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The role of environmentally mediated drug resistance in facilitating the spatial distribution of residual disease

Amy Milne, Andriy Marusyk Orcid Logo, Philip K. Maini Orcid Logo, Alexander R. A. Anderson Orcid Logo, Noemi Picco Orcid Logo

Communications Biology, Volume: 8, Issue: 1

Swansea University Authors: Amy Milne, Noemi Picco Orcid Logo

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DOI (Published version): 10.1038/s42003-025-08585-9

Abstract

The development of de novo resistance is a major disadvantage in molecularly targeted therapies. While much focus is on cell-intrinsic mechanisms, the microenvironment is also known to play a crucial role. This study examines interactions between cancer cells and cancer associated fibroblasts (CAFs)...

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Published in: Communications Biology
ISSN: 2399-3642
Published: Springer Science and Business Media LLC 2025
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URI: https://cronfa.swan.ac.uk/Record/cronfa70117
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last_indexed 2025-09-30T08:55:39Z
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spelling 2025-09-29T14:41:42.6349781 v2 70117 2025-08-05 The role of environmentally mediated drug resistance in facilitating the spatial distribution of residual disease efe1499ced0b97fe91cfcbb71e0f2c98 Amy Milne Amy Milne true false 81bb0cb00415aa4895e647fd1553d37c 0000-0001-5028-2083 Noemi Picco Noemi Picco true false 2025-08-05 MACS The development of de novo resistance is a major disadvantage in molecularly targeted therapies. While much focus is on cell-intrinsic mechanisms, the microenvironment is also known to play a crucial role. This study examines interactions between cancer cells and cancer associated fibroblasts (CAFs) to understand the local crosstalk facilitating residual disease. Using a hybrid-discrete-continuum model, we explore how treatment-induced stress responses can elicit CAF activation and how breaks in treatment allow microenvironment normalisation. We investigate how fluctuating environmental conditions shape the local crosstalk and ultimately drive residual disease. Our experimentally calibrated model identifies environmental and treatment conditions that allow tumour eradication and those that enable survival. We find two distinct mechanisms that underpin residual disease: vasculature-limited drug delivery and CAF-mediated rescue. This work provides a better understanding of the mechanisms that drive the creation of localised residual disease, crucial to informing the development of more effective treatment protocols. Journal Article Communications Biology 8 1 Springer Science and Business Media LLC 2399-3642 9 8 2025 2025-08-09 10.1038/s42003-025-08585-9 COLLEGE NANME Mathematics and Computer Science School COLLEGE CODE MACS Swansea University External research funder(s) paid the OA fee (includes OA grants disbursed by the Library) This work was supported by the UK Engineering and Physical Sciences Research Council (EPSRC grant number EP/W523963/1). We acknowledge the support of the Supercomputing Wales project, which is part-funded by the European Regional Development Fund (ERDF) via the Welsh Government. 2025-09-29T14:41:42.6349781 2025-08-05T16:43:44.8824680 Faculty of Science and Engineering School of Mathematics and Computer Science - Mathematics Amy Milne 1 Andriy Marusyk 0000-0002-0087-9575 2 Philip K. Maini 0000-0002-0146-9164 3 Alexander R. A. Anderson 0000-0002-2536-4383 4 Noemi Picco 0000-0001-5028-2083 5 70117__34936__1e5fd270677946e2b29e85e40d896899.pdf 70117.VoR.pdf 2025-08-11T11:50:32.8278140 Output 3390478 application/pdf Version of Record true © The Author(s) 2025. This article is licensed under a Creative Commons Attribution 4.0 International License. true eng http://creativecommons.org/licenses/by/4.0/
title The role of environmentally mediated drug resistance in facilitating the spatial distribution of residual disease
spellingShingle The role of environmentally mediated drug resistance in facilitating the spatial distribution of residual disease
Amy Milne
Noemi Picco
title_short The role of environmentally mediated drug resistance in facilitating the spatial distribution of residual disease
title_full The role of environmentally mediated drug resistance in facilitating the spatial distribution of residual disease
title_fullStr The role of environmentally mediated drug resistance in facilitating the spatial distribution of residual disease
title_full_unstemmed The role of environmentally mediated drug resistance in facilitating the spatial distribution of residual disease
title_sort The role of environmentally mediated drug resistance in facilitating the spatial distribution of residual disease
author_id_str_mv efe1499ced0b97fe91cfcbb71e0f2c98
81bb0cb00415aa4895e647fd1553d37c
author_id_fullname_str_mv efe1499ced0b97fe91cfcbb71e0f2c98_***_Amy Milne
81bb0cb00415aa4895e647fd1553d37c_***_Noemi Picco
author Amy Milne
Noemi Picco
author2 Amy Milne
Andriy Marusyk
Philip K. Maini
Alexander R. A. Anderson
Noemi Picco
format Journal article
container_title Communications Biology
container_volume 8
container_issue 1
publishDate 2025
institution Swansea University
issn 2399-3642
doi_str_mv 10.1038/s42003-025-08585-9
publisher Springer Science and Business Media LLC
college_str Faculty of Science and Engineering
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hierarchy_top_id facultyofscienceandengineering
hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
hierarchy_parent_title Faculty of Science and Engineering
department_str School of Mathematics and Computer Science - Mathematics{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Mathematics and Computer Science - Mathematics
document_store_str 1
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description The development of de novo resistance is a major disadvantage in molecularly targeted therapies. While much focus is on cell-intrinsic mechanisms, the microenvironment is also known to play a crucial role. This study examines interactions between cancer cells and cancer associated fibroblasts (CAFs) to understand the local crosstalk facilitating residual disease. Using a hybrid-discrete-continuum model, we explore how treatment-induced stress responses can elicit CAF activation and how breaks in treatment allow microenvironment normalisation. We investigate how fluctuating environmental conditions shape the local crosstalk and ultimately drive residual disease. Our experimentally calibrated model identifies environmental and treatment conditions that allow tumour eradication and those that enable survival. We find two distinct mechanisms that underpin residual disease: vasculature-limited drug delivery and CAF-mediated rescue. This work provides a better understanding of the mechanisms that drive the creation of localised residual disease, crucial to informing the development of more effective treatment protocols.
published_date 2025-08-09T05:30:01Z
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