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First passage time analysis of spatial mutation patterns reveals sub-clonal evolutionary dynamics in colorectal cancer

The signature of early cancer dynamics on the spatial arrangement of tumour cells is poorly understood, and yet could encode information about how sub-clones grew within the expanding tumour. Novel methods of quantifying spatial tumour data at the cellular scale are required to link evolutionary dyn...

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Autores principales: Haughey, Magnus J., Bassolas, Aleix, Sousa, Sandro, Baker, Ann-Marie, Graham, Trevor A., Nicosia, Vincenzo, Huang, Weini
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10035892/
https://www.ncbi.nlm.nih.gov/pubmed/36913406
http://dx.doi.org/10.1371/journal.pcbi.1010952
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author Haughey, Magnus J.
Bassolas, Aleix
Sousa, Sandro
Baker, Ann-Marie
Graham, Trevor A.
Nicosia, Vincenzo
Huang, Weini
author_facet Haughey, Magnus J.
Bassolas, Aleix
Sousa, Sandro
Baker, Ann-Marie
Graham, Trevor A.
Nicosia, Vincenzo
Huang, Weini
author_sort Haughey, Magnus J.
collection PubMed
description The signature of early cancer dynamics on the spatial arrangement of tumour cells is poorly understood, and yet could encode information about how sub-clones grew within the expanding tumour. Novel methods of quantifying spatial tumour data at the cellular scale are required to link evolutionary dynamics to the resulting spatial architecture of the tumour. Here, we propose a framework using first passage times of random walks to quantify the complex spatial patterns of tumour cell population mixing. First, using a simple model of cell mixing we demonstrate how first passage time statistics can distinguish between different pattern structures. We then apply our method to simulated patterns of mutated and non-mutated tumour cell population mixing, generated using an agent-based model of expanding tumours, to explore how first passage times reflect mutant cell replicative advantage, time of emergence and strength of cell pushing. Finally, we explore applications to experimentally measured human colorectal cancer, and estimate parameters of early sub-clonal dynamics using our spatial computational model. We infer a wide range of sub-clonal dynamics, with mutant cell division rates varying between 1 and 4 times the rate of non-mutated cells across our sample set. Some mutated sub-clones emerged after as few as 100 non-mutant cell divisions, and others only after 50,000 divisions. The majority were consistent with boundary driven growth or short-range cell pushing. By analysing multiple sub-sampled regions in a small number of samples, we explore how the distribution of inferred dynamics could inform about the initial mutational event. Our results demonstrate the efficacy of first passage time analysis as a new methodology in spatial analysis of solid tumour tissue, and suggest that patterns of sub-clonal mixing can provide insights into early cancer dynamics.
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spelling pubmed-100358922023-03-24 First passage time analysis of spatial mutation patterns reveals sub-clonal evolutionary dynamics in colorectal cancer Haughey, Magnus J. Bassolas, Aleix Sousa, Sandro Baker, Ann-Marie Graham, Trevor A. Nicosia, Vincenzo Huang, Weini PLoS Comput Biol Research Article The signature of early cancer dynamics on the spatial arrangement of tumour cells is poorly understood, and yet could encode information about how sub-clones grew within the expanding tumour. Novel methods of quantifying spatial tumour data at the cellular scale are required to link evolutionary dynamics to the resulting spatial architecture of the tumour. Here, we propose a framework using first passage times of random walks to quantify the complex spatial patterns of tumour cell population mixing. First, using a simple model of cell mixing we demonstrate how first passage time statistics can distinguish between different pattern structures. We then apply our method to simulated patterns of mutated and non-mutated tumour cell population mixing, generated using an agent-based model of expanding tumours, to explore how first passage times reflect mutant cell replicative advantage, time of emergence and strength of cell pushing. Finally, we explore applications to experimentally measured human colorectal cancer, and estimate parameters of early sub-clonal dynamics using our spatial computational model. We infer a wide range of sub-clonal dynamics, with mutant cell division rates varying between 1 and 4 times the rate of non-mutated cells across our sample set. Some mutated sub-clones emerged after as few as 100 non-mutant cell divisions, and others only after 50,000 divisions. The majority were consistent with boundary driven growth or short-range cell pushing. By analysing multiple sub-sampled regions in a small number of samples, we explore how the distribution of inferred dynamics could inform about the initial mutational event. Our results demonstrate the efficacy of first passage time analysis as a new methodology in spatial analysis of solid tumour tissue, and suggest that patterns of sub-clonal mixing can provide insights into early cancer dynamics. Public Library of Science 2023-03-13 /pmc/articles/PMC10035892/ /pubmed/36913406 http://dx.doi.org/10.1371/journal.pcbi.1010952 Text en © 2023 Haughey et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Haughey, Magnus J.
Bassolas, Aleix
Sousa, Sandro
Baker, Ann-Marie
Graham, Trevor A.
Nicosia, Vincenzo
Huang, Weini
First passage time analysis of spatial mutation patterns reveals sub-clonal evolutionary dynamics in colorectal cancer
title First passage time analysis of spatial mutation patterns reveals sub-clonal evolutionary dynamics in colorectal cancer
title_full First passage time analysis of spatial mutation patterns reveals sub-clonal evolutionary dynamics in colorectal cancer
title_fullStr First passage time analysis of spatial mutation patterns reveals sub-clonal evolutionary dynamics in colorectal cancer
title_full_unstemmed First passage time analysis of spatial mutation patterns reveals sub-clonal evolutionary dynamics in colorectal cancer
title_short First passage time analysis of spatial mutation patterns reveals sub-clonal evolutionary dynamics in colorectal cancer
title_sort first passage time analysis of spatial mutation patterns reveals sub-clonal evolutionary dynamics in colorectal cancer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10035892/
https://www.ncbi.nlm.nih.gov/pubmed/36913406
http://dx.doi.org/10.1371/journal.pcbi.1010952
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