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Metabolic re-programming by MALAT1 depletion in prostate cancer

ABSTRACT: In this study, we sought to investigate the metabolic role of MALAT1, one of the most abundant cancer-associated long non-coding RNA, in prostate cancer. MALAT1 targeting by gapmerization reduced expression of some tricarboxylic acid cycle enzymes including the malic enzyme 3 and the pyruvate dehydrogenase kinases 1 and 3 as well as the choline kinase A. In consequence, prostate cancer metabolism switched toward a glycolytic phenotype characterized by increased lactate production paralleled by growth arrest, and cell death. Conversely, the function of mitochondrial succinate dehydrogenase and expression of oxphos enzymes was markedly reduced, suggesting for a decreased tricarboxylic acid cycle and mitochondrial respiration activity. Interestingly, a similar effect was observed in several prostate cancer-derived organotypic slice cultures, in which metabolism became more glycolytic and apoptotic. Based on these observations, we elaborated a predictive algorithm, in which those metabolic enzymes sensitive to MALAT1 targeting proven successfully to predict tumor recurrence in a subset of patients. In summary, MALAT1 targeting by gapmerization activates a metabolic switch in the prostate cancer cell and tumor tissue unraveling a role for crucial metabolic enzymes in tumor progression and outcome.

ORGANISM(S): Homo sapiens

PROVIDER: GSE147566 | GEO | 2021/07/30

REPOSITORIES: GEO

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Project description:Cancer cells exhibit metabolic plasticity to meet oncogene-driven dependencies while coping with nutrient availability. A better understanding of how systemic metabolism impacts the accumulation of metabolites that reprogram the tumor microenvironment and drive cancer could facilitate development of precision nutrition approaches. Using the Hi-MYC prostate cancer mouse model, we demonstrated that an obesogenic high-fat diet rich in saturated fats accelerates the development of c-MYC-driven invasive prostate cancer through metabolic rewiring. Although c-MYC modulated key metabolic pathways, interaction with an obesogenic high-fat diet was necessary to induce glycolysis and lactate accumulation in tumors. These metabolic changes were associated with augmented infiltration of CD206+ and PD-L1+ tumor-associated macrophages and FOXP3+ regulatory T cells, as well as with the activation of transcriptional programs linked to disease progression and therapy resistance. Lactate itself also stimulated neoangiogenesis and prostate cancer cell migration, which were significantly reduced following treatment with the lactate dehydrogenase inhibitor FX11. In prostate cancer patients, high saturated fat intake and increased body mass index were associated with tumor glycolytic features that promote the infiltration of M2-like tumor-associated macrophages. Finally, upregulation of lactate dehydrogenase, indicative of a lactagenic phenotype, was associated with a shorter time to biochemical recurrence in independent clinical cohorts. This work identifies cooperation between genetic drivers and systemic metabolism to hijack the tumor microenvironment and promote prostate cancer progression through oncometabolite accumulation. This sets the stage for the assessment of lactate as a prognostic biomarker and supports strategies of dietary intervention and direct lactagenesis blockade in treating advanced prostate cancer. Murine serum assays are reported in the current study MTBLS3316.Murine prostate assays are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS3317' rel='noopener noreferrer' target='_blank'>MTBLS3317</a>.

Project description:Cancer cells exhibit metabolic plasticity to meet oncogene-driven dependencies while coping with nutrient availability. A better understanding of how systemic metabolism impacts the accumulation of metabolites that reprogram the tumor microenvironment and drive cancer could facilitate development of precision nutrition approaches. Using the Hi-MYC prostate cancer mouse model, we demonstrated that an obesogenic high-fat diet rich in saturated fats accelerates the development of c-MYC-driven invasive prostate cancer through metabolic rewiring. Although c-MYC modulated key metabolic pathways, interaction with an obesogenic high-fat diet was necessary to induce glycolysis and lactate accumulation in tumors. These metabolic changes were associated with augmented infiltration of CD206+ and PD-L1+ tumor-associated macrophages and FOXP3+ regulatory T cells, as well as with the activation of transcriptional programs linked to disease progression and therapy resistance. Lactate itself also stimulated neoangiogenesis and prostate cancer cell migration, which were significantly reduced following treatment with the lactate dehydrogenase inhibitor FX11. In prostate cancer patients, high saturated fat intake and increased body mass index were associated with tumor glycolytic features that promote the infiltration of M2-like tumor-associated macrophages. Finally, upregulation of lactate dehydrogenase, indicative of a lactagenic phenotype, was associated with a shorter time to biochemical recurrence in independent clinical cohorts. This work identifies cooperation between genetic drivers and systemic metabolism to hijack the tumor microenvironment and promote prostate cancer progression through oncometabolite accumulation. This sets the stage for the assessment of lactate as a prognostic biomarker and supports strategies of dietary intervention and direct lactagenesis blockade in treating advanced prostate cancer. Murine prostate assays are reported in the current study MTBLS3317.Murine serum assays are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS3316' rel='noopener noreferrer' target='_blank'>MTBLS3316</a>.

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Metabolic re-programming by MALAT1 depletion in prostate cancer

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