PMID- 35290801 OWN - NLM STAT- MEDLINE VI - 185 IP - 7 TI - Spatial CRISPR genomics identifies regulators of the tumor microenvironment. PG - 1223-1239.e20 CI - Copyright © 2022 Elsevier Inc. All rights reserved. LA - eng PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Cell JT - Cell JID - 0413066 IS - 1097-4172 (Electronic) LID - S0092-8674(22)00195-7 [pii] LID - 10.1016/j.cell.2022.02.015 [doi] FAU - Dhainaut, Maxime AU - Dhainaut M AD - 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. FAU - Rose, Samuel A AU - Rose SA AD - 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. FAU - Akturk, Guray AU - Akturk G AD - 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. FAU - Wroblewska, Aleksandra AU - Wroblewska A AD - 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. FAU - Nielsen, Sebastian R AU - Nielsen SR AD - 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. FAU - Park, Eun Sook AU - Park ES AD - 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. FAU - Buckup, Mark AU - Buckup M AD - Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Roudko, Vladimir AU - Roudko V AD - 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. FAU - Pia, Luisanna AU - Pia L AD - 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. FAU - Sweeney, Robert AU - Sweeney R AD - Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Le Berichel, Jessica AU - Le Berichel J AD - Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Wilk, C Matthias AU - Wilk CM AD - Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Bektesevic, Anela AU - Bektesevic A AD - 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. FAU - Lee, Brian H AU - Lee BH AD - Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Bhardwaj, Nina AU - Bhardwaj N AD - 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. FAU - Rahman, Adeeb H AU - Rahman AH AD - 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. FAU - Baccarini, Alessia AU - Baccarini A AD - 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. FAU - Gnjatic, Sacha AU - Gnjatic S AD - 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. FAU - Pe'er, Dana AU - Pe'er D AD - Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. FAU - Merad, Miriam AU - Merad M AD - 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. FAU - Brown, Brian D AU - Brown BD AD - 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. IS - 0092-8674 (Linking) RN - 0 (Transforming Growth Factor beta) SB - IM MH - Animals MH - Clustered Regularly Interspaced Short Palindromic Repeats/genetics MH - Genomics MH - Mice MH - *Neoplasms/genetics MH - Transforming Growth Factor beta/genetics MH - *Tumor Microenvironment OTO - NOTNLM OT - CRISPR screens OT - Socs1 OT - TGF beta OT - cancer immunology OT - interferon gamma OT - lung cancer OT - spatial genomics OT - spatial transcriptomics OT - tumor clonality OT - tumor microenvironment PMC - PMC8992964 DCOM- 20220414 LR - 20240322 DP - 20220331 DEP - 20220314 AB - 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.