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.

The role of fluid stresses in activating the hepatic stem/progenitor cell regenerative response is not well understood. This study hypothesized that immediate early genes (IEGs) with known links to liver regeneration will be upregulated in liver progenitor cells (LPCs) exposed to in vitro shear stresses on the order of those produced from elevated interstitial flow after partial hepatectomy. The objectives were: (1) to develop a shear flow chamber for application of fluid stress to LPCs in 3D culture; and (2) to determine the effects of fluid stress on IEG expression in LPCs. Two hours of shear stress exposure at ∼4 dyn/cm was applied to LPCs embedded individually or as 3D spheroids within a hyaluronic acid/collagen I hydrogel. Results were compared against static controls. Quantitative reverse transcriptase polymerase chain reaction was used to evaluate the effect of experimental treatments on gene expression. Twenty-nine genes were analyzed, including IEGs and other genes linked to liver regeneration. Four IEGs (CFOS, IP10, MKP1, ALB) and three other regeneration-related genes (WNT, VEGF, EpCAM) were significantly upregulated in LPCs in response to fluid mechanical stress. LPCs maintained an early to intermediate stage of differentiation in spheroid culture in the absence of the hydrogel, and addition of the gel initiated cholangiocyte differentiation programs which were abrogated by the onset of flow. Collectively the flow-upregulated genes fit the pattern of an LPC-mediated proliferative/regenerative response. These results suggest that fluid stresses are potentially important regulators of the LPC-mediated regeneration response in liver.

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