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

Yafei Wang,Hermann B Frieboes,Shannon M Mumenthaler,Jessica L Sparks,Kenichiro Nishii,Erik Brodin,Paul Macklin

doi:10.1038/s41598-020-78780-7

Abstract

Colorectal cancer 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 tumor cell behavior in primary and metastatic tumors, the role of these properties in driving or inhibiting metastatic inception remains poorly understood, as are the longer-term multicellular dynamics. This study adopts a multi-model approach to study the dynamics of tumor-parenchyma biomechanical interactions during metastatic seeding and growth. We employ a detailed poroviscoelastic model of a liver lobule to study how micrometastases disrupt flow and pressure on short time scales. Results from short-time simulations in detailed single hepatic lobules motivate constitutive relations and biological hypotheses for a minimal agent-based model of metastatic growth in centimeter-scale tissue over months-long time scales. After a parameter space investigation, we find that the balance of basic tumor-parenchyma biomechanical interactions on shorter time scales (adhesion, repulsion, and elastic tissue deformation over minutes) and longer time scales (plastic tissue relaxation over hours) can explain a broad range of behaviors of micrometastases, without the need for complex molecular-scale signaling. These interactions may arrest the growth of micrometastases in a dormant state and prevent newly arriving cancer cells from establishing successful metastatic foci. Moreover, the simulations indicate ways in which dormant tumors could “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 yields insight into the role of tumor-parenchyma biomechanics in promoting liver metastatic growth, and advances the longer term goal of identifying conditions to clinically arrest and reverse the course of late-stage cancer.

Highlights

Colorectal cancer and other cancers often metastasize to the liver in later stages of the disease, contributing significantly to patient death
We use the PVE results to motivate a minimal set of biological rules to study tumor cells and parenchymal tissue in a centimeter-scale agent-based model (ABM) of tumor metastatic growth in liver tissue
The biomechanical interactions that favor metastases to seed in liver tissue and enhance their growth remain poorly understood

Summary

Introduction

Colorectal cancer and other cancers often metastasize to the liver in later stages of the disease, contributing significantly to patient death. After a parameter space investigation, we find that the balance of basic tumor-parenchyma biomechanical interactions on shorter time scales (adhesion, repulsion, and elastic tissue deformation over minutes) and longer time scales (plastic tissue relaxation over hours) can explain a broad range of behaviors of micrometastases, without the need for complex molecular-scale signaling These interactions may arrest the growth of micrometastases in a dormant state and prevent newly arriving cancer cells from establishing successful metastatic foci. Significant research has focused on the molecular, single-cell alterations that contribute to metastatic disease, yet the biophysical interactions between tumor cells and the metastatic microenvironment remain to be elucidated at multicellular scales over long times This knowledge gap reflects both the emphasis of reductionist biology on molecular mechanisms of individual cancer cells and the difficulty in longitudinally observing tumor-parenchyma interaction dynamics in animal models or patients. Most investigations of age-driven changes in liver tissue have focused on immunologic and molecular-scale changes to ECM, rather than more basic mechanical properties (e.g., s ee[16])

Methods

Results

Conclusion