| Literature DB >> 36266345 |
Zhongchi Li1,2, Vivien Low1,2, Valbona Luga1,3, Janet Sun1,3, Ethan Earlie1,4, Bobak Parang1,2,3, Kripa Shobana Ganesh1,5, Sungyun Cho1,2, Jennifer Endress1,5, Tanya Schild1,5,6, Mengying Hu1,7, David Lyden1,7, Wenbing Jin8, Chunjun Guo8, Noah Dephoure1,5, Lewis C Cantley1,3,9, Ashley M Laughney1,4,10, John Blenis11,12,13.
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.Entities:
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Year: 2022 PMID： 36266345 PMCID： PMC9584945 DOI： 10.1038/s41467-022-33862-0
Source DB: PubMed Journal: Nat Commun ISSN： 2041-1723 Impact factor: 17.694