Disrupting cellular memory to overcome drug resistance.

Autor: Harmange G; Cellular and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Hueros RAR; Department of Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Schaff DL; Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA., Emert B; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA., Saint-Antoine M; Department of Electrical and Computer Engineering, University of Delaware, Newark, DE, 19716, USA., Kim LC; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Niu Z; Department of Chemistry, College of the Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA.; Department of Physics, College of the Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA., Nellore S; Department of Biology, College of the Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA.; The Wharton School, University of Pennsylvania, Philadelphia, PA, USA., Fane ME; Cancer Signaling and Microenvironment Research Program, Fox Chase Cancer Center, Philadelphia, PA, USA., Alicea GM; Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health, Baltimore, MD, USA., Weeraratna AT; Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health, Baltimore, MD, USA.; Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA., Simon MC; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Singh A; Department of Electrical and Computer Engineering, University of Delaware, Newark, DE, 19716, USA., Shaffer SM; Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA. sydshaffer@gmail.com.; Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. sydshaffer@gmail.com.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Nov 06; Vol. 14 (1), pp. 7130. Date of Electronic Publication: 2023 Nov 06.
DOI: 10.1038/s41467-023-41811-8
Abstrakt: Gene expression states persist for varying lengths of time at the single-cell level, a phenomenon known as gene expression memory. When cells switch states, losing memory of their prior state, this transition can occur in the absence of genetic changes. However, we lack robust methods to find regulators of memory or track state switching. Here, we develop a lineage tracing-based technique to quantify memory and identify cells that switch states. Applied to melanoma cells without therapy, we quantify long-lived fluctuations in gene expression that are predictive of later resistance to targeted therapy. We also identify the PI3K and TGF-β pathways as state switching modulators. We propose a pretreatment model, first applying a PI3K inhibitor to modulate gene expression states, then applying targeted therapy, which leads to less resistance than targeted therapy alone. Together, we present a method for finding modulators of gene expression memory and their associated cell fates.
(© 2023. The Author(s).)
Databáze: MEDLINE
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