ArticleNature communications2022
Tumor-produced and aging-associated oncometabolite methylmalonic acid promotes cancer-associated fibroblast activation to drive metastatic progression.
Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
52 citing papers in PubMed, 1 synthesis or guideline pooled it, 61 citations in OpenAlex.
- The underexplored links between cancer and the internal body climate: Implications for cancer prevention and treatment.Frontiers in oncology · 2022Pooled it
- Metabolic adaptations of the tumor macroenvironment and their role in cancer progression and survivorship.Genes & development · 2026Review
- Isoleucine and valine promote prostate cancer progression via propionyl-CoA-mediated cholesterol metabolism.Nature metabolism · 2026Article
- Targeting MMA-induced USP36 methylmalonylation to suppress macrophage polarization and tumor progression in clear-cell renal cell carcinoma.Cell death and differentiation · 2026Article
- Reprogramming the tumor microenvironment: methylmalonic acid at the intersection of ccRCC metabolism and macrophage polarization.Cell death and differentiation · 2026Article
- A multiomic investigation of human milk-derived extracellular vesicles in perinatal HIV and antiretroviral therapy exposure.Molecular medicine (Cambridge, Mass.) · 2026Observational
- Reprogramming of valine metabolism mediated by abnormally low ALDH6A1 expression promotes invasive metastasis of gastric cancer.Science advances · 2026Article
- Nanomedicine novel strategies: deciphering the EV-metabolic axis as a natural nanocarrier network in lung cancer progression and cachexia.Journal of nanobiotechnology · 2026Review
- Propionate metabolism is dysregulated in non-small cell lung cancer patients and EGFR-mutant drug-tolerant persister cells.Scientific reports · 2026Article
- Article
- Prospective Head-to-Head Comparison ofRadiology. Imaging cancer · 2026Article
- The Aging Microenvironment Is a Determinant of Immune Exclusion and Metastatic Fate in Pancreatic Cancer.Cancer research · 2026Article
- Evaluating the implications of K-Ras, KEAP1/NRF2-mediated signaling pathways and metabolic alterations in urethane-induced lung cancer.Journal of molecular histology · 2026Article
- Targeting metabolic-epigenetic-immune axis in cancer: molecular mechanisms and therapeutic implications.Signal transduction and targeted therapy · 2026Review
- Effect of Mitochondria-Derived Methylmalonic Acid on Progress and Mortality Risk in US Adults With Cardiovascular-Kidney-Metabolic Syndrome.Journal of the American Heart Association · 2026Article
- Of Barriers and Loops-How Evolution Limits Most Cancer Risks to Older Ages.Cancer discovery · 2026Review
- Short-chain fatty acids in the tumor microenvironment: from molecular mechanisms to cancer therapy.Theranostics · 2026Review
- Cancer-cell-secreted DDAH1 induces TGF-β1/Smad3 signaling pathway to promote fibrosis and aging in lung.Nature aging · 2026Article
- Metabolic adaptations in cancer progression.Physiological reviews · 2026Review
- Elevated methylmalonic acid, but not vitamin B12, predicts all-cause mortality in hyperlipidemic adults: a prospective cohort study.Frontiers in nutrition · 2026Article
Corrections and comments
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Authors and funding
18 authors at 2 institutions in 1 country.
Funding
Abstract
The systemic metabolic shifts that occur during aging and the local metabolic alterations of a tumor, its stroma and their communication cooperate to establish a unique tumor microenvironment (TME) fostering cancer progression. Here, we show that methylmalonic acid (MMA), an aging-increased oncometabolite also produced by aggressive cancer cells, activates fibroblasts in the TME, which reciprocally secrete IL-6 loaded extracellular vesicles (EVs) that drive cancer progression, drug resistance and metastasis. The cancer-associated fibroblast (CAF)-released EV cargo is modified as a result of reactive oxygen species (ROS) generation and activation of the canonical and noncanonical TGFβ signaling pathways. EV-associated IL-6 functions as a stroma-tumor messenger, activating the JAK/STAT3 and TGFβ signaling pathways in tumor cells and promoting pro-aggressive behaviors. Our findings define the role of MMA in CAF activation to drive metastatic reprogramming, unveiling potential therapeutic avenues to target MMA at the nexus of aging, the tumor microenvironment and metastasis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.