Identification of astrocyte-driven pseudolineages reveals clinical stratification and therapeutic targets in Glioblastoma

Cancer research has predominantly targeted genetic mutations, while only recently has attention shifted to understanding tumor cell-stages. However, the key organizational principles guiding tumor dynamics towards sustainable growth remained unexplored. By analyzing tumor cell ensembles from individuals with glioblastoma through the lens of the healthy adult stem cell lineage, we identified astrocytes as central to glioblastoma progression. We found dormant tumor cells resembling astrocytes progressing to active and differentiated stages, building tumor pseudolineages that ultimately influence patient survival. These tumor stages align with specific methylomes, offering potential for patient classification. Our study identifies the Wnt antagonist SFRP1 as a missing factor in glioblastoma that plays a crucial role in the transition from quiescence to activation in the healthy lineage. Excitingly, re-introduction of SFRP1 in glioblastoma halts tumor dynamics, enhancing survival in a PDX model. This fresh view on glioblastomas underscores the importance of understanding tumor dynamics and unveils novel therapeutic avenues. ### Competing Interest Statement The authors have declared no competing interest.