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Two-level modeling approach to identify the regulatory dynamics capturing drug response heterogeneity in single-cells

Madalena Chaves 1 Luis Gomes-Pereira 1 Jérémie Roux 2, * 
* Corresponding author
1 BIOCORE - Biological control of artificial ecosystems
CRISAM - Inria Sophia Antipolis - Méditerranée , LOV - Laboratoire d'océanographie de Villefranche, INRAE - Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement
Abstract : Abstract Single-cell multimodal technologies reveal the scales of cellular heterogeneity impairing cancer treatment, yet cell response dynamics remain largely underused to decipher the mechanisms of drug resistance they take part in. As the phenotypic heterogeneity of a clonal cell population informs on the capacity of each single-cell to recapitulate the whole range of observed behaviors, we developed a modeling approach utilizing single-cell response data to identify regulatory reactions driving population heterogeneity in drug response. Dynamic data of hundreds of HeLa cells treated with TNF-related apoptosis-inducing ligand (TRAIL) were used to characterize the fate-determining kinetic parameters of an apoptosis receptor reaction model. Selected reactions sets were augmented to incorporate a mechanism that leads to the separation of the opposing response phenotypes. Using a positive feedback loop motif to identify the reaction set, we show that caspase-8 is able to encapsulate high levels of heterogeneity by introducing a response delay and amplifying the initial differences arising from natural protein expression variability. Our approach enables the identification of fate-determining reactions that drive the population response heterogeneity, providing regulatory targets to curb the cell dynamics of drug resistance.
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Submitted on : Saturday, December 11, 2021 - 7:35:22 AM
Last modification on : Saturday, November 5, 2022 - 3:58:38 AM
Long-term archiving on: : Saturday, March 12, 2022 - 6:10:11 PM


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Distributed under a Creative Commons Attribution 4.0 International License



Madalena Chaves, Luis Gomes-Pereira, Jérémie Roux. Two-level modeling approach to identify the regulatory dynamics capturing drug response heterogeneity in single-cells. Scientific Reports, 2021, 11 (1), ⟨10.1038/s41598-021-99943-0⟩. ⟨hal-03439255⟩



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