Spontaneous dormancy of metastatic breast cancer cells in an all human liver microphysiologic system

Abstract

Background:Metastatic outgrowth in breast cancer can occur years after a seeming cure. Existing model systems of dormancy are limited as they do not recapitulate human metastatic dormancy without exogenous manipulations and are unable to query early events of micrometastases.Methods:Here, we describe a human ex vivo hepatic microphysiologic system. The system is established with fresh human hepatocytes and non-parenchymal cells (NPCs) creating a microenvironment into which breast cancer cells (MCF7 and MDA-MB-231) are added.Results:The hepatic tissue maintains function through 15 days as verified by liver-specific protein production and drug metabolism assays. The NPCs form an integral part of the hepatic niche, demonstrated within the system through their participation in differential signalling cascades and cancer cell outcomes. Breast cancer cells intercalate into the hepatic niche without interfering with hepatocyte function. Examination of cancer cells demonstrated that a significant subset enter a quiescent state of dormancy as shown by lack of cell cycling (EdU− or Ki67−). The presence of NPCs altered the cancer cell fraction entering quiescence, and lead to differential cytokine profiles in the microenvironment effluent.Conclusions:These findings establish the liver microphysiologic system as a relevant model for the study of breast cancer metastases and entry into dormancy.

Modeling Therapeutic Antibody–Small Molecule Drug-Drug Interactions Using a Three-Dimensional Perfusable Human Liver Coculture Platform

“…This indicates an initial period of adaptation to the culture after cryopreserved hepatocytes were seeded. Similar patterns for decreases in the clinical liver injury markers aspartate aminotransferase and alanine aminotransferase were observed for freshly isolated human hepatocytes in the LiverChip along similar time scales, although these were not measured in our study (Wheeler et al, 2014).…”

“…Advanced in vitro systems in combination with in silico modeling approaches continue to drive improvements in the early drug development process. As these in vitro models increase in complexity and approach greater physiologic relevance, their application should continue to expand from drug PK and toxicity evaluations to pharmacodynamic and human disease models (Ananthanarayanan et al, 2014;Wheeler et al, 2014;Vernetti et al, 2016).…”

The predictive link between matrix and metastasis

“…Local stromal cells in the metastatic niche likely play a dominant role in paracrine activation of dormant cells, such as glial cells in the brain [65], and hepatocytes and non-parenchymal cells in the liver [66]. Vasculature plays a dual role, in some cases maintaining quiescence [67], and releasing the factors critical for re-activation in others [68].…”

“…Specific combinations of bone marrow or hepatic stromal cells can induce breast cancer cell dormancy via cytokine secretion [66, 73]. For example, the Griffith lab used an engineered liver tissue to study stromal cell and ECM re-activation of dormant breast cancer cells in the liver [66].…”

“…Specific combinations of bone marrow or hepatic stromal cells can induce breast cancer cell dormancy via cytokine secretion [66, 73]. For example, the Griffith lab used an engineered liver tissue to study stromal cell and ECM re-activation of dormant breast cancer cells in the liver [66]. They found that roughly half of infiltrated breast cancer cells were dormant, and not surprisingly, the more aggressive MDA-MB-231 cells were more sensitive to re-activation by non-parenchymal cells than the luminal MCF7s.…”