Parekh Udit, McDonald Daniella, Dailamy Amir, Wu Yan, Cordes Thekla, Zhang Kun, Tipps Ann, Metallo Christian, Mali Prashant
Department of Electrical and Computer Engineering, University of California San Diego, San Diego, USA.
Department of Bioengineering, University of California San Diego, San Diego, USA.
iScience. 2021 Sep 20;24(10):103149. doi: 10.1016/j.isci.2021.103149. eCollection 2021 Oct 22.
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 alone or combined with myristoylated potently drives proliferation in progenitor neural lineages, demonstrating signatures of malignancy. Additionally, mutant provides a proliferative advantage in mesenchymal lineages like fibroblasts. Our method provides a powerful platform for multi-lineage longitudinal study of oncogenesis.
解构基因和变体对增殖的组织特异性影响对于理解细胞转化和系统选择癌症治疗方法至关重要。这需要可扩展的方法来进行多重基因筛选，以跟踪随时间、跨谱系以及在合适的微环境中的适应性，因为生理线索会影响功能差异。为此，我们提出了一种方法，将畸胎瘤中的单细胞癌症驱动筛选与通过连续畸胎瘤再注射进行的命中富集相结合，以在体内同时筛选多个谱系中的驱动因素。使用该系统，我们分析了51个癌症相关基因和变体的群体变化和谱系特异性富集，在两轮连续再注射过程中，对跨越20多个谱系的100,000多个细胞进行了分析。我们证实，单独或与肉豆蔻酰化的 结合，能有效地驱动祖神经谱系中的增殖，显示出恶性特征。此外，突变的 在成纤维细胞等间充质谱系中提供了增殖优势。我们的方法为肿瘤发生的多谱系纵向研究提供了一个强大的平台。
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