Microenvironmental Niches and Sanctuaries: A Route to Acquired Resistance

Pérez-Velázquez, Judith; Gevertz, Jana L.; Karolak, Aleksandra; Rejniak, Katarzyna A.

doi:10.1007/978-3-319-42023-3_8

Cited by 26 publications

(32 citation statements)

References 68 publications

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“…They showed that resistance arises first in cells located in regions with poor drug penetration, named pharmacological sanctuaries, and then populate areas with higher drug levels. Our own research showed that the non-homogeneous drug distribution within the tumor tissue that results in emergence of tissue regions with poor drug penetration but with normal oxygenation levels may lead to the emergence of acquired resistance (13,14). Similar results were previously generated using different mathematical models.…”

Section: Introductionsupporting

confidence: 73%

“…However, this drug-induced damage can be counterbalanced by cell natural ability for damage repair at rate ! (three times faster that damage rate, (13,14)):…”

Section: Cell Resistance Mechanismmentioning

confidence: 97%

“…The current ages of both cells are initialized to zero, and their cell maturation ages are inherited from their mother cell with a small noise term. To preserve cell volume, the repulsive forces are introduced between overlapping cells (13,14). Since both daughter cells are placed in a distance equal to one cell radius, the repulsive forces are exerted to push the cells apart until they reach the distance equal to cell diameter.…”

Section: Individual Cell Dynamicsmentioning

confidence: 99%

“…Cell's resistance mechanism is modeled as a competition between the level of drug-induced damage accumulated by the cell and the level of damage that the cell can withstand (tolerance) without committing to death. However, the cell can also adapt by increasing its tolerance level if it is exposed to the drug for a certain time (flowchart in Figure 1C, (13,14)).…”

Section: Cell Resistance Mechanismmentioning

confidence: 99%

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Drug-induced resistance in micrometastases: analysis of spatio-temporal cell lineages

Pérez-Velázquez

Rejniak

2020

Preprint

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AbstractResistance to anti-cancer drugs is a major cause of treatment failure. While several intracellular mechanisms of resistance have been postulated, the role of extrinsic factors in the development of resistance in individual tumor cells is still not fully understood. Here we used a hybrid agent-based model to investigate how sensitive tumor cells develop drug resistance in the heterogeneous tumor microenvironment. We characterized the spatio-temporal evolution of lineages of the resistant cells and examined how resistance at the single-cell level contributes to the overall tumor resistance. We also developed new methods to track tumor cell adaptation, to trace cell viability trajectories and to examine the three-dimensional spatio-temporal lineage trees. Our findings indicate that drug-induced resistance can result from cells adaptation to the changes in drug distribution. Two modes of cell adaptation were identified that coincide with microenvironmental niches—areas sheltered by cell micro-communities (protectorates) or regions with limited drug penetration (refuga or sanctuaries). We also recognized that certain cells gave rise to lineages of resistant cells (precursors of resistance) and pinpointed three temporal periods and spatial locations at which such cells emerged. This supports the hypothesis that tumor micrometastases do not need to harbor cell populations with pre-existing resistance, but that individual tumor cells can adapt and develop resistance induced by the drug during the treatment.

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Section: Introductionsupporting

confidence: 73%

“…However, this drug-induced damage can be counterbalanced by cell natural ability for damage repair at rate ! (three times faster that damage rate, (13,14)):…”

Section: Cell Resistance Mechanismmentioning

confidence: 97%

Section: Individual Cell Dynamicsmentioning

confidence: 99%

Section: Cell Resistance Mechanismmentioning

confidence: 99%

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Drug-induced resistance in micrometastases: analysis of spatio-temporal cell lineages

Pérez-Velázquez

Rejniak

2020

Preprint

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“…The microPKPD models, including Organoid3D, are based on the coupled reaction-diffusion equations of drug and nutrient kinetics [7,8,10], and the particle-spring model for cell mechanics [9,11].…”

Section: Quick Guide To Mathematical Methodsmentioning

confidence: 99%

Assessment of patient-specific efficacy of chemo- and targeted-therapies: a micropharmacology approach

Karolak

Huffstutler

Khan

et al. 2017

Preprint

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Abstract-Both targeted and standard chemotherapy drugs are subject to various intratumoral barriers that impede their effectiveness. The tortuous vasculature, dense and fibrous extracellular matrix, irregular cellular architecture, and nonuniform expression of cell membrane receptors hinder drug molecule transport and perturb its cellular uptake. In addition, tumor microenvironments undergo dynamic spatio-temporal changes during tumor progression and treatment, which can also obstruct drug efficacy. To examine these aspects of drug delivery on a cell-to-tissue scale (single-cell pharmacology), we developed the microPKPD models and coupled them with patient-specific data to test personalized treatments.

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Hybrid modeling frameworks of tumor development and treatment

Chamseddine

Rejniak

2019

WIREs Mechanisms of Disease

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Tumors are complex multicellular heterogeneous systems comprised of components that interact with and modify one another. Tumor development depends on multiple factors: intrinsic, such as genetic mutations, altered signaling pathways, or variable receptor expression; and extrinsic, such as differences in nutrient supply, crosstalk with stromal or immune cells, or variable composition of the surrounding extracellular matrix. Tumors are also characterized by high cellular heterogeneity and dynamically changing tumor microenvironments. The complexity increases when this multiscale, multicomponent system is perturbed by anticancer treatments. Modeling such complex systems and predicting how tumors will respond to therapies require mathematical models that can handle various types of information and combine diverse theoretical methods on multiple temporal and spatial scales, that is, hybrid models. In this update, we discuss the progress that has been achieved during the last 10 years in the area of the hybrid modeling of tumors. The classical definition of hybrid models refers to the coupling of discrete descriptions of cells with continuous descriptions of microenvironmental factors. To reflect on the direction that the modeling field has taken, we propose extending the definition of hybrid models to include of coupling two or more different mathematical frameworks. Thus, in addition to discussing recent advances in discrete/continuous modeling, we also discuss how these two mathematical descriptions can be coupled with theoretical frameworks of optimal control, optimization, fluid dynamics, game theory, and machine learning. All these methods will be illustrated with applications to tumor development and various anticancer treatments. This article is characterized under: Analytical and Computational Methods > Computational Methods Translational, Genomic, and Systems Medicine > Therapeutic Methods Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models

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Microenvironmental Niches and Sanctuaries: A Route to Acquired Resistance

Cited by 26 publications

References 68 publications

Drug-induced resistance in micrometastases: analysis of spatio-temporal cell lineages

Drug-induced resistance in micrometastases: analysis of spatio-temporal cell lineages

Assessment of patient-specific efficacy of chemo- and targeted-therapies: a micropharmacology approach

Hybrid modeling frameworks of tumor development and treatment

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