Cooke Mariana, Baker Martin J, Kazanietz Marcelo G
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
Front Cell Dev Biol. 2020 Feb 25;8:118. doi: 10.3389/fcell.2020.00118. eCollection 2020.
Lung cancer is the leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) representing ∼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.
肺癌是全球癌症相关死亡的主要原因，其中非小细胞肺癌（NSCLC）约占新诊断病例的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，癌细胞获得了高度运动性和侵袭性表型，这涉及肌动蛋白细胞骨架的动态重组。这些过程受到Rac1的严格调控，Rac1是一种小G蛋白，参与癌细胞运动和细胞外基质（ECM）降解蛋白酶分泌所需的富含肌动蛋白的膜突起的形成。在这篇观点文章中，我们聚焦于NSCLC进展和转移过程中导致Rac1信号异常的机制，强调Rac鸟嘌呤核苷酸交换因子（GEFs）的作用。一种合理的情况是，特定的Rac-GEFs激活Rac1的离散细胞内池，在特定致癌驱动因素（如突变的EGFR或突变的KRAS）的背景下导致独特的功能反应。鉴定失调的Rac信号调节因子可能有助于预测肺癌患者转移性疾病的关键生物标志物，最终有助于改善患者预后并辅助临床决策。
