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

Author

Listed:
  • Zhongchi Li

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Vivien Low

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Valbona Luga

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Janet Sun

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Ethan Earlie

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Bobak Parang

    (Weill Cornell Medicine
    Weill Cornell Medicine
    Weill Cornell Medicine)

  • Kripa Shobana Ganesh

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Sungyun Cho

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Jennifer Endress

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Tanya Schild

    (Weill Cornell Medicine
    Weill Cornell Medicine
    Memorial Sloan Kettering Cancer Center)

  • Mengying Hu

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • David Lyden

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Wenbing Jin

    (Weill Cornell Medicine)

  • Chunjun Guo

    (Weill Cornell Medicine)

  • Noah Dephoure

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Lewis C. Cantley

    (Weill Cornell Medicine
    Weill Cornell Medicine
    Dana Farber Cancer Institute)

  • Ashley M. Laughney

    (Weill Cornell Medicine
    Weill Cornell Medicine
    Weill Cornell Medicine)

  • John Blenis

    (Weill Cornell Medicine
    Weill Cornell Medicine
    Weill Cornell Medicine)

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.

Suggested Citation

  • Zhongchi Li & Vivien Low & Valbona Luga & Janet Sun & Ethan Earlie & Bobak Parang & Kripa Shobana Ganesh & Sungyun Cho & Jennifer Endress & Tanya Schild & Mengying Hu & David Lyden & Wenbing Jin & Chu, 2022. "Tumor-produced and aging-associated oncometabolite methylmalonic acid promotes cancer-associated fibroblast activation to drive metastatic progression," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33862-0
    DOI: 10.1038/s41467-022-33862-0
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    References listed on IDEAS

    as
    1. Ana P. Gomes & Didem Ilter & Vivien Low & Jennifer E. Endress & Juan Fernández-García & Adam Rosenzweig & Tanya Schild & Dorien Broekaert & Adnan Ahmed & Melanie Planque & Ilaria Elia & Julie Han & Ch, 2020. "Age-induced accumulation of methylmalonic acid promotes tumour progression," Nature, Nature, vol. 585(7824), pages 283-287, September.
    2. Alessandro Luciani & Anke Schumann & Marine Berquez & Zhiyong Chen & Daniela Nieri & Mario Failli & Huguette Debaix & Beatrice Paola Festa & Natsuko Tokonami & Andrea Raimondi & Alessio Cremonesi & Di, 2020. "Impaired mitophagy links mitochondrial disease to epithelial stress in methylmalonyl-CoA mutase deficiency," Nature Communications, Nature, vol. 11(1), pages 1-21, December.
    3. Juliane Winkler & Abisola Abisoye-Ogunniyan & Kevin J. Metcalf & Zena Werb, 2020. "Concepts of extracellular matrix remodelling in tumour progression and metastasis," Nature Communications, Nature, vol. 11(1), pages 1-19, December.
    4. Alessandro Luciani & Anke Schumann & Marine Berquez & Zhiyong Chen & Daniela Nieri & Mario Failli & Huguette Debaix & Beatrice Paola Festa & Natsuko Tokonami & Andrea Raimondi & Alessio Cremonesi & Di, 2020. "Author Correction: Impaired mitophagy links mitochondrial disease to epithelial stress in methylmalonyl-CoA mutase deficiency," Nature Communications, Nature, vol. 11(1), pages 1-1, December.
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