Abstract

Local cancer invasion of tissue is a complex, multiscale process which plays an essential role in tumour progression. During the complex interaction between cancer cell population and the extracellular matrix (ECM), of key importance is the role played by both bulk two-scale dynamics of ECM fibres within collective movement of the tumour cells and the multiscale leading edge dynamics driven by proteolytic activity of the matrix-degrading enzymes (MDEs) that are secreted by the cancer cells. As these two multiscale subsystems share and contribute to the same tumour macro-dynamics, in this work we develop further the model introduced in Shuttleworth and Trucu (Bull Math Biol 81:2176–2219, 2019. https://doi.org/10.1007/s11538-019-00598-w) by exploring a new aspect of their interaction that occurs at the cell scale. Specifically, here we will focus on understanding the cell-scale cross talk between the micro-scale parts of these two multiscale subsystems which get to interact directly in the peritumoural region, with immediate consequences both for MDE micro-dynamics occurring at the leading edge of the tumour and for the cell-scale rearrangement of the naturally oriented ECM fibres in the peritumoural region, ultimately influencing the way tumour progresses in the surrounding tissue. To that end, we will propose a new modelling that captures the ECM fibres degradation not only at macro-scale in the bulk of the tumour but also explicitly in the micro-scale neighbourhood of the tumour interface as a consequence of the interactions with molecular fluxes of MDEs that exercise their spatial dynamics at the invasive edge of the tumour.

Highlights

  • Cancer cell invasion of tissue is a complex, multiscale process in which gene mutations in healthy cells promote enhanced proliferation and the production of proteolytic enzymes

  • – we explore the enhancing effect that the presence of the extracellular matrix (ECM) fibres has on secretion of the MMP-2 as well as the way the emerging MMP-2 micro-scale spatiotemporal dynamics is influenced by the spatial distribution of ECM micro-fibres within a cell-scale peritumoural neighbourhood of the tumour boundary;

  • We have presented an integrated two-part multiscale model of cancer invasion, which builds on the approach introduced in Shuttleworth and Trucu (2019) and extends that to capture explicitly the dynamic cell-scale interaction between the matrixdegrading enzymes (MDEs) boundary micro-dynamics and the peritumoural mass distribution of micro-fibres

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Summary

Introduction

Cancer cell invasion of tissue is a complex, multiscale process in which gene mutations in healthy cells promote enhanced proliferation and the production of proteolytic enzymes. One of the first MDEs to interact with the ECM is the membrane-tethered MMP, MT1-MMP or MMP-14 This MMP exhibits strong collagenolytic capabilities in which they are able to cleave the cross-linked collagen type I fibres and break them into shorter, soluble fibres. These soluble fibres are degraded by the freely diffusible MMP-2, activated through the cleavage of proMMP-2 molecules by MT1-MMP. MMP-2 cannot degrade the dense cross-linked fibres, but can degrade the smaller, soluble fibrils within the peritumoural region (Van Doren 2015) These two MMPs work in harmony with one another for successful invasion of tissue

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