Charting oncogenicity of genes and variants across lineages via multiplexed screens in teratomas
Summary: 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,...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-10-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004221011172 |
| _version_ | 1818723518535172096 |
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| author | Udit Parekh Daniella McDonald Amir Dailamy Yan Wu Thekla Cordes Kun Zhang Ann Tipps Christian Metallo Prashant Mali |
| author_facet | Udit Parekh Daniella McDonald Amir Dailamy Yan Wu Thekla Cordes Kun Zhang Ann Tipps Christian Metallo Prashant Mali |
| author_sort | Udit Parekh |
| collection | DOAJ |
| description | Summary: 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 MEK1S218D/S222D provides a proliferative advantage in mesenchymal lineages like fibroblasts. Our method provides a powerful platform for multi-lineage longitudinal study of oncogenesis. |
| first_indexed | 2024-12-17T21:11:48Z |
| format | Article |
| id | doaj.art-1c52608ac0074fbba45fcc690eb6237a |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-12-17T21:11:48Z |
| publishDate | 2021-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-1c52608ac0074fbba45fcc690eb6237a2022-12-21T21:32:26ZengElsevieriScience2589-00422021-10-012410103149Charting oncogenicity of genes and variants across lineages via multiplexed screens in teratomasUdit Parekh0Daniella McDonald1Amir Dailamy2Yan Wu3Thekla Cordes4Kun Zhang5Ann Tipps6Christian Metallo7Prashant Mali8Department of Electrical and Computer Engineering, University of California San Diego, San Diego, USADepartment of Bioengineering, University of California San Diego, San Diego, USA; Biomedical Sciences Graduate Program, University of California San Diego, San Diego, USADepartment of Bioengineering, University of California San Diego, San Diego, USADepartment of Bioengineering, University of California San Diego, San Diego, USADepartment of Bioengineering, University of California San Diego, San Diego, USADepartment of Bioengineering, University of California San Diego, San Diego, USASchool of Medicine, University of California San Diego, San Diego, USADepartment of Bioengineering, University of California San Diego, San Diego, USA; Salk Institute of Biological Studies, La Jolla, USADepartment of Bioengineering, University of California San Diego, San Diego, USA; Corresponding authorSummary: 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 MEK1S218D/S222D provides a proliferative advantage in mesenchymal lineages like fibroblasts. Our method provides a powerful platform for multi-lineage longitudinal study of oncogenesis.http://www.sciencedirect.com/science/article/pii/S2589004221011172Molecular biologySystems biologyTranscriptomics |
| spellingShingle | Udit Parekh Daniella McDonald Amir Dailamy Yan Wu Thekla Cordes Kun Zhang Ann Tipps Christian Metallo Prashant Mali Charting oncogenicity of genes and variants across lineages via multiplexed screens in teratomas iScience Molecular biology Systems biology Transcriptomics |
| 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 | Molecular biology Systems biology Transcriptomics |
| url | http://www.sciencedirect.com/science/article/pii/S2589004221011172 |
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