Spatial CRISPR genomics identifies regulators of the tumor microenvironment

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 MeradBrian D. Brown

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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.

Original languageEnglish
Pages (from-to)1223-1239.e20
JournalCell
Volume185
Issue number7
DOIs
StatePublished - 31 Mar 2022

Keywords

  • CRISPR screens
  • Socs1
  • TGF beta
  • cancer immunology
  • interferon gamma
  • lung cancer
  • spatial genomics
  • spatial transcriptomics
  • tumor clonality
  • tumor microenvironment

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