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

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, Chunjun Guo, Noah Dephoure, Lewis C. Cantley, Ashley M. Laughney and John Blenis ()
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Zhongchi Li: Weill Cornell Medicine
Vivien Low: Weill Cornell Medicine
Valbona Luga: Weill Cornell Medicine
Janet Sun: Weill Cornell Medicine
Ethan Earlie: Weill Cornell Medicine
Bobak Parang: Weill Cornell Medicine
Kripa Shobana Ganesh: Weill Cornell Medicine
Sungyun Cho: Weill Cornell Medicine
Jennifer Endress: Weill Cornell Medicine
Tanya Schild: Weill Cornell Medicine
Mengying Hu: Weill Cornell Medicine
David Lyden: Weill Cornell Medicine
Wenbing Jin: Weill Cornell Medicine
Chunjun Guo: Weill Cornell Medicine
Noah Dephoure: Weill Cornell Medicine
Lewis C. Cantley: Weill Cornell Medicine
Ashley M. Laughney: Weill Cornell Medicine
John Blenis: Weill Cornell Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33862-0

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