Single-cell genomics analysis reveals complex genetic interactions in an in vivo model of acquired BRAF inhibitor resistance

Jacob L Schillo; Charlotte R Feddersen; Rebekah M Peplinski; Lexy S Powell; Afshin Varzavand; Christopher S Stipp; Jesse D Riordan; Adam J Dupuy

doi:10.1093/narcan/zcad061

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Single-cell genomics analysis reveals complex genetic interactions in an in vivo model of acquired BRAF inhibitor resistance

Journal article

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Single-cell genomics analysis reveals complex genetic interactions in an in vivo model of acquired BRAF inhibitor resistance

Jacob L Schillo, Charlotte R Feddersen, Rebekah M Peplinski, Lexy S Powell, Afshin Varzavand, Christopher S Stipp, Jesse D Riordan and Adam J Dupuy

NAR cancer, Vol.6(1), p.zcad061

03/2024

DOI: 10.1093/narcan/zcad061

PMCID: PMC10782916

PMID: 38213996

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Abstract

The evolution of therapeutic resistance is a major obstacle to the success of targeted oncology drugs. While both inter- and intratumoral heterogeneity limit our ability to detect resistant subpopulations that pre-exist or emerge during treatment, our ability to analyze tumors with single-cell resolution is limited. Here, we utilized a cell-based transposon mutagenesis method to identify mechanisms of BRAF inhibitor resistance in a model of cutaneous melanoma. This screen identified overexpression of NEDD4L and VGLL3 as significant drivers of BRAF inhibitor resistance in vivo . In addition, we describe a novel single-cell genomics profiling method to genotype thousands of individual cells within tumors driven by transposon mutagenesis. This approach revealed a surprising genetic diversity among xenograft tumors and identified recurrent co-occurring mutations that emerge within distinct tumor subclones. Taken together, these observations reveal an unappreciated genetic complexity that drives BRAF inhibitor resistance. Graphical Abstract

Cancer Genomics

Details

Title: Subtitle: Single-cell genomics analysis reveals complex genetic interactions in an in vivo model of acquired BRAF inhibitor resistance
Creators: Jacob L Schillo - , Iowa City, IA 52242, , Iowa City, IA 52242
Charlotte R Feddersen - , Iowa City, IA 52242, , Iowa City, IA 52242
Rebekah M Peplinski - , Iowa City, IA 52242, , Iowa City, IA 52242
Lexy S Powell - , Iowa City, IA 52242
Afshin Varzavand - , , IA
Christopher S Stipp - , , IA
Jesse D Riordan - , Iowa City, IA 52242
Adam J Dupuy - , Iowa City, IA 52242, , , IA
Resource Type: Journal article
Publication Details: NAR cancer, Vol.6(1), p.zcad061
DOI: 10.1093/narcan/zcad061
PMID: 38213996
PMCID: PMC10782916
NLM abbreviation: NAR Cancer
eISSN: 2632-8674
Publisher: Oxford University Press
Grant note: T32 GM008629; T32 GM067795 / ;
Language: English
Date published: 03/2024
Academic Unit: Dermatology; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Pathology; Biology
Record Identifier: 9984543460002771

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