Rac-GEF/Rac Signaling and Metastatic Dissemination in Lung Cancer

Abstract

Lung cancer is the leading cause of cancer-related deaths worldwide, with nonsmall 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.

ITGB1-DT Facilitates Lung Adenocarcinoma Progression via Forming a Positive Feedback Loop With ITGB1/Wnt/β-Catenin/MYC

“…The histological types of lung cancer include lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), large cell lung cancer, and small cell lung cancer. LUAD is the most common type, which accounts for 40%–50% of all lung cancers ( Liang et al, 2020 ; Cooke et al, 2020 ). Although most early-stage LUAD could be effectively treated by surgical resection, the prognoses of unresectable LUAD are still very poor with 5-year survival rates less than 20% ( Devarakonda et al, 2020 ).…”

Gβγ mediates activation of Rho guanine nucleotide exchange factor ARHGEF17 that promotes metastatic lung cancer progression

“…These GTPases are activated by multidomain signaling proteins called Rho guanine nucleotide exchange factors (RhoGEFs) ( 6 , 7 , 8 ). Specifically, these multidomain effectors are key signaling proteins, and potential therapeutic targets, that set with precision where and which Rho GTPases are loaded with GTP, acquiring an active conformation that control the assembly of different kinds of actin filaments and actomyosin contractile complexes ( 9 , 10 , 11 , 12 ). Although reorganization of the actin cytoskeleton by RhoGTPases is a ubiquitous mechanism for cell migration, the signaling proteins upstream of these processes are quite diverse.…”

Two Rac1 pools integrate the direction and coordination of collective cell migration

“…Our identification of Mbc-ELMO complex as the intermediator between PVR and protrusive Rac1 activity is consistent with several previous findings: 1) during elimination of oncogenic neighbours by JNK-mediated engulfment in Drosophila , upregulation of PVR in normal cells by JNK activation can induce the downstream Mbc-ELMO mediated phagocytic pathway 55 ; 2) the Mbc-ELMO complex is known to act as a member of Rac guanine nucleotide exchange factors (GEFs) to control Rac1 activity and lamellipodia formation in Drosophila dorsal closure, somatic muscle and dorsal vessel 56, 57 . Regarding EGFR-mediated control of tensile Rac1 activity, ERK/MAPK signalling has been implicated to drive the overexpression and activation of the Rac-GEF in BRAF- and NRAS-mutant melanoma, as well as in KRAS- and EGFR-mutant lung cancer 58, 59 . However, how ERK/MAPK signalling governs Rac-GEF and Rac1 activity, especially tensile Rac1 activity controlled by Raf in border cells, is little explored.…”