Small-molecule inhibitors of FGFR, integrins and FAK selectively decrease L1CAM-stimulated glioblastoma cell motility and proliferation

Abstract

We here show for the first time that small-molecule inhibitors of FGFR, integrins and FAK effectively and selectively abolish L1-stimulated migration and proliferation of glioblastoma-derived cells. Our results suggest that these inhibitors have the potential to reduce the aggressiveness of high-grade gliomas expressing L1.

A simple and accurate rule-based modeling framework for simulation of autocrine/paracrine stimulation of glioblastoma cell motility and proliferation by L1CAM in 2-D culture

“…The interface allows user control over a variety of parameters. By using data collected over a range of experimental conditions (e.g., [ 1 ]) one can adjust the parameters in the model to produce simulated behavior similar to the experimental behavior observed in the laboratory.…”

“…The recurring tumors often are even more aggressive in their spread, resulting in the extremely poor prognosis typical of GBM. We have shown that the neural adhesion molecule L1CAM (L1) stimulates GBM cell motility and invasion both in vitro and in vivo using a variety of approaches [ 1 , 10 , 17 ]. If mechanisms controlling GBM cell motility and invasion can be modeled and simulated, then this likely will aid in experimental design and predicting outcomes of experimental manipulations.…”

“…L1 affects GBM cell motility through autocrine/paracrine stimulation of integrin and fibroblast growth factor receptor (FGFR) signaling that appears to converge through focal adhesion kinase (FAK) [ 1 , 10 , 17 ]. Our in vitro experimental cell motility paradigm primarily has been the SuperScratch assay whereby an area in a confluent monolayer of cells is wiped or “scratched” clean with a pipet tip to leave a free edge within the confluent monolayer from which cells can migrate into the denuded area (see [ 1 , 5 ]). We then collect sequential images of the scratch edge over time and subsequently measure motility rates of the individual cells over that time period, thus giving highly quantitative data on individual and collective cell motility.…”

“…We then collect sequential images of the scratch edge over time and subsequently measure motility rates of the individual cells over that time period, thus giving highly quantitative data on individual and collective cell motility. We have used multiple experimental treatments to elucidate L1 autocrine/paracrine stimulation mechanisms, including attenuation of L1 expression in L1-positive cells, ectopic expression of L1 in L1-negative cells, blocking L1 with specific antibodies and peptides, overexpression of a dominant negative form of FGFR, and blocking cell signaling using small molecule inhibitors of integrins, FGFR, and FAK in L1-positive vs. L1-negative cells [ 1 , 10 , 16 , 17 ]. Based on our experiments so far, we theorize that transmembrane L1 is proteolyzed and released as a large ectodomain fragment from cells at the scratch edge to interact with the cells’ integrin and FGFRs to initiate cell signaling cascades that converge through FAK to stimulate cell motility and proliferation.…”

Direct contact with perivascular tumor cells enhances integrin αvβ3 signaling and migration of endothelial cells

“…Cell adhesion receptors other than integrins, including L1CAM, also can promote cell migration [reviewed in [13]]. L1CAM binds to RGD-peptide-binding integrins, including integrin αvβ3 due to the presence of an RGD-peptide in its extracellular sixth Ig domain and this peptide appears to be necessary for the pro-migratory and pro-invasive effects of L1CAM in cancer cells [13–18]. …”