美国纽约基因组中心Dan A. Landau等研究人员合作定义体细胞演化中细胞表型的遗传力、可塑性和转变动态。这一研究成果于2024年9月24日在线发表在国际学术期刊《自然—遗传学》上。

研究人员表示，单细胞测序已对多种健康和恶性组织中的细胞状态异质性进行了表征。然而，这些细胞状态的可塑性或遗传力仍极大地不清楚。

为了解决这个问题，研究人员引入了PATH（性状遗传力的系统发育分析）这一框架，可用于量化细胞状态的遗传力与可塑性，并从单细胞谱系追踪数据中推断细胞状态转变和增殖动态。

将PATH应用于小鼠胰腺癌模型，研究人员观察到在上皮-间质转变谱的两端存在遗传力，而在中间状态则具有更高的可塑性。在原发性胶质母细胞瘤中，研究人员发现干细胞和间质样细胞之间存在双向转变，且以星形胶质细胞样状态作为中介。

最后，研究人员通过在B细胞急性淋巴细胞白血病中进行单细胞全基因组测序重建了系统发育树，并描绘了与遗传驱动因素相关的B细胞分化状态的遗传力。总之，PATH用定量测量取代了对可塑性的定性概念，提供了研究体细胞演化的框架。

附：英文原文

Title: Defining heritability, plasticity, and transition dynamics of cellular phenotypes in somatic evolution

Author: Schiffman, Joshua S., DAvino, Andrew R., Prieto, Tamara, Pang, Yakun, Fan, Yilin, Rajagopalan, Srinivas, Potenski, Catherine, Hara, Toshiro, Suv, Mario L., Gawad, Charles, Landau, Dan A.

Issue&Volume: 2024-09-24

Abstract: Single-cell sequencing has characterized cell state heterogeneity across diverse healthy and malignant tissues. However, the plasticity or heritability of these cell states remains largely unknown. To address this, we introduce PATH (phylogenetic analysis of trait heritability), a framework to quantify cell state heritability versus plasticity and infer cell state transition and proliferation dynamics from single-cell lineage tracing data. Applying PATH to a mouse model of pancreatic cancer, we observed heritability at the ends of the epithelial-to-mesenchymal transition spectrum, with higher plasticity at more intermediate states. In primary glioblastoma, we identified bidirectional transitions between stem- and mesenchymal-like cells, which use the astrocyte-like state as an intermediary. Finally, we reconstructed a phylogeny from single-cell whole-genome sequencing in B cell acute lymphoblastic leukemia and delineated the heritability of B cell differentiation states linked with genetic drivers. Altogether, PATH replaces qualitative conceptions of plasticity with quantitative measures, offering a framework to study somatic evolution.

DOI: 10.1038/s41588-024-01920-6

Source: https://www.nature.com/articles/s41588-024-01920-6