Maxime Dhainaut, Samuel A Rose, Guray Akturk, Aleksandra Wroblewska, Sebastian R Nielsen, Eun Sook Park, Mark Buckup, Vladimir Roudko, Luisanna Pia, Robert Sweeney, Jessica Le Berichel, C Matthias Wilk, Anela Bektesevic, Brian H Lee, Nina Bhardwaj, Adeeb H Rahman, Alessia Baccarini, Sacha Gnjatic, Dana Pe'er, Miriam Merad, Brian D Brown
{"title":"空间 CRISPR 基因组学确定了肿瘤微环境的调节因子。","authors":"Maxime Dhainaut, Samuel A Rose, Guray Akturk, Aleksandra Wroblewska, Sebastian R Nielsen, Eun Sook Park, Mark Buckup, Vladimir Roudko, Luisanna Pia, Robert Sweeney, Jessica Le Berichel, C Matthias Wilk, Anela Bektesevic, Brian H Lee, Nina Bhardwaj, Adeeb H Rahman, Alessia Baccarini, Sacha Gnjatic, Dana Pe'er, Miriam Merad, Brian D Brown","doi":"10.1016/j.cell.2022.02.015","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":45.5000,"publicationDate":"2022-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8992964/pdf/nihms-1788147.pdf","citationCount":"0","resultStr":"{\"title\":\"Spatial CRISPR genomics identifies regulators of the tumor microenvironment.\",\"authors\":\"Maxime Dhainaut, Samuel A Rose, Guray Akturk, Aleksandra Wroblewska, Sebastian R Nielsen, Eun Sook Park, Mark Buckup, Vladimir Roudko, Luisanna Pia, Robert Sweeney, Jessica Le Berichel, C Matthias Wilk, Anela Bektesevic, Brian H Lee, Nina Bhardwaj, Adeeb H Rahman, Alessia Baccarini, Sacha Gnjatic, Dana Pe'er, Miriam Merad, Brian D Brown\",\"doi\":\"10.1016/j.cell.2022.02.015\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":9656,\"journal\":{\"name\":\"Cell\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":45.5000,\"publicationDate\":\"2022-03-31\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8992964/pdf/nihms-1788147.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1016/j.cell.2022.02.015\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2022/3/14 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.cell.2022.02.015","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2022/3/14 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
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 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.
期刊介绍:
Cells is an international, peer-reviewed, open access journal that focuses on cell biology, molecular biology, and biophysics. It is affiliated with several societies, including the Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH), and Society for Regenerative Medicine (Russian Federation) (RPO).
The journal publishes research findings of significant importance in various areas of experimental biology, such as cell biology, molecular biology, neuroscience, immunology, virology, microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. The primary criterion for considering papers is whether the results contribute to significant conceptual advances or raise thought-provoking questions and hypotheses related to interesting and important biological inquiries.
In addition to primary research articles presented in four formats, Cells also features review and opinion articles in its "leading edge" section, discussing recent research advancements and topics of interest to its wide readership.