Regulation of Brain Tumor Dispersal by NKCC1 Through a Novel Role in Focal Adhesion Regulation

Garzón-Muvdi, Tomás; Schiapparelli, Paula; Rhys, Colette ap; Guerrero-Cázares, Hugo; Smith, Christopher L.; Kim, Deok Ho; Kone, Lyonell; Farber, Harrison W.; Lee, Danielle Y.; An, Steven S.; Levchenko, Andre; Quiñones‐Hinojosa, Alfredo

doi:10.1371/journal.pbio.1001320

Cited by 136 publications

(178 citation statements)

References 100 publications

(157 reference statements)

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“…We measured traction forces of ADC cell lines expressing different levels of LAMC2 using Fourier transform traction microscopy as described previously. 53,54 Here, the computed traction field was used to obtain net contractile moment, which is a scalar measure of the cell's contractile strength. 54 Net contractile moment is expressed in units of pico-Newton meters (pNm).…”

Section: Methodsmentioning

confidence: 99%

LAMC2 enhances the metastatic potential of lung adenocarcinoma

et al. 2015

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Lung cancer is the number one cancer killer, and metastasis is the main cause of high mortality in lung cancer patients. However, mechanisms underlying the development of lung cancer metastasis remain unknown. Using genome-wide transcriptional analysis in an experimental metastasis model, we identified laminin γ2 (LAMC2), an epithelial basement membrane protein, to be significantly upregulated in lung adenocarcinoma metastatic cells. Elevated LAMC2 increased traction force, migration, and invasion of lung adenocarcinoma cells accompanied by the induction of epithelial-mesenchymal transition (EMT). LAMC2 knockdown decreased traction force, migration, and invasion accompanied by EMT reduction in vitro, and attenuated metastasis in mice. LAMC2 promoted migration and invasion via EMT that was integrin β1-and ZEB1-dependent. High LAMC2 was significantly correlated with the mesenchymal marker vimentin expression in lung adenocarcinomas, and with higher risk of recurrence or death in patients with lung adenocarcinoma. We suggest that LAMC2 promotes metastasis in lung adenocarcinoma via EMT and may be a potential therapeutic target. Cell Death and Differentiation (2015) 22, 1341-1352; doi:10.1038/cdd.2014.228; published online 16 January 2015Lung cancer is the leading cause of cancer-related death. 1 Non-small-cell lung cancer (NSCLC) accounts for~80-85% of lung cancers. 2 Only 20-30% of NSCLC are radically resectable and the majority of lung cancer patients succumb to the disease. The high mortality of NSCLC is largely attributable to late diagnosis, when metastases are present. 2 The molecular mechanisms governing metastasis of NSCLC remain poorly understood.Metastasis is a complex, multistep process, involving migration and invasion of malignant cells from the primary tumor to blood vessels, intravasation, and survival in the circulation, and ultimately extravasation, colonization, and formation of secondary tumor at distant target organs. 3 Each of these events is classically driven by the acquisition of genetic and/or epigenetic traits in tumor cells and the cooperation of nonneoplastic stromal cells. Increased or decreased expression of several genes in tumors has been found to be correlated with metastasis. 3 However, specific gene alterations that drive NSCLC metastasis remain largely elusive.Laminin γ2 (LAMC2) is a subunit of the heterotrimeric glycoprotein laminin-332 (LAM-332, formerly laminin-5), consisting of the α3, β3, and γ2 chains. Although LAMC2 is an important structural component of the epithelial basement membrane (BM) in various normal tissues, 4 there is an emerging evidence for a pathological role of LAMC2 monomer in cancer. It has been demonstrated that LAMC2 protein expression correlates with clinical outcome of stage I lung adenocarcinoma (ADC) patients. 5,6 In addition, noncontinuous expression pattern of LAMC2 predicts the prognosis of esophageal squamous cell carcinoma (SCC), 7 and secreted LAMC2 in the serum is associated with the aggressiveness of pancreatic cancer. 8 Besides, LAMC2 monom...

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Section: Methodsmentioning

confidence: 99%

LAMC2 enhances the metastatic potential of lung adenocarcinoma

et al. 2015

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“…Unlike adult neurons, glioma cells have high intracellular Cl − levels (120). This is due to the constitutive expression and prolonged activity of the Na + /K + /Cl − cotransporter 1 (NKCC1) that correlates with glioma grade and invasiveness (121). Upon opening of Cl − channels, the outflow of Cl − is accompanied by the efflux of water through aquaporins due to osmotic forces, leading to volume shrinkage.…”

Section: Hydrodynamic Model Of Glioma Cell Migrationmentioning

confidence: 99%

Molecular Mechanisms of Glioma Cell Motility

et al. 2017

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Gliomas are the most common intracranial tumors in humans. The most malignant among these tumors is glioblastoma (GBM), with an incidence of 3-5 out of 100,000 persons in Western countries. GBM arises either de novo (primary GBM) or develops from a lower grade glioma (secondary GBM). The prognosis is poor. GBMs are lethal tumors and even optimal surgical resection, followed by chemotherapy and irradiation, results in a median survival of about 12-15 months. One characteristic that is responsible for GBM malignancy, and its worse prognosis, is the highly infiltrative growth of GBM cells into the healthy brain. GBM cell migration and invasion is a very complex process that is regulated by several factors, which include changes in the migrating cell itself as well as the tumor microenvironment. This chapter provides an overview of routes of invasion of glioma cells, the signaling pathways that drive glioma cell motility, and the processes through which glioma cells modulate their surrounding environment.

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“…Recent studies suggest that WNK3 can also be phosphorylated by Akt (37). Growth factor-activated PI3K/Akt signaling pathways have been previously documented as a major pathway enhancing neuronal survival (38).…”

Section: Discussionmentioning

confidence: 99%

LINGO-1 Receptor Promotes Neuronal Apoptosis by Inhibiting WNK3 Kinase Activity

Zhang

Xiang

et al. 2013

Journal of Biological Chemistry

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Background: Although antagonism of LINGO-1 is known to improve neuronal survival after injury, the mechanism is unknown. Results: LINGO-1 interacts with and inhibits WNK3 kinase activity, thereby facilitating neuronal apoptosis. Conclusion: LINGO-1 potentiates neuronal apoptosis, likely by inhibiting WNK3 kinase activity. Significance: Learning how LINGO-1/WNK3 signaling regulates neuronal survival is crucial for understanding the pathology of neurodegenerative diseases and injury.

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Regulation of Brain Tumor Dispersal by NKCC1 Through a Novel Role in Focal Adhesion Regulation

Abstract: The ion transporter NKCC1 determines brain tumor cell migration by regulating the interplay between cell adhesion and growth factor signaling, and is a potential therapeutic target to treat brain cancer.

Cited by 136 publications

References 100 publications

LAMC2 enhances the metastatic potential of lung adenocarcinoma

LAMC2 enhances the metastatic potential of lung adenocarcinoma

Molecular Mechanisms of Glioma Cell Motility

LINGO-1 Receptor Promotes Neuronal Apoptosis by Inhibiting WNK3 Kinase Activity

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