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

• DOI: 10.21203/rs.3.rs-1643401/v1
• Publication Date: 2022-05-13T20:08:43Z
• Authors: Zhongchi Li; Vivien Low; Valbona Luga; Janet Sun; Ethan Earlie; Bobak Parang; Kripa Shobana Ganesh; Sungyun Cho; Jennifer Endress; Tanya Schild; Menying Hu; David Lyden; Wenbing Jin; Chun-Jun Guo; Noah Dephoure; Lewis Cantley; Ashley Laughney; John Blenis
• Keywords: 0301 basic medicine; Interleukin-6; Science; Q; Article; 3. Good health; Extracellular Vesicles; 03 medical and health sciences; Cancer-Associated Fibroblasts; Transforming Growth Factor beta; Neoplasms; Tumor Microenvironment; Humans; Reactive Oxygen Species; Methylmalonic Acid

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) that fosters cancer progression. Here, we show that methylmalonic acid (MMA), an aging-increased oncometabolite that is 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 in CAFs. EV-associated IL-6 functions as a stroma-tumor messenger that activates the JAK/STAT3 and TGFβ signaling pathways in tumor cells and promote an epithelial-to-mesenchymal transition (EMT) and drug resistance in vitro, and metastatic progression in vivo. Our findings reveal the role of MMA in the activation of CAFs to drive metastatic reprogramming, unveiling multiple potential therapeutic avenues to target MMA at the nexus of aging, the tumor microenvironment and metastasis.