Metabolic adaptations of micrometastases alter EV production to generate invasive microenvironments

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Gounis, Michalis and Campos, America V. and Shokry, Engy and Mitchell, Louise and Deshmukh, Ruhi and Dornier, Emmanuel and Rooney, Nicholas and Dhayade, Sandeep and Pardo, Luis and Moore, Madeleine and Novo, David and Mowat, Jenna and Jamieson, Craig and Kay, Emily and Zanivan, Sara and Paul, Nikki R. and Mitchell, Claire and Nixon, Colin and Macpherson, Iain and Tardito, Saverio and Sumpton, David and Blyth, Karen and Norman, Jim C. and Clarke, Cassie J. (2025) Metabolic adaptations of micrometastases alter EV production to generate invasive microenvironments. Journal of Cell Biology, 224 (8). e202405061. ISSN 1540-8140 (https://doi.org/10.1083/jcb.202405061)

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Abstract

Altered cellular metabolism has been associated with the acquisition of invasive phenotypes during metastasis. To study this, we combined a genetically engineered mouse model of mammary carcinoma with syngeneic transplantation and primary tumor resection to generate isogenic cells from primary tumors and their corresponding lung micrometastases. Metabolic analyses indicated that micrometastatic cells increase proline production at the expense of glutathione synthesis, leading to a reduction in total glutathione levels. Micrometastatic cells also have altered sphingomyelin metabolism, leading to increased intracellular levels of specific ceramides. The combination of these metabolic adaptations alters extracellular vesicle (EV) production to render the microenvironment more permissive for invasion. Indeed, micrometastatic cells shut down Rab27-dependent production of EVs and, instead, switch on neutral sphingomyelinase-2 (nSM2)-dependent EV release. EVs released in an nSM2-dependent manner from micrometastatic cells, in turn, influence the ability of fibroblasts to deposit extracellular matrix, which promotes cancer cell invasiveness. These data provide evidence that metabolic rewiring drives invasive processes in metastasis by influencing EV release.

ORCID iDs

Gounis, Michalis, Campos, America V., Shokry, Engy, Mitchell, Louise, Deshmukh, Ruhi, Dornier, Emmanuel, Rooney, Nicholas, Dhayade, Sandeep, Pardo, Luis, Moore, Madeleine, Novo, David, Mowat, Jenna, Jamieson, Craig ORCID logoORCID: https://orcid.org/0000-0002-6567-8272, Kay, Emily, Zanivan, Sara, Paul, Nikki R., Mitchell, Claire, Nixon, Colin, Macpherson, Iain, Tardito, Saverio, Sumpton, David, Blyth, Karen, Norman, Jim C. and Clarke, Cassie J.;
CORE (COnnecting REpositories)