Metabolic adaptations of micrometastases alter EV production to generate invasive microenvironments
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.
Authors
- Ruhi Deshmukh (ORCID: https://orcid.org/0000-0002-9700-8556)
- América Campos (ORCID: https://orcid.org/0000-0002-7068-3391)
- Jim C. Norman (ORCID: https://orcid.org/0000-0002-0098-3014)
- Michalis Gounis (ORCID: https://orcid.org/0000-0001-7142-4677)
- David Sumpton (ORCID: https://orcid.org/0000-0002-9004-4079)
- Emily Kay (ORCID: https://orcid.org/0000-0002-3398-0960)
- Jenna M. Mowat
- Luis Pardo (ORCID: https://orcid.org/0000-0002-4355-1369)
- Karen Blyth (ORCID: https://orcid.org/0000-0002-9304-439X)
- Emmanuel Dornier (ORCID: https://orcid.org/0000-0002-3482-8637)
- Sara Zanivan (ORCID: https://orcid.org/0000-0002-9880-9099)
- Cassie J. Clarke (ORCID: https://orcid.org/0000-0003-2232-1609)
- Saverio Tardito (ORCID: https://orcid.org/0000-0002-5294-8683)
- Iain R. Macpherson (ORCID: https://orcid.org/0000-0003-4295-8885)
- Colin Nixon (ORCID: https://orcid.org/0000-0002-8085-2160)
- David Novo (ORCID: https://orcid.org/0000-0001-5344-0083)
- Craig Jamieson (ORCID: https://orcid.org/0000-0002-6567-8272)
- Engy Shokry (ORCID: https://orcid.org/0000-0002-5932-9332)
- Nikki R. Paul (ORCID: https://orcid.org/0000-0002-0953-4709)
- Sandeep Dhayade (ORCID: https://orcid.org/0000-0002-1681-8216)
- C. A. Mitchell (ORCID: https://orcid.org/0000-0001-9960-2340)
- M. H. Moore (ORCID: https://orcid.org/0009-0003-5246-3955)
- Louise E. Mitchell (ORCID: https://orcid.org/0009-0004-3173-5074)
- Nicholas Rooney (ORCID: https://orcid.org/0009-0008-0652-4207)
Institutions
- University of Strathclyde (GB)
- Cancer Research UK (GB)
- Comprehensive Cancer Center Vienna (AT)
- Center for Cancer Research (US)
- Medical University of Vienna (AT)
- University of Glasgow (GB)
Publication Details
- Journal
- The Journal of Cell Biology
- Published
- 2025-05-07
- DOI
- https://doi.org/10.1083/jcb.202405061
- Citations
- 2
- Primary Topic
- Extracellular vesicles in disease
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- Breast Cancer Now
- Pancreatic Cancer UK
- Wellcome Trust
- Cancer Research UK
- Medical Research Council