Interactions between Ploidy and Resource Availability Shape Clonal Evolution in Glioblastoma
Cancer Research, vol. 85, pp. 1544–1559
Abstract
Glioblastoma (GBM) is the most aggressive form of primary brain tumor. The infiltrative nature of GBM makes complete surgical resection impossible. The selective forces that govern gliomagenesis are strong, shaping the composition of tumor cells during the initial progression to malignancy with late consequences for invasiveness and therapy response. Here, we developed a mathematical model that incorporates ploidy level and the nature of the brain tissue microenvironment to simulate the growth and invasion of GBM and used the model to make inferences about GBM initiation and response to the standard-of-care treatment. The spatial distribution of resource access in the brain was approximated through integration of in silico modeling, multiomics data, and image analysis of primary and recurrent GBM. The in silico results suggested that high-ploidy cells transition faster from oxidative phosphorylation to glycolysis than low-ploidy cells because they are more sensitive to hypoxia. Between surgeries, simulated tumors with different ploidy compositions progressed at different rates; however, whether higher ploidy predicted fast recurrence was a function of the brain microenvironment. Historical data supported the dependence on available resources in the brain, as shown by a significant correlation between the median oxygen levels in human tissues and the median ploidy of cancers that arise in the respective tissues. Taken together, these findings suggest that the availability of metabolic substrates in the brain drives different cell fate decisions for cells with different ploidy, thereby modulating both gliomagenesis and GBM recurrence. Significance: Ploidy viewed in the context of the resources in the microenvironment has the potential to inform whether modulation of energetic availability can delay tumor progression and could help guide clinical decision making.
Authors 28
-
Affiliation as printed
1Department of Biostatistics and Translational Medicine, Medical University of Łódź, Łódź, Poland
Medical University of Lodz, Łódź, Poland
-
Icahn School of Medicine at Mount Sinai
Affiliation as printed
2Icahn School of Medicine at Mount Sinai, New York City, New York
Icahn School of Medicine at Mount Sinai, New York City, United States
-
Affiliation as printed
3Department of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, Florida
Moffitt Cancer Center, Tampa, Florida, United States
-
Affiliation as printed
4Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States
-
Affiliation as printed
5Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
Moffitt Cancer Center, Tampa, FL, United States
-
Richard J. Beck Aachen
Leiden University · Moffitt Cancer Center
Affiliation as printed
3Department of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, Florida
Leiden University, Leiden, Zuid Holland, Netherlands
-
Affiliation as printed
3Department of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, Florida
Moffitt Cancer Center, United States
-
University of South Florida · Moffitt Cancer Center
Affiliation as printed
3Department of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, Florida
6Cancer Biology PhD Program, University of South Florida, Tampa, Florida
Moffitt Cancer Center, Tampa, Florida, United States
-
Affiliation as printed
7Department of Molecular Medicine, University of South Florida Morsani College of Medicine, Tampa, Florida
University of South Florida, Tampa, FL, United States
-
Queen Mary University of London
Affiliation as printed
8Queen Mary University of London, School of Mathematical Sciences, London, United Kingdom
Queen Mary University of London, London, United Kingdom
-
University of South Florida · Moffitt Cancer Center
Affiliation as printed
3Department of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, Florida
6Cancer Biology PhD Program, University of South Florida, Tampa, Florida
Moffitt Cancer Center, Tampa, FL, United States
-
Affiliation as printed
9Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
-
Royal Berkshire NHS Foundation Trust · WSHIU Akademia Nauk Stosowanych
Affiliation as printed
10The University of Commerce and Services, Medical Department (WSHIU), Poznan, Poland
Royal Berkshire NHS Foundation Trust, Poznan, Poland
-
Stanford Medicine · Stanford University
Affiliation as printed
11Stanford Center for Biomedical Informatics Research (BMIR), Stanford University, School of Medicine, Stanford, California
Stanford University, Stanford, CA, United States
-
Stanford Medicine · Stanford University
Affiliation as printed
11Stanford Center for Biomedical Informatics Research (BMIR), Stanford University, School of Medicine, Stanford, California
12Department of Biomedical Data Science, Stanford University, Stanford, California
Stanford University, Palo Alto, CA, United States
-
Affiliation as printed
5Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
Moffitt Cancer Center, Tampa, United States
-
Affiliation as printed
5Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
Moffitt Cancer Center, Tampa, United States
-
Affiliation as printed
13Quantitative Imaging Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
Moffitt Cancer Center, Tampa, FL, United States
-
Centre National de la Recherche Scientifique · Institut national de recherche en sciences et technologies du numérique · University of Trento · Sorbonne Université · Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement
Affiliation as printed
14Université Côte d’Azur, Inria, INRAE, CNRS, Sorbonne Université, Macbes Team, Sophia Antipolis, Valbonne, France
University of Trento, Trento, Trento, Italy
-
Affiliation as printed
3Department of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, Florida
Moffitt Cancer Center, Tampa, Florida, United States
-
Affiliation as printed
3Department of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, Florida
Moffitt Cancer Center, Tampa, FL, United States
-
Affiliation as printed
3Department of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, Florida
Moffitt Cancer Center, Tampa, FL, United States
-
Affiliation as printed
3Department of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, Florida
Moffitt Cancer Center, Tampa, FL, United States
-
National Cancer Institute · Division of Cancer Epidemiology and Genetics
Affiliation as printed
15Center for Biomedical Informatics and Information Technology and Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
National Cancer Institute, Rockville, MD, United States
-
Affiliation as printed
16Department of Radiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
Moffitt Cancer Center, Tampa, Florida, United States
-
Affiliation as printed
5Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
-
Affiliation as printed
17Department of Mechanical Engineering and the Computational Sciences Research Center, San Diego State University, San Diego, California
San Diego State University, San Diego, United States
-
Affiliation as printed
3Department of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, Florida
Moffitt Cancer Center, Tampa, Florida, United States
Cited by 2 stored of 2
2 results
No patents citing this paper on Lens.org (checked 2026-10-11).