How do cancer cells manage to leave the brain capillaries that transport them in order to form brain metastases?
Works* by the team of Jacky Goetz (unit 1109 Inserm/University of Strasbourg, team Biomechanics of tumors) carried out for several years in collaboration with the teams of Frank Winkler (DKFZ) and Yannick Schwab (EMBL), have made it possible to partly solve this mystery and to confirm an unexpected mechanism where the vascular endothelium proves to be an ally of cells tumours.
In 2013, Jacky Goetz’s team joined forces with Yannick Schwab’s (EMBL) to pursue the development of an avant-garde microscopy technique that allows them to follow a single cell, in this case a tumour, in its peregrinations towards the formation of metastases (Karreman et al., Plos one, 2014).
Very quickly, these technological developments allow them to follow a single cell in a vascular environment, opening up the possibility of tracking very closely and at very high resolution, for the first time, the mechanisms employed by circulating tumor cells.
By teaming up with the team of Frank Winkler, world expert in brain metastases, they shed light for the first time on the entrails of a metastatic cell during its last moments in a vascular environment, before crossing the blood-brain barrier and form metastases (Karreman et al., JCS, 2016).
Thanks to these technologies, they then observed for the first time that the endothelial wall of blood capillaries is reactive to the presence of circulating tumor cells by the intravascular extension of protrusive micrometric structures which are close to the tumor cell trapped in the capillary (Follain et al. DevCell 2018).
By continuing their work and modeling these stages in a zebrafish embryo, they demonstrate that the reactivity of the vascular endothelium to blood flow allows these cells to generate this intravascular remodeling. The team is able to eradicate them using drugs used in the clinic and known for their anti-angiogenic (Follain, Osmani et al Sci Rep 2021).
In this latest work** based on the approaches for longitudinal follow-up of cerebral metastases developed by F. Winkler’s team as well as the correlative microscopy techniques developed by the 3 teams, the researchers were able to demonstrate that this intravascular remodeling (which promotes tumor cell extravasation), but also post-extravasation (and which promotes metastatic growth), was controlled by the secretion of MMP9 (Matrix metalloprotease 9) by the tumor cells, which is a protease known to digest extracellular matrix. Using pharmacological approaches and models lacking MMP9, they were able to shed light on the central role played by this secreted molecule in promoting vascular remodeling and thus enabling the genesis and growth of cerebral metastases.
These results validate the discovery of a new mechanism of extravasation of tumor cells in the context of brain metastases, they also identify molecular mechanisms whose targeting would make it possible to stop them.
*supported by the National Cancer Institute and the League Against Cancer
**Active remodeling of capillary endothelium via cancer cell-derived MMP‑9 promotes metastatic brain colonization – Cancer Research, online first, January 19th 2023
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