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Simulations probe the role of space in the interplay between drug-sensitive and drug-resistant cancer cells

Kira Pugh, Rhys D.O. Jones, Gibin Powathil Orcid Logo, Sara Hamis Orcid Logo

Journal of Theoretical Biology, Volume: 602-603, Start page: 112048

Swansea University Authors: Kira Pugh, Gibin Powathil Orcid Logo

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DOI (Published version): 10.1016/j.jtbi.2025.112048

Abstract

The interplay between drug-sensitive and drug-resistant cancer cells has been observed to impact cell-to-cell interactions in experimental settings. However, the role that space plays in these interactions remains unclear. In this study, we develop mathematical models to investigate how spatial fact...

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Published in: Journal of Theoretical Biology
ISSN: 0022-5193 1095-8541
Published: Elsevier BV 2025
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URI: https://cronfa.swan.ac.uk/Record/cronfa68810
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However, the role that space plays in these interactions remains unclear. In this study, we develop mathematical models to investigate how spatial factors affect cell-to-cell competition between drug-sensitive and drug-resistant cancer cells in silico. We develop two baseline models to study cells from the epithelial FaDu cell line subjected to two drugs, specifically the ATR inhibitor ceralasertib and the PARP inhibitor olaparib, that target DNA damage response pathways. Our baseline models are: (1) a temporally resolved ordinary differential equation (ODE) model, and (2) a spatio-temporally resolved agent-based model (ABM). The models simulate cells in well-mixed and spatially structured cell systems, respectively. The ODE model is calibrated against in vitro data and is thereafter mapped onto the baseline ABM which, in turn, is extended to enable a simulation-based investigation on how spatial factors impact cell-to-cell competition. Simulation results from the extended ABMs demonstrate that the in silico treatment responses are simultaneously affected by: (i) the initial spatial cell configurations, (ii) the initial fraction of drug-resistant cells, (iii) the drugs to which cells express resistance, (iv) drug combinations, (v) drug doses, and (vi) the doubling time of drug-resistant cells compared to the doubling time of drug-sensitive cells. These results reveal that spatial structures of the simulated cancer cells affect both cell-to-cell interactions, and the impact that these interactions have on the ensuing population dynamics. 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spelling 2025-02-18T14:07:43.3987105 v2 68810 2025-02-06 Simulations probe the role of space in the interplay between drug-sensitive and drug-resistant cancer cells e2bcf0a296532267950a2fc033540ef4 Kira Pugh Kira Pugh true false f23646a94239f673e2a43ebe7397aabd 0000-0002-8372-7349 Gibin Powathil Gibin Powathil true false 2025-02-06 MACS The interplay between drug-sensitive and drug-resistant cancer cells has been observed to impact cell-to-cell interactions in experimental settings. However, the role that space plays in these interactions remains unclear. In this study, we develop mathematical models to investigate how spatial factors affect cell-to-cell competition between drug-sensitive and drug-resistant cancer cells in silico. We develop two baseline models to study cells from the epithelial FaDu cell line subjected to two drugs, specifically the ATR inhibitor ceralasertib and the PARP inhibitor olaparib, that target DNA damage response pathways. Our baseline models are: (1) a temporally resolved ordinary differential equation (ODE) model, and (2) a spatio-temporally resolved agent-based model (ABM). The models simulate cells in well-mixed and spatially structured cell systems, respectively. The ODE model is calibrated against in vitro data and is thereafter mapped onto the baseline ABM which, in turn, is extended to enable a simulation-based investigation on how spatial factors impact cell-to-cell competition. Simulation results from the extended ABMs demonstrate that the in silico treatment responses are simultaneously affected by: (i) the initial spatial cell configurations, (ii) the initial fraction of drug-resistant cells, (iii) the drugs to which cells express resistance, (iv) drug combinations, (v) drug doses, and (vi) the doubling time of drug-resistant cells compared to the doubling time of drug-sensitive cells. These results reveal that spatial structures of the simulated cancer cells affect both cell-to-cell interactions, and the impact that these interactions have on the ensuing population dynamics. This leads us to suggest that the role that space plays in cell-to-cell interactions should be further investigated and quantified in experimental settings. Journal Article Journal of Theoretical Biology 602-603 112048 Elsevier BV 0022-5193 1095-8541 Mathematical oncology; Agent-based model; DNA damage response inhibitor drugs 7 4 2025 2025-04-07 10.1016/j.jtbi.2025.112048 COLLEGE NANME Mathematics and Computer Science School COLLEGE CODE MACS Swansea University SU Library paid the OA fee (TA Institutional Deal) KP was supported by EPSRC DTP via Swansea University [Grant EP/T517987/1]. SH was funded by Wenner-Gren Stiftelserna/the Wenner-Gren Foundations (WGF2022-0044), the Tampere Institute for Advanced Study (2021–2023), and the Kjell och Märta Beijer Foundation . 2025-02-18T14:07:43.3987105 2025-02-06T08:58:39.0305094 Faculty of Science and Engineering School of Mathematics and Computer Science - Mathematics Kira Pugh 1 Rhys D.O. Jones 2 Gibin Powathil 0000-0002-8372-7349 3 Sara Hamis 0000-0002-1105-8078 4 68810__33631__5f7fb0f1bfaf4f64aa8dba22620e04e7.pdf 68810.VOR.pdf 2025-02-18T14:03:24.2342798 Output 3715964 application/pdf Version of Record true © 2025 The Authors. This is an open access article distributed under the terms of the Creative Commons CC-BY license. true eng http://creativecommons.org/licenses/by/4.0/
title Simulations probe the role of space in the interplay between drug-sensitive and drug-resistant cancer cells
spellingShingle Simulations probe the role of space in the interplay between drug-sensitive and drug-resistant cancer cells
Kira Pugh
Gibin Powathil
title_short Simulations probe the role of space in the interplay between drug-sensitive and drug-resistant cancer cells
title_full Simulations probe the role of space in the interplay between drug-sensitive and drug-resistant cancer cells
title_fullStr Simulations probe the role of space in the interplay between drug-sensitive and drug-resistant cancer cells
title_full_unstemmed Simulations probe the role of space in the interplay between drug-sensitive and drug-resistant cancer cells
title_sort Simulations probe the role of space in the interplay between drug-sensitive and drug-resistant cancer cells
author_id_str_mv e2bcf0a296532267950a2fc033540ef4
f23646a94239f673e2a43ebe7397aabd
author_id_fullname_str_mv e2bcf0a296532267950a2fc033540ef4_***_Kira Pugh
f23646a94239f673e2a43ebe7397aabd_***_Gibin Powathil
author Kira Pugh
Gibin Powathil
author2 Kira Pugh
Rhys D.O. Jones
Gibin Powathil
Sara Hamis
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container_title Journal of Theoretical Biology
container_volume 602-603
container_start_page 112048
publishDate 2025
institution Swansea University
issn 0022-5193
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doi_str_mv 10.1016/j.jtbi.2025.112048
publisher Elsevier BV
college_str Faculty of Science and Engineering
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hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
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department_str School of Mathematics and Computer Science - Mathematics{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Mathematics and Computer Science - Mathematics
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description The interplay between drug-sensitive and drug-resistant cancer cells has been observed to impact cell-to-cell interactions in experimental settings. However, the role that space plays in these interactions remains unclear. In this study, we develop mathematical models to investigate how spatial factors affect cell-to-cell competition between drug-sensitive and drug-resistant cancer cells in silico. We develop two baseline models to study cells from the epithelial FaDu cell line subjected to two drugs, specifically the ATR inhibitor ceralasertib and the PARP inhibitor olaparib, that target DNA damage response pathways. Our baseline models are: (1) a temporally resolved ordinary differential equation (ODE) model, and (2) a spatio-temporally resolved agent-based model (ABM). The models simulate cells in well-mixed and spatially structured cell systems, respectively. The ODE model is calibrated against in vitro data and is thereafter mapped onto the baseline ABM which, in turn, is extended to enable a simulation-based investigation on how spatial factors impact cell-to-cell competition. Simulation results from the extended ABMs demonstrate that the in silico treatment responses are simultaneously affected by: (i) the initial spatial cell configurations, (ii) the initial fraction of drug-resistant cells, (iii) the drugs to which cells express resistance, (iv) drug combinations, (v) drug doses, and (vi) the doubling time of drug-resistant cells compared to the doubling time of drug-sensitive cells. These results reveal that spatial structures of the simulated cancer cells affect both cell-to-cell interactions, and the impact that these interactions have on the ensuing population dynamics. This leads us to suggest that the role that space plays in cell-to-cell interactions should be further investigated and quantified in experimental settings.
published_date 2025-04-07T08:35:02Z
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