A microphysiological system model of therapy for liver micrometastases

Abstract

Metastasis accounts for almost 90% of cancer-associated mortality. The effectiveness of cancer therapeutics is limited by the protective microenvironment of the metastatic niche and consequently these disseminated tumors remain incurable. Metastatic disease progression continues to be poorly understood due to the lack of appropriate model systems. To address this gap in understanding, we propose an all-human microphysiological system that facilitates the investigation of cancer behavior in the liver metastatic niche. This existing LiverChip is a 3D-system modeling the hepatic niche; it incorporates a full complement of human parenchymal and non-parenchymal cells and effectively recapitulates micrometastases. Moreover, this system allows for real-time monitoring of micrometastasis and assessment of human-specific signaling. It is being utilized to further our understanding of the efficacy of chemotherapeutics by examining the activity of established and novel agents on micrometastases under conditions replicating diurnal variations in hormones, nutrients and mild inflammatory states using programmable microdispensers. These inputs affect the cues that govern tumor cell responses. Three critical signaling groups are targeted: the glucose/insulin responses, the stress hormone cortisol and the gut microbiome in relation to inflammatory cues. Currently, the system sustains functioning hepatocytes for a minimum of 15 days; confirmed by monitoring hepatic function (urea, α-1-antitrypsin, fibrinogen, and cytochrome P450) and injury (AST and ALT). Breast cancer cell lines effectively integrate into the hepatic niche without detectable disruption to tissue and preliminary evidence suggests growth attenuation amongst a subpopulation of breast cancer cells. xMAP technology combined with systems biology modeling are also employed to evaluate cellular crosstalk and illustrate communication networks in the early microenvironment of micrometastases. This model is anticipated to identify new therapeutic strategies for metastasis by elucidating the paracrine effects between the hepatic and metastatic cells, while concurrently evaluating agent efficacy for metastasis, metabolism and tolerability.

Modelling the metastatic cascade by in vitro microfluidic platforms

“…The successful platform targeted for metastasis research was developed by the groups of Linda Griffith and Alan Wells (Yates et al, 2007) and after further development is now commercialized by Zyoxel, Ltd as a LiverChip (Clark et al, 2014). The typical experimental outline includes seeding of fresh human hepatocytes along with non-parenchymal liver cells into the scaffold area of a chip with subsequent formation of functional hepatic niches after 3 days of maintenance by the recirculating medium.…”

Fitting tissue chips and microphysiological systems into the grand scheme of medicine, biology, pharmacology, and toxicology

“…The previous MPS thematic issue in EBM published manuscripts highlighting early progress from both of these efforts. [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] It was recognized that MPS might help close the hermeneutic circle of biology, which describes how it is impossible to understand the whole (the compete organism) without understanding the parts (the genome, proteome, metabolome, etc. ), and that understanding the parts requires an understanding of the whole.…”

The relevance and potential roles of microphysiological systems in biology and medicine

“…39 Next is a perspective on the scientific, practical, and governmental regulatory expectations for such efforts. 40 The body of the issue comprises fourteen articles describing constructs that can serve as in vitro models for bone and cartilage, 41 brain, 42 gastrointestinal tract, 43;44 lung, 45 liver, 46;47 microvasculature, 48 reproductive tract, 49 skeletal muscle, 50 and skin, 51 as well as the interconnection of organs-on-chips to support physiologically based pharmacokinetics 52 and anticancer drug screening. 53 These research areas will eventually benefit from microscale technologies that regulate stem cell differentiation.…”