Spatial CRISPR genomics identifies regulators of the tumor microenvironment
Menée à partir du criblage génétique de différents types tumoraux au moyen de la technologie CRISPR, cette étude identifie des régulateurs du microenvironnement tumoral
While CRISPR screens are helping uncover genes regulating many cell-intrinsic processes, existing approaches are suboptimal for identifying extracellular gene functions, particularly in the tissue context. Here, we developed an approach for spatial functional genomics called Perturb-map. We applied Perturb-map to knock out dozens of genes in parallel in a mouse model of lung cancer and simultaneously assessed how each knockout influenced tumor growth, histopathology, and immune composition. Moreover, we paired Perturb-map and spatial transcriptomics for unbiased analysis of CRISPR-edited tumors. We found that in Tgfbr2 knockout tumors, the tumor microenvironment (TME) was converted to a fibro-mucinous state, and T cells excluded, concomitant with upregulated TGF? and TGF?-mediated fibroblast activation, indicating that TGF?-receptor loss on cancer cells increased TGF? bioavailability and its immunosuppressive effects on the TME. These studies establish Perturb-map for functional genomics within the tissue at single-cell resolution with spatial architecture preserved and provide insight into how TGF? responsiveness of cancer cells can affect the TME.
Cell , résumé, 2021