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Charting oncogenicity of genes and variants across lineages via multiplexed screens in teratomas
Deconstructing tissue-specific effects of genes and variants on proliferation is critical to understanding cellular transformation and systematically selecting cancer therapeutics. This requires scalable methods for multiplexed genetic screens tracking fitness across time, across lineages, and in a...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8496177/ https://www.ncbi.nlm.nih.gov/pubmed/34646987 http://dx.doi.org/10.1016/j.isci.2021.103149 |
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author | Parekh, Udit McDonald, Daniella Dailamy, Amir Wu, Yan Cordes, Thekla Zhang, Kun Tipps, Ann Metallo, Christian Mali, Prashant |
author_facet | Parekh, Udit McDonald, Daniella Dailamy, Amir Wu, Yan Cordes, Thekla Zhang, Kun Tipps, Ann Metallo, Christian Mali, Prashant |
author_sort | Parekh, Udit |
collection | PubMed |
description | Deconstructing tissue-specific effects of genes and variants on proliferation is critical to understanding cellular transformation and systematically selecting cancer therapeutics. This requires scalable methods for multiplexed genetic screens tracking fitness across time, across lineages, and in a suitable niche, since physiological cues influence functional differences. Towards this, we present an approach, coupling single-cell cancer driver screens in teratomas with hit enrichment by serial teratoma reinjection, to simultaneously screen drivers across multiple lineages in vivo. Using this system, we analyzed population shifts and lineage-specific enrichment for 51 cancer associated genes and variants, profiling over 100,000 cells spanning over 20 lineages, across two rounds of serial reinjection. We confirmed that c-MYC alone or combined with myristoylated AKT1 potently drives proliferation in progenitor neural lineages, demonstrating signatures of malignancy. Additionally, mutant MEK1(S218D/S222D) provides a proliferative advantage in mesenchymal lineages like fibroblasts. Our method provides a powerful platform for multi-lineage longitudinal study of oncogenesis. |
format | Online Article Text |
id | pubmed-8496177 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-84961772021-10-12 Charting oncogenicity of genes and variants across lineages via multiplexed screens in teratomas Parekh, Udit McDonald, Daniella Dailamy, Amir Wu, Yan Cordes, Thekla Zhang, Kun Tipps, Ann Metallo, Christian Mali, Prashant iScience Article Deconstructing tissue-specific effects of genes and variants on proliferation is critical to understanding cellular transformation and systematically selecting cancer therapeutics. This requires scalable methods for multiplexed genetic screens tracking fitness across time, across lineages, and in a suitable niche, since physiological cues influence functional differences. Towards this, we present an approach, coupling single-cell cancer driver screens in teratomas with hit enrichment by serial teratoma reinjection, to simultaneously screen drivers across multiple lineages in vivo. Using this system, we analyzed population shifts and lineage-specific enrichment for 51 cancer associated genes and variants, profiling over 100,000 cells spanning over 20 lineages, across two rounds of serial reinjection. We confirmed that c-MYC alone or combined with myristoylated AKT1 potently drives proliferation in progenitor neural lineages, demonstrating signatures of malignancy. Additionally, mutant MEK1(S218D/S222D) provides a proliferative advantage in mesenchymal lineages like fibroblasts. Our method provides a powerful platform for multi-lineage longitudinal study of oncogenesis. Elsevier 2021-09-20 /pmc/articles/PMC8496177/ /pubmed/34646987 http://dx.doi.org/10.1016/j.isci.2021.103149 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Parekh, Udit McDonald, Daniella Dailamy, Amir Wu, Yan Cordes, Thekla Zhang, Kun Tipps, Ann Metallo, Christian Mali, Prashant Charting oncogenicity of genes and variants across lineages via multiplexed screens in teratomas |
title | Charting oncogenicity of genes and variants across lineages via multiplexed screens in teratomas |
title_full | Charting oncogenicity of genes and variants across lineages via multiplexed screens in teratomas |
title_fullStr | Charting oncogenicity of genes and variants across lineages via multiplexed screens in teratomas |
title_full_unstemmed | Charting oncogenicity of genes and variants across lineages via multiplexed screens in teratomas |
title_short | Charting oncogenicity of genes and variants across lineages via multiplexed screens in teratomas |
title_sort | charting oncogenicity of genes and variants across lineages via multiplexed screens in teratomas |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8496177/ https://www.ncbi.nlm.nih.gov/pubmed/34646987 http://dx.doi.org/10.1016/j.isci.2021.103149 |
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