{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T07:07:48Z","timestamp":1775027268548,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1012648","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T00:00:00Z","timestamp":1736467200000}}],"reference-count":121,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2024,12,23]],"date-time":"2024-12-23T00:00:00Z","timestamp":1734912000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010661","name":"Horizon 2020 Framework Programme","doi-asserted-by":"publisher","award":["826494"],"award-info":[{"award-number":["826494"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Neuroblastoma is the most common extra-cranial solid tumour in children. Over half of all high-risk cases are expected to succumb to the disease even after chemotherapy, surgery, and immunotherapy. Although the importance of <jats:italic>MYCN<\/jats:italic> amplification in this disease is indisputable, the mechanistic details remain enigmatic. Here, we present a multicellular model of neuroblastoma comprising a continuous automaton, discrete cell agents, and a centre-based mechanical model, as well as the simulation results we obtained with it. The continuous automaton represents the tumour microenvironment as a grid-like structure, where each voxel is associated with continuous variables such as the oxygen level therein. Each discrete cell agent is defined by several attributes, including its cell cycle position, mutations, gene expression pattern, and more with behaviours such as cell cycling and cell death being stochastically dependent on these attributes. The centre-based mechanical model represents the properties of these agents as physical objects, describing how they repel each other as soft spheres. By implementing a stochastic simulation algorithm on modern GPUs, we simulated the dynamics of over one million neuroblastoma cells over a period of months. Specifically, we set up 1200 heterogeneous tumours and tracked the <jats:italic>MYCN<\/jats:italic>-amplified clone\u2019s dynamics in each, revealed the conditions that favour its growth, and tested its responses to 5000 drug combinations. Our results are in agreement with those reported in the literature and add new insights into how the <jats:italic>MYCN<\/jats:italic>-amplified clone\u2019s reproductive advantage in a tumour, its gene expression profile, the tumour\u2019s other clones (with different mutations), and the tumour\u2019s microenvironment are inter-related. Based on the results, we formulated a hypothesis, which argues that there are two distinct populations of neuroblastoma cells in the tumour; the p53 protein is pro-survival in one and pro-apoptosis in the other. It follows that alternating between inhibiting MDM2 to restore p53 activity and inhibiting ARF to attenuate p53 activity is a promising, if unorthodox, therapeutic strategy. The multicellular model has the advantages of modularity, high resolution, and scalability, making it a potential foundation for creating digital twins of neuroblastoma patients.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1012648","type":"journal-article","created":{"date-parts":[[2024,12,23]],"date-time":"2024-12-23T18:46:52Z","timestamp":1734979612000},"page":"e1012648","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Multicellular model of neuroblastoma proposes unconventional therapy based on multiple roles of p53"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4152-2898","authenticated-orcid":true,"given":"Kenneth Y.","family":"Wertheim","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3379-9042","authenticated-orcid":true,"given":"Robert","family":"Chisholm","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4657-5518","authenticated-orcid":true,"given":"Paul","family":"Richmond","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8801-8093","authenticated-orcid":true,"given":"Dawn","family":"Walker","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2024,12,23]]},"reference":[{"issue":"1","key":"pcbi.1012648.ref001","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s41747-020-00150-9","article-title":"PRIMAGE project: predictive in silico multiscale analytics to support childhood cancer personalised evaluation empowered by imaging biomarkers","volume":"4","author":"L Mart\u00ed-Bonmat\u00ed","year":"2020","journal-title":"European radiology experimental"},{"key":"pcbi.1012648.ref002","doi-asserted-by":"crossref","first-page":"107742","DOI":"10.1016\/j.cmpb.2023.107742","article-title":"A Multiscale Orchestrated Computational Framework to Reveal Emergent Phenomena in Neuroblastoma","author":"C Borau","year":"2023","journal-title":"Computer Methods and Programs in Biomedicine"},{"key":"pcbi.1012648.ref003","doi-asserted-by":"crossref","first-page":"16078","DOI":"10.1038\/nrdp.2016.78","article-title":"Neuroblastoma","volume":"2","author":"K Matthay","year":"2016","journal-title":"Nature reviews. 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