Spatial CRISPR genomics identifies regulators of the tumor microenvironment

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 beta and TGF beta-mediated fibroblast activation, indicating that TGF beta-receptor loss on cancer cells increased TGFI 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 beta responsiveness of cancer cells can affect the TME.

Automated summary

This study developed a method called Perturb-map for spatial functional genomics, which allows the study of gene functions within the tissue context. By applying Perturb-map to a mouse model of lung cancer, multiple genes were knocked out and their effects on tumor growth, histopathology, and immune composition were assessed. Furthermore, Perturb-map was paired with spatial transcriptomics for unbiased analysis of CRISPR-edited tumors.