Publications by authors named "Haralampos Hatzikirou"

17 Publications

  • Page 1 of 1

BIO-LGCA: A cellular automaton modelling class for analysing collective cell migration.

PLoS Comput Biol 2021 Jun 15;17(6):e1009066. Epub 2021 Jun 15.

Centre for Information Services and High Performance Computing, Technische Universität Dresden, Dresden, Germany.

Collective dynamics in multicellular systems such as biological organs and tissues plays a key role in biological development, regeneration, and pathological conditions. Collective tissue dynamics-understood as population behaviour arising from the interplay of the constituting discrete cells-can be studied with on- and off-lattice agent-based models. However, classical on-lattice agent-based models, also known as cellular automata, fail to replicate key aspects of collective migration, which is a central instance of collective behaviour in multicellular systems. To overcome drawbacks of classical on-lattice models, we introduce an on-lattice, agent-based modelling class for collective cell migration, which we call biological lattice-gas cellular automaton (BIO-LGCA). The BIO-LGCA is characterised by synchronous time updates, and the explicit consideration of individual cell velocities. While rules in classical cellular automata are typically chosen ad hoc, rules for cell-cell and cell-environment interactions in the BIO-LGCA can also be derived from experimental cell migration data or biophysical laws for individual cell migration. We introduce elementary BIO-LGCA models of fundamental cell interactions, which may be combined in a modular fashion to model complex multicellular phenomena. We exemplify the mathematical mean-field analysis of specific BIO-LGCA models, which allows to explain collective behaviour. The first example predicts the formation of clusters in adhesively interacting cells. The second example is based on a novel BIO-LGCA combining adhesive interactions and alignment. For this model, our analysis clarifies the nature of the recently discovered invasion plasticity of breast cancer cells in heterogeneous environments.
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http://dx.doi.org/10.1371/journal.pcbi.1009066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232544PMC
June 2021

A least microenvironmental uncertainty principle (LEUP) as a generative model of collective cell migration mechanisms.

Sci Rep 2020 12 22;10(1):22371. Epub 2020 Dec 22.

Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Rebenring 56, 38106, Braunschweig, Germany.

Collective migration is commonly observed in groups of migrating cells, in the form of swarms or aggregates. Mechanistic models have proven very useful in understanding collective cell migration. Such models, either explicitly consider the forces involved in the interaction and movement of individuals or phenomenologically define rules which mimic the observed behavior of cells. However, mechanisms leading to collective migration are varied and specific to the type of cells involved. Additionally, the precise and complete dynamics of many important chemomechanical factors influencing cell movement, from signalling pathways to substrate sensing, are typically either too complex or largely unknown. The question is how to make quantitative/qualitative predictions of collective behavior without exact mechanistic knowledge. Here we propose the least microenvironmental uncertainty principle (LEUP) that may serve as a generative model of collective migration without precise incorporation of full mechanistic details. Using statistical physics tools, we show that the famous Vicsek model is a special case of LEUP. Finally, to test the biological applicability of our theory, we apply LEUP to construct a model of the collective behavior of spherical Serratia marcescens bacteria, where the underlying migration mechanisms remain elusive.
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http://dx.doi.org/10.1038/s41598-020-79119-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755925PMC
December 2020

Mechanical Control of Cell Proliferation Increases Resistance to Chemotherapeutic Agents.

Phys Rev Lett 2020 Sep;125(12):128103

CNRS, UPR8001, LAAS-CNRS, 7 Avenue du Colonel Roche, F-31400 Toulouse, France.

While many cellular mechanisms leading to chemotherapeutic resistance have been identified, there is an increasing realization that tumor-stroma interactions also play an important role. In particular, mechanical alterations are inherent to solid cancer progression and profoundly impact cell physiology. Here, we explore the influence of compressive stress on the efficacy of chemotherapeutics in pancreatic cancer spheroids. We find that increased compressive stress leads to decreased drug efficacy. Theoretical modeling and experiments suggest that mechanical stress decreases cell proliferation which in turn reduces the efficacy of chemotherapeutics that target proliferating cells. Our work highlights a mechanical form of drug resistance and suggests new strategies for therapy.
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http://dx.doi.org/10.1103/PhysRevLett.125.128103DOI Listing
September 2020

Modelling collective cell motion: are on- and off-lattice models equivalent?

Philos Trans R Soc Lond B Biol Sci 2020 09 27;375(1807):20190378. Epub 2020 Jul 27.

Laboratoire J. A. Dieudonné, Université Côte d'Azur, UMR 7351 CNRS, Parc Valrose, 06108 Nice Cedex 02, France.

Biological processes, such as embryonic development, wound repair and cancer invasion, or bacterial swarming and fruiting body formation, involve collective motion of cells as a coordinated group. Collective cell motion of eukaryotic cells often includes interactions that result in polar alignment of cell velocities, while bacterial patterns typically show features of apolar velocity alignment. For analysing the population-scale effects of these different alignment mechanisms, various on- and off-lattice agent-based models have been introduced. However, discriminating model-specific artefacts from general features of collective cell motion is challenging. In this work, we focus on equivalence criteria at the population level to compare on- and off-lattice models. In particular, we define prototypic off- and on-lattice models of polar and apolar alignment, and show how to obtain an on-lattice from an off-lattice model of velocity alignment. By characterizing the behaviour and dynamical description of collective migration models at the macroscopic level, we suggest the type of phase transitions and possible patterns in the approximative macroscopic partial differential equation descriptions as informative equivalence criteria between on- and off-lattice models. This article is part of the theme issue 'Multi-scale analysis and modelling of collective migration in biological systems'.
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http://dx.doi.org/10.1098/rstb.2019.0378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423376PMC
September 2020

Investigating the Physical Effects in Bacterial Therapies for Avascular Tumors.

Front Microbiol 2020 4;11:1083. Epub 2020 Jun 4.

Braunschweig Integrated Centre of Systems Biology and Helmholtz Centre for Infection Research, Braunschweig, Germany.

Tumor-targeting bacteria elicit anticancer effects by infiltrating hypoxic regions, releasing toxic agents and inducing immune responses. Although current research has largely focused on the influence of chemical and immunological aspects on the mechanisms of bacterial therapy, the impact of physical effects is still elusive. Here, we propose a mathematical model for the anti-tumor activity of bacteria in avascular tumors that takes into account the relevant chemo-mechanical effects. We consider a time-dependent administration of bacteria and analyze the impact of bacterial chemotaxis and killing rate. We show that active bacterial migration toward tumor hypoxic regions provides optimal infiltration and that high killing rates combined with high chemotactic values provide the smallest tumor volumes at the end of the treatment. We highlight the emergence of steady states in which a small population of bacteria is able to constrain tumor growth. Finally, we show that bacteria treatment works best in the case of tumors with high cellular proliferation and low oxygen consumption.
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http://dx.doi.org/10.3389/fmicb.2020.01083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287150PMC
June 2020

On the Immunological Consequences of Conventionally Fractionated Radiotherapy.

iScience 2020 Mar 11;23(3):100897. Epub 2020 Feb 11.

Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Rebenring 56, 38106 Braunschweig, Germany. Electronic address:

Emerging evidence demonstrates that radiotherapy induces immunogenic death on tumor cells that emit immunostimulating signals resulting in tumor-specific immune responses. However, the impact of tumor features and microenvironmental factors on the efficacy of radiation-induced immunity remains to be elucidated. Herein, we use a calibrated model of tumor-effector cell interactions to investigate the potential benefits and immunological consequences of radiotherapy. Simulations analysis suggests that radiotherapy success depends on the functional tumor vascularity extent and reveals that the pre-treatment tumor size is not a consistent determinant of treatment outcomes. The one-size-fits-all approach of conventionally fractionated radiotherapy is predicted to result in some overtreated patients. In addition, model simulations also suggest that an arbitrary increase in treatment duration does not necessarily result in better tumor control. This study highlights the potential benefits of tumor-immune ecosystem profiling during treatment planning to better harness the immunogenic potential of radiotherapy.
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http://dx.doi.org/10.1016/j.isci.2020.100897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038527PMC
March 2020

A minimal modeling framework of radiation and immune system synergy to assist radiotherapy planning.

J Theor Biol 2020 02 29;486:110099. Epub 2019 Nov 29.

Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany; Centre for Individualised Infection Medicine (CIIM), Hannover, Germany; Institute of Biochemistry, Biotechnology and Bioinformatics, Technische Universität Braunschweig, Germany. Electronic address:

Recent evidence indicates the ability of radiotherapy to induce local and systemic tumor-specific immune responses as a result of immunogenic cell death. However, fractionation regimes routinely used in clinical practice typically ignore the synergy between radiation and the immune system, and instead attempt to completely eradicate tumors by the direct lethal effect of radiation on cancer cells. This paradigm is expected to change in the near future due to the potential benefits of considering radiation-induced antitumor immunity during treatment planning. Towards this goal, we propose a minimal modeling framework based on key aspects of the tumor-immune system interplay to simulate the effects of radiation on tumors and the immunological consequences of radiotherapy. The impacts of tumor-associated vasculature and intratumoral oxygen-mediated heterogeneity on treatment outcomes are ininvestigated. The model provides estimates of the minimum radiation doses required for tumor eradication given a certain number of treatment fractions. Moreover, estimates of treatment duration for disease control given predetermined fractional radiation doses can be also obtained. Although theoretical in nature, this study motivates the development and establishment of immune-based decision-support tools in radiotherapy planning.
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http://dx.doi.org/10.1016/j.jtbi.2019.110099DOI Listing
February 2020

Decreased plasma phospholipid concentrations and increased acid sphingomyelinase activity are accurate biomarkers for community-acquired pneumonia.

J Transl Med 2019 11 11;17(1):365. Epub 2019 Nov 11.

Research Group "Biomarkers for Infectious Diseases", TWINCORE Centre for Experimental and Clinical Infection Research, Feodor-Lynen-Str. 7, 30625, Hannover, Germany.

Background: There continues to be a great need for better biomarkers and host-directed treatment targets for community-acquired pneumonia (CAP). Alterations in phospholipid metabolism may constitute a source of small molecule biomarkers for acute infections including CAP. Evidence from animal models of pulmonary infections and sepsis suggests that inhibiting acid sphingomyelinase (which releases ceramides from sphingomyelins) may reduce end-organ damage.

Methods: We measured concentrations of 105 phospholipids, 40 acylcarnitines, and 4 ceramides, as well as acid sphingomyelinase activity, in plasma from patients with CAP (n = 29, sampled on admission and 4 subsequent time points), chronic obstructive pulmonary disease exacerbation with infection (COPD, n = 13) as a clinically important disease control, and 33 age- and sex-matched controls.

Results: Phospholipid concentrations were greatly decreased in CAP and normalized along clinical improvement. Greatest changes were seen in phosphatidylcholines, followed by lysophosphatidylcholines, sphingomyelins and ceramides (three of which were upregulated), and were least in acylcarnitines. Changes in COPD were less pronounced, but also differed qualitatively, e.g. by increases in selected sphingomyelins. We identified highly accurate biomarkers for CAP (AUC ≤ 0.97) and COPD (AUC ≤ 0.93) vs. Controls, and moderately accurate biomarkers for CAP vs. COPD (AUC ≤ 0.83), all of which were phospholipids. Phosphatidylcholines, lysophosphatidylcholines, and sphingomyelins were also markedly decreased in S. aureus-infected human A549 and differentiated THP1 cells. Correlations with C-reactive protein and procalcitonin were predominantly negative but only of mild-to-moderate extent, suggesting that these markers reflect more than merely inflammation. Consistent with the increased ceramide concentrations, increased acid sphingomyelinase activity accurately distinguished CAP (fold change = 2.8, AUC = 0.94) and COPD (1.75, 0.88) from Controls and normalized with clinical resolution.

Conclusions: The results underscore the high potential of plasma phospholipids as biomarkers for CAP, begin to reveal differences in lipid dysregulation between CAP and infection-associated COPD exacerbation, and suggest that the decreases in plasma concentrations are at least partially determined by changes in host target cells. Furthermore, they provide validation in clinical blood samples of acid sphingomyelinase as a potential treatment target to improve clinical outcome of CAP.
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http://dx.doi.org/10.1186/s12967-019-2112-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849224PMC
November 2019

On the Impact of Chemo-Mechanically Induced Phenotypic Transitions in Gliomas.

Cancers (Basel) 2019 May 24;11(5). Epub 2019 May 24.

Braunschweig Integrated Centre of Systems Biology and Helmholtz Center for Infectious Research, 38106 Braunschweig, Germany.

Tumor microenvironment is a critical player in glioma progression, and novel therapies for its targeting have been recently proposed. In particular, stress-alleviation strategies act on the tumor by reducing its stiffness, decreasing solid stresses and improving blood perfusion. However, these microenvironmental changes trigger chemo-mechanically induced cellular phenotypic transitions whose impact on therapy outcomes is not completely understood. In this work we analyze the effects of mechanical compression on migration and proliferation of glioma cells. We derive a mathematical model of glioma progression focusing on cellular phenotypic plasticity. Our results reveal a trade-off between tumor infiltration and cellular content as a consequence of stress-alleviation approaches. We discuss how these novel findings increase the current understanding of glioma/microenvironment interactions and can contribute to new strategies for improved therapeutic outcomes.
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http://dx.doi.org/10.3390/cancers11050716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562768PMC
May 2019

Hook length of the bacterial flagellum is optimized for maximal stability of the flagellar bundle.

PLoS Biol 2018 09 6;16(9):e2006989. Epub 2018 Sep 6.

Institute for Biology - Bacterial Physiology, Humboldt-Universität zu Berlin, Berlin, Germany.

Most bacteria swim in liquid environments by rotating one or several flagella. The long external filament of the flagellum is connected to a membrane-embedded basal body by a flexible universal joint, the hook, which allows the transmission of motor torque to the filament. The length of the hook is controlled on a nanometer scale by a sophisticated molecular ruler mechanism. However, why its length is stringently controlled has remained elusive. We engineered and studied a diverse set of hook-length variants of Salmonella enterica. Measurements of plate-assay motility, single-cell swimming speed, and directional persistence in quasi-2D and population-averaged swimming speed and body angular velocity in 3D revealed that the motility performance is optimal around the wild-type hook length. We conclude that too-short hooks may be too stiff to function as a junction and too-long hooks may buckle and create instability in the flagellar bundle. Accordingly, peritrichously flagellated bacteria move most efficiently as the distance travelled per body rotation is maximal and body wobbling is minimized. Thus, our results suggest that the molecular ruler mechanism evolved to control flagellar hook growth to the optimal length consistent with efficient bundle formation. The hook-length control mechanism is therefore a prime example of how bacteria evolved elegant but robust mechanisms to maximize their fitness under specific environmental constraints.
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http://dx.doi.org/10.1371/journal.pbio.2006989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126814PMC
September 2018

Multidimensional Analysis Integrating Human T-Cell Signatures in Lymphatic Tissues with Sex of Humanized Mice for Prediction of Responses after Dendritic Cell Immunization.

Front Immunol 2017 8;8:1709. Epub 2017 Dec 8.

Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.

Mice transplanted with human cord blood-derived hematopoietic stem cells (HSCs) became a powerful experimental tool for studying the heterogeneity of human immune reconstitution and immune responses . Yet, analyses of human T cell maturation in humanized models have been hampered by an overall low immune reactivity and lack of methods to define predictive markers of responsiveness. Long-lived human lentiviral induced dendritic cells expressing the cytomegalovirus pp65 protein (iDCpp65) promoted the development of pp65-specific human CD8 T cell responses in NOD.Cg-Rag1 -Il2rγ humanized mice through the presentation of immune-dominant antigenic epitopes (signal 1), expression of co-stimulatory molecules (signal 2), and inflammatory cytokines (signal 3). We exploited this validated system to evaluate the effects of mouse sex in the dynamics of T cell homing and maturation status in thymus, blood, bone marrow, spleen, and lymph nodes. Statistical analyses of cell relative frequencies and absolute numbers demonstrated higher CD8 memory T cell reactivity in spleen and lymph nodes of immunized female mice. In order to understand to which extent the multidimensional relation between organ-specific markers predicted the immunization status, the immunophenotypic profiles of individual mice were used to train an artificial neural network designed to discriminate immunized and non-immunized mice. The highest accuracy of immune reactivity prediction could be obtained from lymph node markers of female mice (77.3%). Principal component analyses further identified clusters of markers best suited to describe the heterogeneity of immunization responses . A correlation analysis of these markers reflected a tissue-specific impact of immunization. This allowed for an organ-resolved characterization of the immunization status of individual mice based on the identified set of markers. This new modality of multidimensional analyses can be used as a framework for defining minimal but predictive signatures of human immune responses in mice and suggests critical markers to characterize responses to immunization after HSC transplantation.
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http://dx.doi.org/10.3389/fimmu.2017.01709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727047PMC
December 2017

Image analysis of immune cell patterns in the human mammary gland during the menstrual cycle refines lymphocytic lobulitis.

Breast Cancer Res Treat 2017 Jul 25;164(2):305-315. Epub 2017 Apr 25.

Institute of Pathology, Neuropathology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany.

Purpose: To improve microscopic evaluation of immune cells relevant in breast cancer oncoimmunology, we aim at distinguishing normal infiltration patterns from lymphocytic lobulitis by advanced image analysis. We consider potential immune cell variations due to the menstrual cycle and oral contraceptives in non-neoplastic mammary gland tissue.

Methods: Lymphocyte and macrophage distributions were analyzed in the anatomical context of the resting mammary gland in immunohistochemically stained digital whole slide images obtained from 53 reduction mammoplasty specimens. Our image analysis workflow included automated regions of interest detection, immune cell recognition, and co-registration of regions of interest.

Results: In normal lobular epithelium, seven CD8[Formula: see text] lymphocytes per 100 epithelial cells were present on average and about 70% of this T-lymphocyte population was lined up along the basal cell layer in close proximity to the epithelium. The density of CD8[Formula: see text] T-cell was 1.6 fold higher in the luteal than in the follicular phase in spontaneous menstrual cycles and 1.4 fold increased under the influence of oral contraceptives, and not co-localized with epithelial proliferation. CD4[Formula: see text] T-cells were infrequent. Abundant CD163[Formula: see text] macrophages were widely spread, including the interstitial compartment, with minor variation during the menstrual cycle.

Conclusions: Spatial patterns of different immune cell subtypes determine the range of normal, as opposed to inflammatory conditions of the breast tissue microenvironment. Advanced image analysis enables quantification of hormonal effects, refines lymphocytic lobulitis, and shows potential for comprehensive biopsy evaluation in oncoimmunology.
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http://dx.doi.org/10.1007/s10549-017-4239-zDOI Listing
July 2017

Therapeutic Potential of Bacteria against Solid Tumors.

Cancer Res 2017 04 15;77(7):1553-1563. Epub 2017 Feb 15.

Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany.

Intentional bacterial infections can produce efficacious antitumor responses in mice, rats, dogs, and humans. However, low overall success rates and intense side effects prevent such approaches from being employed clinically. In this work, we titered bacteria and/or the proinflammatory cytokine TNFα in a set of established murine models of cancer. To interpret the experiments conducted, we considered and calibrated a tumor-effector cell recruitment model under the influence of functional tumor-associated vasculature. In this model, bacterial infections and TNFα enhanced immune activity and altered vascularization in the tumor bed. Information to predict bacterial therapy outcomes was provided by pretreatment tumor size and the underlying immune recruitment dynamics. Notably, increasing bacterial loads did not necessarily produce better long-term tumor control, suggesting that tumor sizes affected optimal bacterial loads. Short-term treatment responses were favored by high concentrations of effector cells postinjection, such as induced by higher bacterial loads, but in the longer term did not correlate with an effective restoration of immune surveillance. Overall, our findings suggested that a combination of intermediate bacterial loads with low levels TNFα administration could enable more favorable outcomes elicited by bacterial infections in tumor-bearing subjects. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-1621DOI Listing
April 2017

Avian photoreceptor patterns represent a disordered hyperuniform solution to a multiscale packing problem.

Phys Rev E Stat Nonlin Soft Matter Phys 2014 Feb 24;89(2):022721. Epub 2014 Feb 24.

Princeton Institute of the Science and Technology of Materials, Princeton University, Princeton, New Jersey 08540, USA and Department of Chemistry, Department of Physics, Program in Computational and Applied Mathematics, Princeton University, Princeton, New Jersey 08544, USA.

Optimal spatial sampling of light rigorously requires that identical photoreceptors be arranged in perfectly regular arrays in two dimensions. Examples of such perfect arrays in nature include the compound eyes of insects and the nearly crystalline photoreceptor patterns of some fish and reptiles. Birds are highly visual animals with five different cone photoreceptor subtypes, yet their photoreceptor patterns are not perfectly regular. By analyzing the chicken cone photoreceptor system consisting of five different cell types using a variety of sensitive microstructural descriptors, we find that the disordered photoreceptor patterns are "hyperuniform" (exhibiting vanishing infinite-wavelength density fluctuations), a property that had heretofore been identified in a unique subset of physical systems, but had never been observed in any living organism. Remarkably, the patterns of both the total population and the individual cell types are simultaneously hyperuniform. We term such patterns "multihyperuniform" because multiple distinct subsets of the overall point pattern are themselves hyperuniform. We have devised a unique multiscale cell packing model in two dimensions that suggests that photoreceptor types interact with both short- and long-ranged repulsive forces and that the resultant competition between the types gives rise to the aforementioned singular spatial features characterizing the system, including multihyperuniformity. These findings suggest that a disordered hyperuniform pattern may represent the most uniform sampling arrangement attainable in the avian system, given intrinsic packing constraints within the photoreceptor epithelium. In addition, they show how fundamental physical constraints can change the course of a biological optimization process. Our results suggest that multihyperuniform disordered structures have implications for the design of materials with novel physical properties and therefore may represent a fruitful area for future research.
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http://dx.doi.org/10.1103/PhysRevE.89.022721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836809PMC
February 2014

In silico analysis of cell cycle synchronisation effects in radiotherapy of tumour spheroids.

PLoS Comput Biol 2013 14;9(11):e1003295. Epub 2013 Nov 14.

Department of Systems Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany ; Frankfurt Institute for Advanced Studies, Frankfurt, Germany.

Tumour cells show a varying susceptibility to radiation damage as a function of the current cell cycle phase. While this sensitivity is averaged out in an unperturbed tumour due to unsynchronised cell cycle progression, external stimuli such as radiation or drug doses can induce a resynchronisation of the cell cycle and consequently induce a collective development of radiosensitivity in tumours. Although this effect has been regularly described in experiments it is currently not exploited in clinical practice and thus a large potential for optimisation is missed. We present an agent-based model for three-dimensional tumour spheroid growth which has been combined with an irradiation damage and kinetics model. We predict the dynamic response of the overall tumour radiosensitivity to delivered radiation doses and describe corresponding time windows of increased or decreased radiation sensitivity. The degree of cell cycle resynchronisation in response to radiation delivery was identified as a main determinant of the transient periods of low and high radiosensitivity enhancement. A range of selected clinical fractionation schemes is examined and new triggered schedules are tested which aim to maximise the effect of the radiation-induced sensitivity enhancement. We find that the cell cycle resynchronisation can yield a strong increase in therapy effectiveness, if employed correctly. While the individual timing of sensitive periods will depend on the exact cell and radiation types, enhancement is a universal effect which is present in every tumour and accordingly should be the target of experimental investigation. Experimental observables which can be assessed non-invasively and with high spatio-temporal resolution have to be connected to the radiosensitivity enhancement in order to allow for a possible tumour-specific design of highly efficient treatment schedules based on induced cell cycle synchronisation.
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http://dx.doi.org/10.1371/journal.pcbi.1003295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828142PMC
July 2014

Integrative physical oncology.

Wiley Interdiscip Rev Syst Biol Med 2012 Jan-Feb;4(1):1-14. Epub 2011 Aug 18.

Department of Pathology, University of New Mexico, Albuquerque, NM, USA.

Cancer is arguably the ultimate complex biological system. Solid tumors are microstructured soft matter that evolves as a consequence of spatio-temporal events at the intracellular (e.g., signaling pathways, macromolecular trafficking), intercellular (e.g., cell-cell adhesion/communication), and tissue (e.g., cell-extracellular matrix interactions, mechanical forces) scales. To gain insight, tumor and developmental biologists have gathered a wealth of molecular, cellular, and genetic data, including immunohistochemical measurements of cell type-specific division and death rates, lineage tracing, and gain-of-function/loss-of-function mutational analyses. These data are empirically extrapolated to a diagnosis/prognosis of tissue-scale behavior, e.g., for clinical decision. Integrative physical oncology (IPO) is the science that develops physically consistent mathematical approaches to address the significant challenge of bridging the nano (nm)-micro (µm) to macro (mm, cm) scales with respect to tumor development and progression. In the current literature, such approaches are referred to as multiscale modeling. In the present article, we attempt to assess recent modeling approaches on each separate scale and critically evaluate the current 'hybrid-multiscale' models used to investigate tumor growth in the context of brain and breast cancers. Finally, we provide our perspective on the further development and the impact of IPO.
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http://dx.doi.org/10.1002/wsbm.158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3622087PMC
April 2012

Mathematical Oncology: How Are the Mathematical and Physical Sciences Contributing to the War on Breast Cancer?

Curr Breast Cancer Rep 2010 Sep 22;2(3):121-129. Epub 2010 Jul 22.

Mathematical modeling has recently been added as a tool in the fight against cancer. The field of mathematical oncology has received great attention and increased enormously, but over-optimistic estimations about its ability have created unrealistic expectations. We present a critical appraisal of the current state of mathematical models of cancer. Although the field is still expanding and useful clinical applications may occur in the future, managing over-expectation requires the proposal of alternative directions for mathematical modeling. Here, we propose two main avenues for this modeling: 1) the identification of the elementary biophysical laws of cancer development, and 2) the development of a multiscale mathematical theory as the framework for models predictive of tumor growth. Finally, we suggest how these new directions could contribute to addressing the current challenges of understanding breast cancer growth and metastasis.
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http://dx.doi.org/10.1007/s12609-010-0020-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2987530PMC
September 2010
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