Impact of tumor-parenchyma biomechanics on liver metastatic progression: a multi-model approach

Abstract

Colorectal carcinoma (CRC) and other cancers often metastasize to the liver in later stages of the disease, contributing significantly to patient death. While the biomechanical properties of the liver parenchyma (normal liver tissue) are known to affect primary and metastatic tumor growth in liver tissues, the role of these properties in driving or inhibiting metastatic inception remains poorly understood. This study uses a multi-model approach to study the effect of tumor-parenchyma biomechanical interactions on metastatic seeding and growth; the framework also allows investigating the impact of changing tissue biomechanics on tumor dormancy and "reawakening." We employ a detailed poroviscoelastic (PVE) model to study how tumor metastases deform the surrounding tissue, induce pressure increases, and alter interstitial fluid flow in and near the metastases. Results from these short-time simulations in detailed single hepatic lobules motivate constitutive relations and biological hypotheses for use in an agent-based model of metastatic seeding and growth in centimeter-scale tissue over months-long time scales. We find that biomechanical tumor-parenchyma interactions on shorter time scales (adhesion, repulsion, and elastic tissue deformation over minutes) and longer time scales (plastic tissue relaxation over hours) may play a key role in tumor cell seeding and growth within liver tissue. These interactions may arrest the growth of micrometastases in a dormant state and can prevent newly arriving cancer cells from establishing successful metastatic foci. Moreover, the simulations indicate ways in which dormant tumors can "reawaken" after changes in parenchymal tissue mechanical properties, as may arise during aging or following acute liver illness or injury. We conclude that the proposed modeling approach can yield insight into the role of tumor-parenchyma biomechanics in promoting liver metastatic growth, with the longer term goal of identifying conditions to clinically arrest and reverse the course of late-stage cancer. 4/25

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