Spatial CRISPR genomics identifies regulators of the tumor microenvironment.
CRISPR screens
Socs1
TGF beta
cancer immunology
interferon gamma
lung cancer
spatial genomics
spatial transcriptomics
tumor clonality
tumor microenvironment
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
31 03 2022
31 03 2022
Historique:
received:
05
07
2021
revised:
02
12
2021
accepted:
12
02
2022
pubmed:
16
3
2022
medline:
15
4
2022
entrez:
15
3
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35290801
pii: S0092-8674(22)00195-7
doi: 10.1016/j.cell.2022.02.015
pmc: PMC8992964
mid: NIHMS1788147
pii:
doi:
Substances chimiques
Transforming Growth Factor beta
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1223-1239.e20Subventions
Organisme : NCI NIH HHS
ID : U24 CA224319
Pays : United States
Organisme : NCI NIH HHS
ID : R33 CA223947
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK124165
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA254104
Pays : United States
Organisme : NCCIH NIH HHS
ID : R01 AT011326
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI078892
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA196521
Pays : United States
Organisme : NCI NIH HHS
ID : F31 CA247401
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA257195
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2022 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests B.D.B. and A.W. have filed a patent application related to the Pro-Code technology.
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