Mathematics-based strategies for repairing tumour blood vessels
How does the extracellular matrix coordinate endothelial cell behavior during angiogenesis, and how do metabolic waste-products and matrix-degrading enzymes produced by the tumour modify the extracellular matrix so as the change the cellular coordination?
- 2018 - 2024
- Roeland Merks
- NWO VICI
Mathematical Institute, Leiden University
Capillaries, the smallest blood vessels of our body, are highly dynamic. In physiological processes like wound healing, a balance of promoting and inhibitory growth factors (e.g., VEGF) tightly control their growth and regression. This ensures that all tissues receive sufficient oxygen and nutrients. In cancer this process goes awry, resulting in an irregular and leaky tumour vasculature. New anti-cancer therapies try to revert tumour blood vessels back to those found in normal tissues, so as to normalize (i.e., ‘repair’) the blood flow in the tumour.
In addition to tuning VEGF, recent experiments point at two new targets for vasculature normalisation: endothelial and cancer cell metabolism and biomechanics of the extracellular matrix (ECM). These targets are thoroughly entangled as they both affect the coordination of ECs during the formation of blood vessel. Cancer-associated stiffening of the ECM induces tumour-like vasculature, while acidic waste products of cancer metabolism and ECs lead to remodelling of the ECM. The resulting insights will inspire new strategies for vasculature normalization and impact a wider range of ECM-related conditions, including diabetic retinopathy and fibrosis. In addition, the work will impact a widely applicable mathematics-driven, quantitative approach to developmental biology.
Hoffmann, L. A., Schakenraad, K., Merks, R. M. H., & Giomi, L. (2020). Chiral stresses in nematic cell monolayers. Soft Matter, 41, 545–11. http://doi.org/10.1039/C9SM01851D
Wolff, H. B., Davidson, L. A., & Merks, R. M. H. (2019). Adapting a Plant Tissue Model to Animal Development: Introducing Cell Sliding into VirtualLeaf. Bulletin of Mathematical Biology, 1–20. http://doi.org/10.1007/s11538-019-00599-9