BMI Seminar // Sten Linnarsson "Spatial Organization of Cellular Reactive States in Human Brain Cancer"

Glioblastoma therapy has remained essentially unchanged for decades, and no targeted therapies have worked despite numerous attempts. In order to better understand the organization of the tumor and its interactions with immune and stromal cells, we have performed spatial transcriptomic analysis of a large cohort. Comparisons with human brain reference atlases revealed tumor cell states analogous to developmental glioblasts, as well as reactive cell states specific to distinct tumor niches. We revisit the concept of ‘mesenchymal-like’ tumor cells and show that these cells are not undergoing differentiation but rather a wound-healing reaction to hypoxia and plasma leakage into the tumor. We validate these findings in tumor-derived organoids, and demonstrate that the wound-healing reaction is a cross-cell type molecular program activated in both tumor and non-tumor cells.