In vivo single-cell CRISPR uncovers distinct TNF programmes in tumour evolution

The tumour evolution model posits that malignant transformation is preceded by randomly distributed driver mutations in cancer genes, which cause clonal expansions in phenotypically normal tissues. Although clonal expansions can remodel entire tissues 1 – 3 , the mechanisms that result in only a sma...

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Bibliographic Details
Published in:Nature (London) Vol. 632; no. 8024; pp. 419 - 428
Main Authors: Renz, Peter F., Ghoshdastider, Umesh, Baghai Sain, Simona, Valdivia-Francia, Fabiola, Khandekar, Ameya, Ormiston, Mark, Bernasconi, Martino, Duré, Clara, Kretz, Jonas A., Lee, Minkyoung, Hyams, Katie, Forny, Merima, Pohly, Marcel, Ficht, Xenia, Ellis, Stephanie J., Moor, Andreas E., Sendoel, Ataman
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 08.08.2024
Nature Publishing Group
Subjects:
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631/1647/2017
631/208/191/2018
631/67/1244
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64/60
Animals
Autocrine signalling
Cancer
Carcinogenesis - genetics
Carcinogenesis - pathology
Carcinoma, Squamous Cell - genetics
Carcinoma, Squamous Cell - pathology
Cell Transformation, Neoplastic - genetics
Clonal Evolution - genetics
Clone Cells - metabolism
Cloning
Clustered Regularly Interspaced Short Palindromic Repeats - genetics
CRISPR
CRISPR-Cas Systems - genetics
Down-regulation
Epithelial-Mesenchymal Transition - genetics
Evolution
Evolutionary genetics
Female
Gene Expression Regulation, Neoplastic
Gene sequencing
Genes
Humanities and Social Sciences
Humans
In vivo methods and tests
Invasiveness
Libraries
Macrophages
Macrophages - metabolism
Male
Mice
Modules
multidisciplinary
Mutation
Neoplasm Invasiveness - genetics
Receptors, Tumor Necrosis Factor, Type I - genetics
Receptors, Tumor Necrosis Factor, Type I - metabolism
Science
Science (multidisciplinary)
Signal Transduction - genetics
Single-Cell Analysis
Squamous cell carcinoma
Stem cells
Tissues
Transcriptome - genetics
Transcriptomics
Tumor necrosis factor
Tumor necrosis factor receptors
Tumor Necrosis Factor-alpha - genetics
Tumor Necrosis Factor-alpha - metabolism
Tumor necrosis factor-TNF
Tumor Necrosis Factors - genetics
Tumor Necrosis Factors - metabolism
Tumorigenesis
Tumors
Ultrasonic imaging
ISSN:0028-0836, 1476-4687, 1476-4687
Online Access:Get full text
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Summary:The tumour evolution model posits that malignant transformation is preceded by randomly distributed driver mutations in cancer genes, which cause clonal expansions in phenotypically normal tissues. Although clonal expansions can remodel entire tissues 1 – 3 , the mechanisms that result in only a small number of clones transforming into malignant tumours remain unknown. Here we develop an in vivo single-cell CRISPR strategy to systematically investigate tissue-wide clonal dynamics of the 150 most frequently mutated squamous cell carcinoma genes. We couple ultrasound-guided in utero lentiviral microinjections, single-cell RNA sequencing and guide capture to longitudinally monitor clonal expansions and document their underlying gene programmes at single-cell transcriptomic resolution. We uncover a tumour necrosis factor (TNF) signalling module, which is dependent on TNF receptor 1 and involving macrophages, that acts as a generalizable driver of clonal expansions in epithelial tissues. Conversely, during tumorigenesis, the TNF signalling module is downregulated. Instead, we identify a subpopulation of invasive cancer cells that switch to an autocrine TNF gene programme associated with epithelial–mesenchymal transition. Finally, we provide in vivo evidence that the autocrine TNF gene programme is sufficient to mediate invasive properties and show that the TNF signature correlates with shorter overall survival of patients with squamous cell carcinoma. Collectively, our study demonstrates the power of applying in vivo single-cell CRISPR screening to mammalian tissues, unveils distinct TNF programmes in tumour evolution and highlights the importance of understanding the relationship between clonal expansions in epithelia and tumorigenesis. A CRISPR-based strategy for screening genes that affect clonal expansion finds that genes that are frequently mutated in squamous cell carcinoma converge on a TNF signalling module involving macrophages.
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ISSN:0028-0836
1476-4687
1476-4687
DOI:10.1038/s41586-024-07663-y