Mapping single-cell drug responses in Glioblastoma

Glioblastoma (GBM) remains the most malignant primary brain
tumor. In spite of intensive treatment, current approaches seem
insufficiently effective to achieve major clinical benefits. GBM
typically exhibits complex genetic aberrations which lead to extensive
inter- and intratumoral heterogeneity. The presence of exceptional
responders across many failed clinical trials suggests that GBM
probably consists of dozens of small subgroups that likely all require
a different therapeutic approach. Because this functional
heterogeneity remains largely unexplored, the aim of this project is to
map single-cell drug responses across GBM tumor types. To achieve
this, we will compare ex vivo control- and drug-treated tumor
samples using a combination of transcriptomic and protein-based
single cell technologies. As such, we will not only be able to define
responsive and resistant tumor cell (sub)populations, it will also allow
us to identify potential biomarkers for each included therapy.
Appropriate experimental conditions and biomarkers will first be
identified using a heterogeneous library of patient-derived GBM cell
lines. Next, we will use mouse models of GBM to correlate the ex
vivo and in vivo response capabilities at single cell level, to finally
analyse these features in freshly resected clinical tumor samples.
This project will as such describe the landscape of drug
responsiveness across GBM at unseen resolution, and provide a
fundamental step towards more tailored therapy.