title: 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 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.
authors.affiliation: Departments of Pathology, Cell Biology, Pharmaceutical Sciences, and Bioengineering, and the McGowan Institute for Regenerative Medicine, University of Pittsburgh and Pittsburgh VA Health System, Pittsburgh, PA 15213, USA.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Clark
authors.affiliation: Departments of Pathology, Cell Biology, Pharmaceutical Sciences, and Bioengineering, and the McGowan Institute for Regenerative Medicine, University of Pittsburgh and Pittsburgh VA Health System, Pittsburgh, PA 15213, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Wheeler
authors.affiliation: Departments of Pathology, Cell Biology, Pharmaceutical Sciences, and Bioengineering, and the McGowan Institute for Regenerative Medicine, University of Pittsburgh and Pittsburgh VA Health System, Pittsburgh, PA 15213, USA.
authors.forename: Donald P
authors.initials: DP
authors.lastname: Taylor
authors.affiliation: Departments of Pathology, Cell Biology, Pharmaceutical Sciences, and Bioengineering, and the McGowan Institute for Regenerative Medicine, University of Pittsburgh and Pittsburgh VA Health System, Pittsburgh, PA 15213, USA.
authors.forename: Venkateswaran C
authors.initials: VC
authors.lastname: Pillai
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02319, USA.
authors.forename: Carissa L
authors.initials: CL
authors.lastname: Young
authors.affiliation: Charles Stark Draper Laboratory, Cambridge, MA 02139, USA.
authors.forename: Rachelle
authors.initials: R
authors.lastname: Prantil-Baun
authors.affiliation: Charles Stark Draper Laboratory, Cambridge, MA 02139, USA.
authors.forename: Transon
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Departments of Pathology, Cell Biology, Pharmaceutical Sciences, and Bioengineering, and the McGowan Institute for Regenerative Medicine, University of Pittsburgh and Pittsburgh VA Health System, Pittsburgh, PA 15213, USA.
authors.forename: Donna B
authors.initials: DB
authors.lastname: Stolz
authors.affiliation: Charles Stark Draper Laboratory, Cambridge, MA 02139, USA.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Borenstein
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02319, USA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Lauffenburger
authors.affiliation: Departments of Pathology, Cell Biology, Pharmaceutical Sciences, and Bioengineering, and the McGowan Institute for Regenerative Medicine, University of Pittsburgh and Pittsburgh VA Health System, Pittsburgh, PA 15213, USA.
authors.forename: Raman
authors.initials: R
authors.lastname: Venkataramanan
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02319, USA.
authors.forename: Linda G
authors.initials: LG
authors.lastname: Griffith
authors.affiliation: Departments of Pathology, Cell Biology, Pharmaceutical Sciences, and Bioengineering, and the McGowan Institute for Regenerative Medicine, University of Pittsburgh and Pittsburgh VA Health System, Pittsburgh, PA 15213, USA wellsa@upmc.edu.
authors.forename: Alan
authors.initials: A
authors.lastname: Wells
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018929:Cell Culture Techniques / Q000295:instrumentation / Q000379:methods; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor / Q000295:instrumentation / Q000379:methods; D005260:Female; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D008954:Models, Biological; D009362:Neoplasm Metastasis; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents
keywords: Micrometastasis; chemotherapeutics; liver; mammary carcinoma