Spatial CRISPR genomics identifies regulators of the tumor microenvironment.

Autor:	Dhainaut M; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Rose SA; Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Akturk G; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Wroblewska A; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Nielsen SR; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Park ES; Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Buckup M; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Roudko V; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Pia L; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Sweeney R; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Le Berichel J; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Wilk CM; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Bektesevic A; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Lee BH; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Bhardwaj N; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Rahman AH; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Baccarini A; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Gnjatic S; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Pe'er D; Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Merad M; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center of Excellence for Thoracic Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Brown BD; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: brian.brown@mssm.edu.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2022 Mar 31; Vol. 185 (7), pp. 1223-1239.e20. Date of Electronic Publication: 2022 Mar 14.
DOI:	10.1016/j.cell.2022.02.015
Abstrakt:	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 TGFβ and TGFβ-mediated fibroblast activation, indicating that TGFβ-receptor loss on cancer cells increased TGFβ 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 TGFβ responsiveness of cancer cells can affect the TME. Competing Interests: Declaration of interests B.D.B. and A.W. have filed a patent application related to the Pro-Code technology. (Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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