Speaker: Miguel Bernabeu  (Oxford)
Host: Kristina Haase  (EMBL BCN)

Tumour hypoxia is a defining feature of the tumour microenvironment and a major cause of therapeutic resistance. Although abnormal vascular organisation is widely recognised to impair oxygen delivery, the biophysical mechanisms connecting vascular structure, red blood cell (RBC) transport and tissue hypoxia remain incompletely understood. In this talk, I will summarise published work showing how specific vascular abnormalities disrupt RBC partitioning and thereby generate heterogeneous oxygenation. Quantitative analysis of tumour vascular networks, combined with mathematical modelling, showed that a reduced vessel length-to-diameter ratio biases haematocrit distribution and promotes spatial heterogeneity in oxygenation, identifying this metric as a structural surrogate of tumour perfusion and oxygenation (Bernabeu et al., PNAS 2020). Complementary computational studies further showed that vessel compression first perturbs RBC partitioning at individual bifurcations (Enjalbert et al., PNAS 2021), before these local disturbances propagate across networks and increase haematocrit heterogeneity (Enjalbert et al., Communications Physics 2024). Together, these studies establish a mechanistic framework linking abnormal vascular structure, disordered RBC transport and tumour hypoxia.

I will then present unpublished data from a glioblastoma (GBM) model that test this framework experimentally. In GBM, focal adhesion kinase (FAK) has been implicated in tumour progression, invasive behaviour and tumour–microenvironment interactions. To examine whether tumour cell FAK also shapes the vascular determinants of hypoxia, we used a tumour cell FAK knockout model. Loss of FAK increased tumour hypoxia without altering intrinsic tumour cell oxygen consumption, and this effect was not explained by vascular density. Instead, FAK-deficient tumours exhibited more abnormal three-dimensional vascular architecture. We further show that the vessel length-to-diameter ratio is the strongest microvascular predictor of hypoxic fraction, with lower values associated with greater hypoxia. These results suggest that tumour-cell-driven abnormalities in vascular structure, rather than vessel abundance alone, are closely associated with impaired oxygenation in GBM.