A quantitative and multiplexed approach to uncover the fitness landscape of tumor suppression in vivo

Nature Methods
Zoë N RogersMonte M Winslow

Abstract

Cancer growth is a multistage, stochastic evolutionary process. While cancer genome sequencing has been instrumental in identifying the genomic alterations that occur in human tumors, the consequences of these alterations on tumor growth remain largely unexplored. Conventional genetically engineered mouse models enable the study of tumor growth in vivo, but they are neither readily scalable nor sufficiently quantitative to unravel the magnitude and mode of action of many tumor-suppressor genes. Here, we present a method that integrates tumor barcoding with ultradeep barcode sequencing (Tuba-seq) to interrogate tumor-suppressor function in mouse models of human cancer. Tuba-seq uncovers genotype-dependent distributions of tumor sizes. By combining Tuba-seq with multiplexed CRISPR-Cas9-mediated genome editing, we quantified the effects of 11 tumor-suppressor pathways that are frequently altered in human lung adenocarcinoma. Tuba-seq enables the broad quantification of the function of tumor-suppressor genes with unprecedented resolution, parallelization, and precision.

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Citations

Apr 4, 2018·Nature Genetics·Zoë N RogersMonte M Winslow
Jul 17, 2018·Cell Cycle·Sarah A Best, Kate D Sutherland
Jan 22, 2019·Nature Reviews. Clinical Oncology·Hao YinDaniel G Anderson
Apr 11, 2018·Nature Genetics·James Kim, John D Minna
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Sep 15, 2021·Cold Spring Harbor Perspectives in Medicine·Anna Arnal-EstapéKaterina Politi

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Datasets Mentioned

BETA
AB40759
AB5535

Methods Mentioned

BETA
Tuba-seq
PCR
transfection
electrophoresis

Software Mentioned

DADA2
LOESS
Tuba
AddGene
ENSEMBL
seq
BLAST

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