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FAK modulates glioblastoma stem cell energetics via actomyosin contractility: regulation of glycolysis and mitochondrial function

ABSTRACT: Glycolysis and the TCA cycle are commonly reprogrammed to fulfil the bioenergetic and biosynthetic demands of cancer cells. Although the extracellular matrix is known to influence glycolysis and the TCA cycle, it is not well understood how specific adhesion proteins and their downstream effectors contribute to metabolic changes and to the mitigation of metabolic stress. Here, we report that the canonical focal adhesion protein FAK is required for optimal cellular energetics through both glycolysis and the TCA cycle in a transformed neural stem cell model of glioblastoma. Mechanistically, FAK promotes the TCA cycle by keeping myosin II activity low in cells with a mesenchymal-like morphology. Genetic deletion of FAK induces an epithelial-like morphology with elevated myosin II activity as evidenced by phospho-myosin light chain accumulation at cell-cell contacts. In this context these cells have impaired glycolysis and TCA cycle flux that is accompanied by shortening of mitochondria fragments. Treating FAK depleted cells with multiple Rho-kinase (ROCK) inhibitors restores efficient TCA cycle flux, mitochondrial morphology, cells’ mesenchymal nature and viability. Phenotypically, the reduction in cell energetics after FAK depletion is accompanied by reduced cancer cell motility and invasiveness in vitro and suppression of tumour growth and increased survival in an orthotopic murine model. We demonstrate a novel role for FAK as an adhesion protein which can modulate cellular energetics and mitochondria morphology in glioblastoma stem cells with profound consequences for cancer-associated cell phenotypes and tumour growth in vivo.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Alex von Kriegsheim

LAB HEAD: Alex von Kriegsheim

PROVIDER: PXD058998 | Pride | 2025-12-15

REPOSITORIES: Pride

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FAK modulates glioblastoma stem cell energetics via regulation of glycolysis and glutamine oxidation.

Masalmeh Roza H A RHA Dawson John C JC Garcia Virginia Alvarez VA Muir Morwenna T MT Carter Roderick N RN Hardingham Giles E GE Davies Cameron C Graham Rosina R von Kriegsheim Alex A Marques Jair J Pednekar Chinmayi C Pollard Steven M SM Carragher Neil O NO Brunton Valerie G VG Frame Margaret C MC

Disease models & mechanisms 20251128 11

Glycolysis and the tricarboxylic acid cycle (TCA) cycle are reprogrammed in cancer cells to meet bioenergetic and biosynthetic demands, including by engagement with the extracellular matrix (ECM). However, the mechanisms by which the ECM engagement reprograms core energy metabolism is still unknown. We showed that the canonical cell-ECM adhesion protein focal adhesion kinase (FAK, also known as PTK2) and, specifically, its kinase activity, is driving cellular energetics. Using a mouse stem cell ...[more]

PMID: 40977288

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Project description:Purpose: Focal adhesion kinase (FAK), hyaluronan (HA), and hyaluronan synthase-3 (HAS3) have been implicated in cancer growth and progression. FAK inhibition with the small molecule inhibitor Y15 decreases colon cancer cell growth in vitro and in vivo. HAS3 inhibition in colon cancer cells decreases FAK expression and activation, and exogenous HA increases FAK activation. We sought to determine the genes affected by HAS and FAK inhibition and hypothesized that dual inhibition would synergistically inhibit viability. Methods: We treated SW620 colon cancer cells with Y15 to inhibit FAK. We used two strategies to inhibit HAS: (1) cells were transfected with siRNA (HAS3 inhibited); a scrambled sequence was used as a control (HAS3 scrambled), and (2) cells were treated with the HAS inhibitor 4-methylumbelliferone (4-MU). To determine the effect on viability, MTT assays were performed on transfected cells treated with Y15, and wild type cells treated with Y15 alone, 4-MU alone or Y15+4-MU. Treated and untreated cells were submitted to the gene microarray facility for expression profiling. RT-PCR was done to confirm the results. Results: HAS and FAK inhibition affected cell viability. Y15 and 4-MU decreased viability in a dose-dependent manner; viability was further inhibited by treatment with Y15+4-MU in combination (p<0.05). HAS-inhibited cells treated with as little as 2 M of Y15 showed significantly decreased viability compared to HAS scrambled cells treated with the same dose (p<0.05), suggesting synergistic inhibition of viability with dual FAK/HAS inhibition. Microarray analysis showed more than 2-fold up- or down-regulation of 121 genes by HAS inhibition, and 696 genes by FAK inhibition (p<0.05). Of 29 genes that were common to both groups, 9 were down-regulated (CBS, DHRS3, EEPD1, ESPN, FAM46C, GRTP1, IL20RA, INHBE, SCNN1A) and 4 were up-regulated (ANXA1, MALL, RGS2, SNAI2). RT-PCR confirmed these findings. Among the genes affected by FAK or HAS3 inhibition were FOX genes (apoptosis, cell cycle regulation), ANXA1 (apoptosis, proliferation), IL8 (cell cycle regulation, adhesion, proliferation), RGS2 (cell cycle regulation), CEACAM6 (adhesion), SNAI2 (transcription regulation), and SFRP5 (apoptosis). Several genes were specific to either FAK or HAS3 inhibition and several were common to both. Gene expression profiles of samples isolated from human colorectal cancer cells (SW620). A comparison of gene expression between untreated cells and cells treated with 4mcM of Y15. A second comparison between cells transfected with siRNA to HAS3 (HAS3-silenced) and cells transfected with a scrambled control sequence (sc). Two replicates each.

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FAK modulates glioblastoma stem cell energetics via actomyosin contractility: regulation of glycolysis and mitochondrial function

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FAK modulates glioblastoma stem cell energetics via regulation of glycolysis and glutamine oxidation.

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