Three-Dimensional Spatiotemporal Modeling of Colon Cancer Organoids Reveals that Multimodal Control of Stem Cell Self-Renewal is a Critical Determinant of Size and Shape in Early Stages of Tumor Growth

We develop a three-dimensional multispecies mathematical model to simulate the growth of colon cancer organoids containing stem, progenitor and terminally differentiated cells, as a model of early (prevascular) tumor growth. Stem cells (SCs) secrete short-range self-renewal promoters (e.g., Wnt) and...

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Bibliographic Details
Published inBulletin of mathematical biology Vol. 80; no. 5; pp. 1404 - 1433
Main Authors Yan, Huaming, Konstorum, Anna, Lowengrub, John S.
Format Journal Article
LanguageEnglish
Published New York Springer US 01.05.2018
Springer Nature B.V
Subjects
Animals
Bone morphogenetic proteins
Brain cancer
Cancer
Cell Biology
Cell Death
Cell Differentiation
Cell Lineage
Cell Self Renewal
Colon
Colon cancer
Colonic Neoplasms - pathology
Colorectal cancer
Computer Simulation
Control theory
Feedback
Feedback loops
Feedback, Physiological
Fingers
Hepatocyte growth factor
Humans
Imaging, Three-Dimensional
Invasiveness
Life Sciences
Low concentrations
Mathematical and Computational Biology
Mathematical Concepts
Mathematical models
Mathematics
Mathematics and Statistics
Models, Biological
Negative feedback
Neoplastic Stem Cells - pathology
Organoids
Organoids - pathology
Promoters
Proteins
Spatio-Temporal Analysis
Special Issue : Mathematical Oncology
Stem cells
Three dimensional models
Tumors
Wnt protein
Feedback regulation
Mathematical modeling
Cancer stem cells
Cancer therapies
Brain tumors
Online AccessGet full text
ISSN0092-8240
1522-9602
1522-9602
DOI10.1007/s11538-017-0294-1

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Abstract We develop a three-dimensional multispecies mathematical model to simulate the growth of colon cancer organoids containing stem, progenitor and terminally differentiated cells, as a model of early (prevascular) tumor growth. Stem cells (SCs) secrete short-range self-renewal promoters (e.g., Wnt) and their long-range inhibitors (e.g., Dkk) and proliferate slowly. Committed progenitor (CP) cells proliferate more rapidly and differentiate to produce post-mitotic terminally differentiated cells that release differentiation promoters, forming negative feedback loops on SC and CP self-renewal. We demonstrate that SCs play a central role in normal and cancer colon organoids. Spatial patterning of the SC self-renewal promoter gives rise to SC clusters, which mimic stem cell niches, around the organoid surface, and drive the development of invasive fingers. We also study the effects of externally applied signaling factors. Applying bone morphogenic proteins, which inhibit SC and CP self-renewal, reduces invasiveness and organoid size. Applying hepatocyte growth factor, which enhances SC self-renewal, produces larger sizes and enhances finger development at low concentrations but suppresses fingers at high concentrations. These results are consistent with recent experiments on colon organoids. Because many cancers are hierarchically organized and are subject to feedback regulation similar to that in normal tissues, our results suggest that in cancer, control of cancer stem cell self-renewal should influence the size and shape in similar ways, thereby opening the door to novel therapies.
AbstractList We develop a three-dimensional multispecies mathematical model to simulate the growth of colon cancer organoids containing stem, progenitor and terminally differentiated cells, as a model of early (prevascular) tumor growth. Stem cells (SCs) secrete short-range self-renewal promoters (e.g., Wnt) and their long-range inhibitors (e.g., Dkk) and proliferate slowly. Committed progenitor (CP) cells proliferate more rapidly and differentiate to produce post-mitotic terminally differentiated cells that release differentiation promoters, forming negative feedback loops on SC and CP self-renewal. We demonstrate that SCs play a central role in normal and cancer colon organoids. Spatial patterning of the SC self-renewal promoter gives rise to SC clusters, which mimic stem cell niches, around the organoid surface, and drive the development of invasive fingers. We also study the effects of externally applied signaling factors. Applying bone morphogenic proteins, which inhibit SC and CP self-renewal, reduces invasiveness and organoid size. Applying hepatocyte growth factor, which enhances SC self-renewal, produces larger sizes and enhances finger development at low concentrations but suppresses fingers at high concentrations. These results are consistent with recent experiments on colon organoids. Because many cancers are hierarchically organized and are subject to feedback regulation similar to that in normal tissues, our results suggest that in cancer, control of cancer stem cell self-renewal should influence the size and shape in similar ways, thereby opening the door to novel therapies.
We develop a three-dimensional multispecies mathematical model to simulate the growth of colon cancer organoids containing stem, progenitor and terminally differentiated cells, as a model of early (prevascular) tumor growth. Stem cells (SCs) secrete short-range self-renewal promoters (e.g., Wnt) and their long-range inhibitors (e.g., Dkk) and proliferate slowly. Committed progenitor (CP) cells proliferate more rapidly and differentiate to produce post-mitotic terminally differentiated cells that release differentiation promoters, forming negative feedback loops on SC and CP self-renewal. We demonstrate that SCs play a central role in normal and cancer colon organoids. Spatial patterning of the SC self-renewal promoter gives rise to SC clusters, which mimic stem cell niches, around the organoid surface, and drive the development of invasive fingers. We also study the effects of externally applied signaling factors. Applying bone morphogenic proteins, which inhibit SC and CP self-renewal, reduces invasiveness and organoid size. Applying hepatocyte growth factor, which enhances SC self-renewal, produces larger sizes and enhances finger development at low concentrations but suppresses fingers at high concentrations. These results are consistent with recent experiments on colon organoids. Because many cancers are hierarchically organized and are subject to feedback regulation similar to that in normal tissues, our results suggest that in cancer, control of cancer stem cell self-renewal should influence the size and shape in similar ways, thereby opening the door to novel therapies.We develop a three-dimensional multispecies mathematical model to simulate the growth of colon cancer organoids containing stem, progenitor and terminally differentiated cells, as a model of early (prevascular) tumor growth. Stem cells (SCs) secrete short-range self-renewal promoters (e.g., Wnt) and their long-range inhibitors (e.g., Dkk) and proliferate slowly. Committed progenitor (CP) cells proliferate more rapidly and differentiate to produce post-mitotic terminally differentiated cells that release differentiation promoters, forming negative feedback loops on SC and CP self-renewal. We demonstrate that SCs play a central role in normal and cancer colon organoids. Spatial patterning of the SC self-renewal promoter gives rise to SC clusters, which mimic stem cell niches, around the organoid surface, and drive the development of invasive fingers. We also study the effects of externally applied signaling factors. Applying bone morphogenic proteins, which inhibit SC and CP self-renewal, reduces invasiveness and organoid size. Applying hepatocyte growth factor, which enhances SC self-renewal, produces larger sizes and enhances finger development at low concentrations but suppresses fingers at high concentrations. These results are consistent with recent experiments on colon organoids. Because many cancers are hierarchically organized and are subject to feedback regulation similar to that in normal tissues, our results suggest that in cancer, control of cancer stem cell self-renewal should influence the size and shape in similar ways, thereby opening the door to novel therapies.
Author Yan, Huaming
Konstorum, Anna
Lowengrub, John S.
AuthorAffiliation 1 Department of Mathematics, University of California, Irvine, Irvine, CA 92697, USA
2 Center for Quantitative Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA
3 Department of Mathematics, Department of Biomedical Engineering, Center for Complex Biological Systems, and Chao Comprehensive Cancer Center, University of California, Irvine, Irvine, CA 92697, USA
AuthorAffiliation_xml – name: 3 Department of Mathematics, Department of Biomedical Engineering, Center for Complex Biological Systems, and Chao Comprehensive Cancer Center, University of California, Irvine, Irvine, CA 92697, USA
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  organization: Department of Mathematics, University of California, Irvine
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  fullname: Konstorum, Anna
  organization: Center for Quantitative Medicine, University of Connecticut Health Center
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  surname: Lowengrub
  fullname: Lowengrub, John S.
  email: lowengrb@math.uci.edu
  organization: Department of Mathematics, Department of Biomedical Engineering, Center for Complex Biological Systems, and Chao Comprehensive Cancer Center, University of California, Irvine
BackLink https://www.ncbi.nlm.nih.gov/pubmed/28681151$$D View this record in MEDLINE/PubMed
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ISSN 0092-8240
1522-9602
IngestDate Wed Oct 29 11:44:07 EDT 2025
Tue Sep 30 16:58:53 EDT 2025
Sun Sep 28 04:36:10 EDT 2025
Tue Oct 07 05:45:43 EDT 2025
Thu Apr 03 07:07:46 EDT 2025
Wed Oct 01 03:09:42 EDT 2025
Thu Apr 24 23:05:57 EDT 2025
Fri Feb 21 02:39:59 EST 2025
IsDoiOpenAccess true
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Issue 5
Keywords Feedback regulation
Mathematical modeling
Cancer stem cells
Cancer therapies
Brain tumors
Language English
LinkModel DirectLink
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content type line 14
content type line 23
Huaming Yan and Anna Konstorum have contributed equally to this work.
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Snippet We develop a three-dimensional multispecies mathematical model to simulate the growth of colon cancer organoids containing stem, progenitor and terminally...
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SubjectTerms Animals
Bone morphogenetic proteins
Brain cancer
Cancer
Cell Biology
Cell Death
Cell Differentiation
Cell Lineage
Cell Self Renewal
Colon
Colon cancer
Colonic Neoplasms - pathology
Colorectal cancer
Computer Simulation
Control theory
Feedback
Feedback loops
Feedback, Physiological
Fingers
Hepatocyte growth factor
Humans
Imaging, Three-Dimensional
Invasiveness
Life Sciences
Low concentrations
Mathematical and Computational Biology
Mathematical Concepts
Mathematical models
Mathematics
Mathematics and Statistics
Models, Biological
Negative feedback
Neoplastic Stem Cells - pathology
Organoids
Organoids - pathology
Promoters
Proteins
Spatio-Temporal Analysis
Special Issue : Mathematical Oncology
Stem cells
Three dimensional models
Tumors
Wnt protein
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Title Three-Dimensional Spatiotemporal Modeling of Colon Cancer Organoids Reveals that Multimodal Control of Stem Cell Self-Renewal is a Critical Determinant of Size and Shape in Early Stages of Tumor Growth
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