Spatial CRISPR genomics identifies regulators of the tumor microenvironment Journal Article
| Authors: | Dhainaut, M.; Rose, S. A.; Akturk, G.; Wroblewska, A.; Nielsen, S. R.; Park, E. S.; Buckup, M.; Roudko, V.; Pia, L.; Sweeney, R.; Le Berichel, J.; Wilk, C. M.; Bektesevic, A.; Lee, B. H.; Bhardwaj, N.; Rahman, A. H.; Baccarini, A.; Gnjatic, S.; Pe'er, D.; Merad, M.; Brown, B. D. |
| Article Title: | Spatial CRISPR genomics identifies regulators of the tumor microenvironment |
| Abstract: | 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. © 2022 Elsevier Inc. |
| Keywords: | controlled study; human cell; genetics; histopathology; nonhuman; genetic analysis; neoplasm; neoplasms; t lymphocyte; animal cell; mouse; animal; animals; mice; animal tissue; cell structure; biological model; transforming growth factor beta; protein depletion; animal experiment; animal model; cohort analysis; lung cancer; transcriptomics; gene mapping; oncogene; immune response; cancer cell; transforming growth factor beta receptor; fibroblast; genomics; tumor immunity; upregulation; tumor growth; cell activation; functional genomics; tumor microenvironment; single cell analysis; cancer immunology; socs1; tgf beta; tumor clonality; human; female; article; clustered regularly interspaced short palindromic repeat; interferon gamma; tgfbr2 gene; gene knockout; spatial genomics; clustered regularly interspaced short palindromic repeats; spatial transcriptomics; crispr screens |
| Journal Title: | Cell |
| Volume: | 185 |
| Issue: | 7 |
| ISSN: | 0092-8674 |
| Publisher: | Cell Press |
| Date Published: | 2022-03-31 |
| Start Page: | 1223 |
| End Page: | 1239.e20 |
| Language: | English |
| DOI: | 10.1016/j.cell.2022.02.015 |
| PUBMED: | 35290801 |
| PROVIDER: | scopus |
| PMCID: | PMC8992964 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 May 2022 -- Source: Scopus |
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