Congratulations to this year’s
Nobel prize winners in Medicine: William Kaelin, Peter Ratcliffe and Gregg Semenza. Their work on cell’s adaptation to oxygen concentration is as relevant to those of us doing mathematical models as it was last year’s award to scientists working on cancer immunotherapy.
Cancer adaptation to hypoxia is particularly dear to me as it was the subject of my first mathematical oncology model. Kaelin, Ratcliffe and Semenza discovered that, under hypoxia, cells release HIF (Hypoxia Inducible Factor) which either degrades in the presence of oxygen (in which case things are alright), or not, in which case the cells proceed to adapt to the absence of oxygen. One of the ways a cell can adapt is by relying on glycolysis, a type of metabolism that, although inefficient in terms of energy (ATP) production, does not require oxygen. Using Evolutionary Game Theory (EGT)
this model explored how hypoxia can lead to the emergence of glycolytic cells and how those glycolytic cells will, in turn, help select for more invasive/metastatic cells.
Later, Jake Scott, Sandy Anderson and I (among others) used an agent-based model to explore how oxygen concentration influences cancer initiation in a tissue organized using a
stem-cell based hierarchy. It is clear that oxygen not only influences cells directly but also indirectly by exerting a selection force towards certain cell types. Intrigued by these results, Jake and I partnered with David Robert Grimes, who has been working on the physics of oxygen in medicine for longer than us, to see what more realistic (and heterogeneous) oxygen maps could do in the context of cancer. Turns out that hypoxia can change not only the evolutionary dynamics but also the evolutionary tempo creating
hotspots for evolution.
These are not the first, nor the latest...not even the best examples of mathematical models studying the interplay between cell adaptation and oxygen. There are many others, which only goes to show how important this research is. So kudos to Kaelin, Ratcliffe and Semenza, whose work has inspired so many of us to look at the microenvironment in cancer, the interplay between said microenvironment and the tumor and the influence of its change and heterogeneity in shaping somatic evolution.