Rac-GEF/Rac Signaling and Metastatic Dissemination in Lung Cancer
Rac-GEF/Rac Signaling and Metastatic Dissemination in Lung Cancer
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DOI：
10.3389/fcell.2020.00118
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发表时间：
2020-02-25
影响因子：
5.5
通讯作者：
Kazanietz, Marcelo G.
中科院分区：
文献类型：
--
作者：
Cooke, Mariana;Baker, Martin J.;Kazanietz, Marcelo G.
肺癌是全球癌症相关死亡的主要原因，非小细胞肺癌（NSCLC）占新诊断的85%。该疾病通常在晚期转移阶段被检测到，预后和临床结果较差。为了逃离原发性肿瘤，癌细胞获得高度运动和侵袭性的表型，其涉及肌动蛋白细胞骨架的动态重组。这些过程受到Rac 1的严格调控，Rac 1是一种小G蛋白，参与形成癌细胞运动和分泌细胞外基质（ECM）降解蛋白酶所需的富含肌动蛋白的膜突起。在这篇前瞻性文章中，我们关注导致Rac 1信号异常在NSCLC进展和转移中的机制，突出Rac鸟嘌呤核苷酸交换因子（GEF）的作用。一种合理的情况是，特定的Rac-GEF激活Rac 1的离散细胞内池，导致在特定致癌驱动因素（如突变型EGFR或突变型KRAS）背景下的独特功能反应。Rac信号转导调节因子失调的鉴定可用于预测肺癌患者中转移性疾病的关键生物标志物，最终有助于改善患者预后和临床环境中的决策。
Lung cancer is the leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) representing similar to 85% of new diagnoses. The disease is often detected in an advanced metastatic stage, with poor prognosis and clinical outcome. In order to escape from the primary tumor, cancer cells acquire highly motile and invasive phenotypes that involve the dynamic reorganization of the actin cytoskeleton. These processes are tightly regulated by Rac1, a small G-protein that participates in the formation of actin-rich membrane protrusions required for cancer cell motility and for the secretion of extracellular matrix (ECM)-degrading proteases. In this perspective article we focus on the mechanisms leading to aberrant Rac1 signaling in NSCLC progression and metastasis, highlighting the role of Rac Guanine nucleotide Exchange Factors (GEFs). A plausible scenario is that specific Rac-GEFs activate discrete intracellular pools of Rac1, leading to unique functional responses in the context of specific oncogenic drivers, such as mutant EGFR or mutant KRAS. The identification of dysregulated Rac signaling regulators may serve to predict critical biomarkers for metastatic disease in lung cancer patients, ultimately aiding in refining patient prognosis and decision-making in the clinical setting.