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Age-induced methylmalonic acid accumulation promotes tumor progression

ABSTRACT: From age 65 onwards, the risk of cancer incidence and associated mortality is substantially higher. Nonetheless, our understanding of the complex relationship between age and cancer is still in its infancy. For decades, the link has largely been attributed to increased exposure time to mutagens in older individuals. However, this view does not account for the well-established role of diet, exercise and small molecules that target the pace of metabolic aging. Here, we show that metabolic alterations that occur with age can render a systemic environment favorable to progression and aggressiveness of tumors. Specifically, we show that methylmalonic acid (MMA), a by-product of propionate metabolism, is significantly up-regulated in the serum of older people, and functions as a mediator of tumor progression. We traced this to the induction of SOX4 and a consequent transcriptional reprogramming that can endow cancer cells with aggressive properties. Thus, accumulation of MMA represents a novel link between aging and cancer progression, implicating MMA as a novel therapeutic target for advanced carcinomas.

ORGANISM(S): Homo sapiens

PROVIDER: GSE127001 | GEO | 2020/07/03

REPOSITORIES: GEO

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Methylmalonic acid induces metabolic abnormalities and exhaustion in CD8+ T cells to suppress anti-tumor immunity

Project description:Systemic levels of methylmalonic acid (MMA), a byproduct of propionate metabolism, increase with age and MMA promotes tumor progression via its direct effects in tumor cells. However, the role of MMA in modulating the tumor ecosystem remains to be investigated. The proliferation and function of CD8+ T cells, key anti-tumor immune cells, declines with age and in conditions of vitamin B12 deficiency, which are the two most well-established conditions that lead to increased systemic levels of MMA. Thus, we hypothesized that increased circulatory levels of MMA would lead to a suppression of CD8+ T cell immunity. Treatment of primary CD8+ T cells with MMA induced a dysfunctional phenotype characterized by robust immunosuppressive transcriptional reprogramming and marked increases in the expression of the exhaustion regulator, TOX. Accordingly, MMA treatment upregulated exhaustion markers in CD8+ T cells and decreased their effector functions, which drove the suppression of anti-tumor immunity in vitro and in vivo. Mechanistically, MMA-induced CD8+ T cell exhaustion was associated with a suppression of NADH-regenerating reactions in the TCA cycle and concomitant defects in mitochondrial function. Thus, MMA has immunomodulatory roles, thereby highlighting MMA as an important link between aging, immune dysfunction, and cancer.

2024-10-17 | GSE256487 | GEO

Tumor-produced and aging-associated oncometabolite, methylmalonic acid, promotes cancer-associated fibroblast activation to drive metastatic progression

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Project description:Methylmalonic academia (MMA) is a rare inborn error of the metabolism due to defects of the methylmalonyl-CoA mutase (MUT) enzyme that result in methylmalonic acid accumulation in the blood and increased excretion in urine. Affected patients can manifest vomiting, dehydration, hypotonia, developmental delay and failure to thrive. The emergency treatment of the newborns with MMA mainly comprises rehydration and promotion of anabolism, followed by long-term dietary management that mostly includes restriction of propiogenic amino acids by a low protein diet and carnitine and vitamin B12 supplementation. The effects of MUT deficiency on the cellular damage in patients is still unknown. Fibroblasts obtained from two distinct MMA patients were analyzed by shotgun label-free quantitative (LFQ) proteomics.

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Hormesis underlies the adaptive response in methylmalonic acidemia (MMA)

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Age-induced methylmalonic acid accumulation promotes tumor progression

Project description:Age-induced methylmalonic acid accumulation promotes tumor progression

| PRJNA524129 | ENA

MethylMalonic Acidemia (MMA) is predicted by lipocalin-2 (LCN2) and attenuated by antioxidant therapy.

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2013-05-01 | E-GEOD-41044 | biostudies-arrayexpress

Methylmalonic acidemia triggers lysosomal-autophagy dysfunctions

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2024-05-23 | PXD044101 | Pride

Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia

2013-05-01 | GSE41044 | GEO

Hormesis underlies the adaptive response in methylmalonic acidemia (MMA)

Project description:Hormesis underlies the adaptive response in methylmalonic acidemia (MMA)

| PRJNA487064 | ENA

Altered propionate metabolism contributes to tumor progression and aggressiveness

Project description:The alteration of metabolic pathways is a critical strategy for cancer cells to attain the traits necessary for metastasis in disease progression. We found that dysregulation of propionate metabolism occurs through TGFbeta- and ERK2-driven downregulation of methylmalonyl-CoA epimerase (MCEE). MCEE downregulation occurs through a transcription factor Sp1/EGR1 switch at its promoter region, resulting in reduced flux through this anapleurotic pathway and leading to accumulation of methylmalonic acid (MMA), a byproduct of the propionate metabolism. MMA accumulation through alteration of propionate metabolism produces a pro-aggressive signature in breast and lung cancer cells and increases their metastatic potential. Altogether, we present a previously uncharacterized dysregulation of propionate metabolism as a novel contributor to cancer and a valuable potential target in the therapeutic treatment of metastatic carcinomas.

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