintains directionality persistence. Our objectives are to determine how STRAD1-LKB1 oversees vimentin function, how vimentin goes on to regulate NSCLC motility, and the molecular and clinical consequences of vimentin expression in NSCLC patients. Importantly, we have published that STRAD1-LKB1 interact with the canonical cell polarity and motility proteins cdc42-PAK1. We build upon this data to determine whether STRAD1-LKB1 regulate vimentin through cdc42-PAK1. Moreover, we propose that vimentin then goes on to regulate NSCLC directionality persistence through a positive feedback loop containing cdc42, and the cdc42 guanine exchange factor (GEF) VAV2. We take an innovative and comprehensive mechanistic approach by combining state-of-the-art cell and molecular biology, in vivo xenograft models, and patient tissue-based approaches to fully translate these findings. By understanding how STRAD1-LKB1 regulates vimentin and how vimentin expression contributes to NSCLC metastasis, we can impact our understanding of the biology of LKB1 mutant (~50,000 patients) and vimentin overexpressing NSCLC patients. Thus, this proposal can develop a new paradigm for vimentin function in NSCLC and present vimentin as a major player in the regulation of lung cancer metastatic invasion.