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

in Nature genetics by Joshua S Schiffman, Andrew R D'Avino, Tamara Prieto, Yakun Pang, Yilin Fan, Srinivas Rajagopalan, Catherine Potenski, Toshiro Hara, Mario L Suvà, Charles Gawad, Dan A Landau

TLDR

  • The study aims to understand how cells change over time and whether these changes are inherited or happen randomly. The authors use a new method called PATH to measure how much cells change or stay the same. They apply PATH to three different types of cells in mice and humans. The study suggests that cells can change in different ways and that these changes can be inherited or happen randomly. The authors also found that single-cell lineage tracing data can help us understand how cells change over time.

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.

Overview

  • The study aims to quantify cell state heritability versus plasticity and infer cell state transition and proliferation dynamics from single-cell lineage tracing data. The authors introduce PATH (phylogenetic analysis of trait heritability) to achieve this goal. The study applies PATH to a mouse model of pancreatic cancer, primary glioblastoma, and B cell acute lymphoblastic leukemia. The primary objective of the study is to replace qualitative conceptions of plasticity with quantitative measures, offering a framework to study somatic evolution.

Comparative Analysis & Findings

  • In the mouse model of pancreatic cancer, the study observed heritability at the ends of the epithelial-to-mesenchymal transition spectrum, with higher plasticity at more intermediate states. In primary glioblastoma, the authors identified bidirectional transitions between stem- and mesenchymal-like cells, which use the astrocyte-like state as an intermediary. Finally, the study 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.

Implications and Future Directions

  • The study's findings suggest that heritability and plasticity are not mutually exclusive and can coexist in different cell states. The authors propose that PATH could be used to study somatic evolution in various tissues and diseases. Future research could explore the role of heritability and plasticity in disease progression and response to therapy. Additionally, the study highlights the importance of single-cell lineage tracing data in understanding cell state dynamics and evolution.
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