Unleashing CRISPR technologies to find novel tumor vessel tuning strategies

The tumor vasculature is intrinsically abnormal, ill-perfused and leaky and as such co-determines the reduced efficiency of otherwise highly potential anti-cancer strategies like immunotherapy (IT). The host lab pioneered the concept of tumor vessel normalization (TVN) through targeting the metabolism of tumor endothelial cells (TECs; cells lining tumor vessels), and constructed a mathematical model to predict novel therapeutically relevant metabolic targets. By using single cell RNA-sequencing (scRNA-seq), the host lab identified “immune TEC” subpopulations resembling (i) high endothelial venules (HEVs) involved in immune cell recruitment (hevTECs), and (ii) antigen presentating cells (APCs), which may function as semi-professional APCs (apTECs). I hypothesize that targeting novel metabolic TEC targets may induce TVN, and that tuning of TECs to a hev-/apTEC phenotype may represent a complementary approach to current IT strategies. Here, by using innovative CRISPR-based screening techniques that allow for (i) studying the disruption of hundreds of metabolic target genes simultaneously, or (ii) studying the exact gene expression profile of a cell upon target gene disruption, I aim to identify the most relevant metabolic target genes as well as genes underlying hev-/apTEC phenotypes. Combined with functional validation of the most promising candidate genes, this approach promises to unravel fundamental insights to support future development of TVN- and TEC-based IT strategies.