Charting oncogenicity of genes and variants across lineages via multiplexed screens in teratomas

Udit Parekh; Daniella McDonald; Amir Dailamy; Yan Wu; Thekla Cordes; Kun Zhang; Ann Tipps; Christian Metallo; Prashant Mali

doi:10.1016/j.isci.2021.103149

Charting oncogenicity of genes and variants across lineages via multiplexed screens in teratomas

iScience. 2021 Sep 20;24(10):103149. doi: 10.1016/j.isci.2021.103149. eCollection 2021 Oct 22.

Authors

Udit Parekh¹, Daniella McDonald^{2

3}, Amir Dailamy², Yan Wu², Thekla Cordes², Kun Zhang², Ann Tipps⁴, Christian Metallo^{2

5}, Prashant Mali²

Affiliations

¹ Department of Electrical and Computer Engineering, University of California San Diego, San Diego, USA.
² Department of Bioengineering, University of California San Diego, San Diego, USA.
³ Biomedical Sciences Graduate Program, University of California San Diego, San Diego, USA.
⁴ School of Medicine, University of California San Diego, San Diego, USA.
⁵ Salk Institute of Biological Studies, La Jolla, USA.

Abstract

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.

Keywords: Molecular biology; Systems biology; Transcriptomics.

Abstract

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