Disrupting cellular memory to overcome drug resistance

Guillaume Harmange, Raúl A. Reyes Hueros, Dylan L. Schaff, Benjamin Emert, Michael Saint-Antoine, Laura C. Kim, Zijian Niu, Shivani Nellore, Mitchell E. Fane, Gretchen M. Alicea, Ashani T. Weeraratna, M. Celeste Simon, Abhyudai Singh and Sydney M. Shaffer ()
Additional contact information
Guillaume Harmange: University of Pennsylvania
Raúl A. Reyes Hueros: University of Pennsylvania
Dylan L. Schaff: University of Pennsylvania
Benjamin Emert: California Institute of Technology
Michael Saint-Antoine: University of Delaware
Laura C. Kim: University of Pennsylvania
Zijian Niu: University of Pennsylvania
Shivani Nellore: University of Pennsylvania
Mitchell E. Fane: Fox Chase Cancer Center
Gretchen M. Alicea: Johns Hopkins School of Public Health
Ashani T. Weeraratna: Johns Hopkins School of Public Health
M. Celeste Simon: University of Pennsylvania
Abhyudai Singh: University of Delaware
Sydney M. Shaffer: University of Pennsylvania

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-41811-8

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