Metabolic Plasticity of Tumor Cells: How They Do Adapt to Food Deprivation

Schoonjans, Céline A; Gallez, Bernard

doi:10.1007/978-3-030-34025-4_6

Cited by 3 publications

(4 citation statements)

References 80 publications

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“…Another possible contributor to this lower acidification of the TME could be a compensatory mechanism occurring when tumors are treated chronically with an MPC inhibitor. Tumor cells indeed exhibit extraordinary metabolic plasticity to adapt to constraints or changes in their environment [ 6 , 43 , 44 , 45 , 46 ]. It has been previously demonstrated that cells may tolerate loss of MPC activity by metabolic rewiring to compensate for the loss of pyruvate oxidation [ 8 ].…”

Section: Discussionmentioning

confidence: 99%

Impact of Inhibition of the Mitochondrial Pyruvate Carrier on the Tumor Extracellular pH as Measured by CEST-MRI

Buyse

Joudiou

Corbet

et al. 2021

Cancers

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(1) Background: The acidosis of the tumor micro-environment may have profound impact on cancer progression and on the efficacy of treatments. In the present study, we evaluated the impact of a treatment with UK-5099, a mitochondrial pyruvate carrier (MPC) inhibitor on tumor extracellular pH (pHe); (2) Methods: glucose consumption, lactate secretion and extracellular acidification rate (ECAR) were measured in vitro after exposure of cervix cancer SiHa cells and breast cancer 4T1 cells to UK-5099 (10 µM). Mice bearing the 4T1 tumor model were treated daily during four days with UK-5099 (3 mg/kg). The pHe was evaluated in vivo using either chemical exchange saturation transfer (CEST)-MRI with iopamidol as pHe reporter probe or 31P-NMR spectroscopy with 3-aminopropylphosphonate (3-APP). MR protocols were applied before and after 4 days of treatment; (3) Results: glucose consumption, lactate release and ECAR were increased in both cell lines after UK-5099 exposure. CEST-MRI showed a significant decrease in tumor pHe of 0.22 units in UK-5099-treated mice while there was no change over time for mice treated with the vehicle. Parametric images showed a large heterogeneity in response with 16% of voxels shifting to pHe values under 7.0. In contrast, 31P-NMR spectroscopy was unable to detect any significant variation in pHe; (4) Conclusions: MPC inhibition led to a moderate acidification of the extracellular medium in vivo. CEST-MRI provided high resolution parametric images (0.44 µL/voxel) of pHe highlighting the heterogeneity of response within the tumor when exposed to UK-5099.

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Section: Discussionmentioning

confidence: 99%

Impact of Inhibition of the Mitochondrial Pyruvate Carrier on the Tumor Extracellular pH as Measured by CEST-MRI

Buyse

Joudiou

Corbet

et al. 2021

Cancers

Self Cite

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show abstract

“…The analysis demonstrated that these cells exhibited different redox ratio and NAD(P)H lifetime. Additionally, multiple studies have explored the molecular changes driving these metabolic adaptations [12,24,27,28]. However, solid tumors are heterogeneous systems where multiple metabolic phenotypes co-exist and evolve across the tumor mass.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, blocking one metabolic pathway commonly leads to compensatory upregulation of alternative metabolic routes, allowing tumor cell survival [10]. Further, the limited supply of oxygen and nutrients in highly metabolically active tumors commonly leads to nutrient starvation, hypoxia, and waste product accumulation [11,12]. Therefore, tumor cells rewire their metabolic phenotype, and reduce cell proliferation and macromolecule demand [13,14].…”

Section: Introductionmentioning

confidence: 99%

Microfluidic Tumor-on-a-Chip Model to Study Tumor Metabolic Vulnerability

Ayuso

Rehman

Farooqui

et al. 2020

IJMS

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Tumor-specific metabolic adaptations offer an interesting therapeutic opportunity to selectively destroy cancer cells. However, solid tumors also present gradients of nutrients and waste products across the tumor mass, forcing tumor cells to adapt their metabolism depending on nutrient availability in the surrounding microenvironment. Thus, solid tumors display a heterogenous metabolic phenotype across the tumor mass, which complicates the design of effective therapies that target all the tumor populations present. In this work, we used a microfluidic device to study tumor metabolic vulnerability to several metabolic inhibitors. The microdevice included a central chamber to culture tumor cells in a three-dimensional (3D) matrix, and a lumen in one of the chamber flanks. This design created an asymmetric nutrient distribution across the central chamber, generating gradients of cell viability. The results revealed that tumor cells located in a nutrient-enriched environment showed low to no sensitivity to metabolic inhibitors targeting glycolysis, fatty acid oxidation, or oxidative phosphorylation. Conversely, when cell density inside of the model was increased, compromising nutrient supply, the addition of these metabolic inhibitors disrupted cellular redox balance and led to tumor cell death.

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“…On the other hand, the efficiency of metforminbased treatment in the therapy of drug-resistant prostate tumors has been questioned by reports on its relatively negligible anticancer potential [19,20]. These conflicting data prompted us to hypothesize that the cytostatic effects of metformin can be counterbalanced by the metabolic adaptation of drug-resistant cells [21].…”

Section: Introductionmentioning

confidence: 99%

Acquired drug resistance interferes with the susceptibility of prostate cancer cells to metabolic stress

et al. 2022

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Background Metformin is an inhibitor of oxidative phosphorylation that displays an array of anticancer activities. The interference of metformin with the activity of multi-drug resistance systems in cancer cells has been reported. However, the consequences of the acquired chemoresistance for the adaptative responses of cancer cells to metformin-induced stress and for their phenotypic evolution remain unaddressed. Methods Using a range of phenotypic and metabolic assays, we assessed the sensitivity of human prostate cancer PC-3 and DU145 cells, and their drug-resistant lineages (PC-3_DCX20 and DU145_DCX20), to combined docetaxel/metformin stress. Their adaptation responses have been assessed, in particular the shifts in their metabolic profile and invasiveness. Results Metformin increased the sensitivity of PC-3 wild-type (WT) cells to docetaxel, as illustrated by the attenuation of their motility, proliferation, and viability after the combined drug application. These effects correlated with the accumulation of energy carriers (NAD(P)H and ATP) and with the inactivation of ABC drug transporters in docetaxel/metformin-treated PC-3 WT cells. Both PC-3 WT and PC-3_DCX20 reacted to metformin with the Warburg effect; however, PC-3_DCX20 cells were considerably less susceptible to the cytostatic/misbalancing effects of metformin. Concomitantly, an epithelial–mesenchymal transition and Cx43 upregulation was seen in these cells, but not in other more docetaxel/metformin-sensitive DU145_DCX20 populations. Stronger cytostatic effects of the combined fenofibrate/docetaxel treatment confirmed that the fine-tuning of the balance between energy supply and expenditure determines cellular welfare under metabolic stress. Conclusions Collectively, our data identify the mechanisms that underlie the limited potential of metformin for the chemotherapy of drug-resistant tumors. Metformin can enhance the sensitivity of cancer cells to chemotherapy by inducing their metabolic decoupling/imbalance. However, the acquired chemoresistance of cancer cells impairs this effect, facilitates cellular adaptation to metabolic stress, and prompts the invasive front formation.

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Metabolic Plasticity of Tumor Cells: How They Do Adapt to Food Deprivation

Cited by 3 publications

References 80 publications

Impact of Inhibition of the Mitochondrial Pyruvate Carrier on the Tumor Extracellular pH as Measured by CEST-MRI

Impact of Inhibition of the Mitochondrial Pyruvate Carrier on the Tumor Extracellular pH as Measured by CEST-MRI

Microfluidic Tumor-on-a-Chip Model to Study Tumor Metabolic Vulnerability

Acquired drug resistance interferes with the susceptibility of prostate cancer cells to metabolic stress

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