Macro-scale models for fluid flow in tumour tissues: impact of microstructure properties

Vaghi, Cristina; Fanciullino, Raphaëlle; Benzekry, Sébastien; Poignard, Clair

doi:10.1007/s00285-022-01719-1

Cited by 3 publications

(5 citation statements)

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“…The model could also be initialised from medical imaging data showing cell locations [93]. We could include a more detailed description of the vasculature, that accounts for tumour blood flow, angiogenesis and vascular remodelling [94][95][96][97][98][99]. This would enable us to account for tumour cell intravasation and metastasis, and to investigate how distinct tumour regions are initiated and evolve over time.…”

Section: Discussionmentioning

confidence: 99%

Quantification of spatial and phenotypic heterogeneity in an agent-based model of tumour-macrophage interactions

Bull

Byrne

2022

Preprint

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Cross-talk between tumour and immune cells, including macrophages, is complex, dynamic and contributes to tumour heterogeneity. In this paper, we introduce a hybrid agent-based model (ABM) to investigate how tumour-macrophage dynamics evolve over time and how they influence spatial patterns of tumour growth. Macrophage phenotype is determined by microenvironmental cues and governs the extent to which macrophages are pro- or anti-tumour, i.e., whether they infiltrate and attack tumour cells, or promote metastasis by guiding tumour cell migration towards blood vessels.We perform extensive ABM simulations to investigate how changes in macrophage sensitivity to microenvironmental cues – specifically, cytokines produced by tumour cells and perivascular fibroblasts – alters their spatial and phenotypic distributions and the tumour’s growth dynamics. We identify outcomes that include: compact tumour growth, tumour elimination, and diffuse patterns of invasion, characterised by clustering of tumour cells and macrophages around blood vessels.We compare the ability of different statistics to characterise the diverse spatial patterns that the ABM generates. These include the weighted pair correlation function (wPCF), a new statistic that quantifies the spatial distributions of cells labelled with a continuous value (e.g., macrophage phenotype). We assess the ability of each statistic to discriminate between the various spatial patterns that the ABM exhibits.By combining statistical analysis with ABM simulations, we show how mechanistic models can be used to generate synthetic data for validation of novel statistics (here, the wPCF) and to assess the extent to which specific statistical descriptions can distinguish different spatial patterns and model behaviours. Such statistics can then be applied to biological imaging data, such as multiplexed medical images, with increased confidence in the interpretation of the results. We show that the wPCF accurately describes differences in macrophage localisation between images, and posit that it would be a valuable tool for analysing multiplexed imaging data.Author summaryMacrophage phenotype is regulated by complex microenvironmental cues. It affects their spatial position and behaviour. In solid tumours, the spatial distribution of macrophages can vary significantly, and correlate with patient prognosis.In this paper, we use an agent-based model (ABM) to investigate how changes in sensitivity to tumour-induced microenvironmental cues affect macrophage phenotype and, in turn, how such phenotypic heterogeneity affects tumour composition and morphology. We illustrate the wide range of tumour outcomes that can arise from changing macrophage sensitivity to microenvironmental cues.We apply a variety of statistics to simulation outputs to characterise the range of observed spatial patterns. Different statistics identify different aspects of these patterns, with the most descriptive characterisations obtained from spatial statistics, such as the weighted pair correlation function (wPCF), that account for both phenotype and cell localisation.More generally, this paper illustrates how ABMs can be used to generate synthetic data which mimics data that can be extracted from different imaging modalities. This synthetic data can be used to test new statistics, like the wPCF, and validate their use for future application to multiplex histological imaging.

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Section: Discussionmentioning

confidence: 99%

Quantification of spatial and phenotypic heterogeneity in an agent-based model of tumour-macrophage interactions

Bull

Byrne

2022

Preprint

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“…ρ is polynomial in ρ and with smooth coefficients in ∂Ω by induction hypothesis. Denoting by (c ) k =1 the sequence of smooth functions defined on ∂Ω by (18) and vanishes at the boundaries ρ = 0 and ρ → +∞. • Proof of the estimates.…”

Section: Asymptotic Analysismentioning

confidence: 99%

“…Due to the high complexity of the architecture of tumors, two-scale asymptotic analysis has been employed to derive macroscopic models that take into account the microscopic properties of the malignant tissues [16,13]. In a recent study, we derived several asymptotic models according to the magnitude of the hydraulic conductivity of the interstitium and of the vessel walls [18]. Under the assumption of a periodic structure of neoplastic tissues, tumors are modeled as double porous media and Darcy's law describes the interstitial fluid flow and the blood transport.…”

mentioning

confidence: 99%

“…Given two Dirichlet boundary conditions π t and π c belonging to H s+1/2 (∂Ω) with s ≥ 0 as large as necessary, we are interested in the analysis of the model derived by Chapman, Shipley et al [17] also derived recently in [18]. In this paper we focus on the case where the porosity tensors involved in [17,18] are colinear. After simple change of notation, the problem reads in the smooth domain Ω as…”

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confidence: 99%

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Asymptotic analysis of a biphase tumor fluid flow. The weak coupling case

Vaghi¹,

Benzekry²,

Poignard³

2021

Preprint

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The aim of this paper is to investigate the asymptotic behavior of a biphase tumor fluid flow derived by 2-scale homogenisation techniques in recent works. This biphase fluid flow model accounts for the capillary wall permeability, and the interstitial avascular phase, both being mixed in the limit homogenised problem. When the vessel walls become more permeable, we show that the biphase fluid flow exhibits a boundary layer that makes the computation of the full problem costly and unstable. In the limit, both capillary and interstitial pressures coincide except in the vicinity of the boundary where different boundary conditions are applied. Thanks to a rigorous asymptotic analysis, we prove that the solution to the full problem can be approached at any order of approximation by a monophasic model with appropriate boundary conditions on the tumor boundary and appropriate correcting terms near the boundary are given. Numerical simulations in spherical geometry illustrate the theoretical results.

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“…Due to lack of molecular markers in protomyofibroblasts (low α-smooth muscle actin (SMA)) 37 , we focused on migratory responses of fibroblast and alignment of actin cytoskeleton stress fibers 39 . Using the same interstitial flow rates, we explored heterogeneous fluid flow conditions that mimic tissue microarchitecture or niche environments 19, 40 and the relationship with fibroblast activation. Using MILL, we further explored how adherent fibroblast cells sense and respond to shear gradients 41 .…”

Section: Introductionmentioning

confidence: 99%

Patterning High to Low Heterogenous Fluid Shear Stress Landscapes with Multiphoton Inner Laser Lithography (MILL) for Live Cell Adhesion and Translocation

Lim

Zhang

Lin

et al. 2022

Preprint

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Current 3D microfluidic fabrication methods require hours and specialized equipment to fabricate microstructures in a single channel so as to recapitulate mixed (homogenous and heterogeneous) in vivo fluid flow. Inspired by the ancient art form of inside painting, we developed a technique for 3D fabrication of micro-patterned flow channels and mixed in vivo fluid flow in a matter of minutes. We termed this technique Multiphoton Inner Laser Lithography (MILL). We further showed that MILL is compatible with both flat and curved channel shapes. MILL recapitulated in vivo tissue topology and 3D fluid flow of the tissue microenvironment, all of which are vital for understanding of how extracellular fluid flow regulates cell function. Cells in MILL capillary tubes response to a variety of in vivo-like laminar flow patterns (homogenous and heterogeneous). Live cells were observed to organize, translocate and adhere along different fluid shear landscapes (0 - 81 dynes/cm2) in real time. Parallel strips of MILL channels were assembled for platelet function tests (~2000 microthrombi per test). The MILL technique heralds a new paradigm where dynamics of in vivo fluid flow can be readily reproduced in minutes on a standard multiphoton imaging microscope and benefit preclinical screening of drug pharmacokinetics.

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Macro-scale models for fluid flow in tumour tissues: impact of microstructure properties

Cited by 3 publications

References 48 publications

Quantification of spatial and phenotypic heterogeneity in an agent-based model of tumour-macrophage interactions

Quantification of spatial and phenotypic heterogeneity in an agent-based model of tumour-macrophage interactions

Asymptotic analysis of a biphase tumor fluid flow. The weak coupling case

Patterning High to Low Heterogenous Fluid Shear Stress Landscapes with Multiphoton Inner Laser Lithography (MILL) for Live Cell Adhesion and Translocation

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