title: All-human microphysical model of metastasis therapy.
abstract: The vast majority of cancer mortalities result from distant metastases. The metastatic microenvironment provides unique protection to ectopic tumors as the primary tumors often respond to specific agents. Although significant interventional progress has been made on primary tumors, the lack of relevant accessible model in vitro systems in which to study metastases has plagued metastatic therapeutic development--particularly among micrometastases. A real-time, all-human model of metastatic seeding and cancer cells that recapitulate metastatic growth and can be probed in real time by a variety of measures and challenges would provide a critical window into the pathophysiology of metastasis and pharmacology of metastatic tumor resistance. To achieve this we are advancing our microscale bioreactor that incorporates human hepatocytes, human nonparenchymal liver cells, and human breast cancer cells to mimic the hepatic niche in three dimensions with functional tissue. This bioreactor is instrumented with oxygen sensors, micropumps capable of generating diurnally varying profiles of nutrients and hormones, while enabling real-time sampling. Since the liver is a major metastatic site for a wide variety of carcinomas and other tumors, this bioreactor uniquely allows us to more accurately recreate the human metastatic microenvironment and probe the paracrine effects between the liver parenchyma and metastatic cells. Further, as the liver is the principal site of xenobiotic metabolism, this reactor will help us investigate the chemotherapeutic response within a metabolically challenged liver microenvironment. This model is anticipated to yield markers of metastatic behavior and pharmacologic metabolism that will enable better clinical monitoring, and will guide the design of clinical studies to understand drug efficacy and safety in cancer therapeutics. This highly instrumented bioreactor format, hosting a growing tumor within a microenvironment and monitoring its responses, is readily transferable to other organs, giving this work impact beyond the liver.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Wheeler
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Borenstein
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Clark
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Ebrahimkhani
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Fox
authors.forename: Linda
authors.initials: L
authors.lastname: Griffith
authors.forename: Walker
authors.initials: W
authors.lastname: Inman
authors.forename: Douglas
authors.initials: D
authors.lastname: Lauffenburger
authors.forename: Transon
authors.initials: T
authors.lastname: Nguyen
authors.forename: Venkateswaran C
authors.initials: VC
authors.lastname: Pillai
authors.forename: Rachelle
authors.initials: R
authors.lastname: Prantil-Baun
authors.forename: Donna B
authors.initials: DB
authors.lastname: Stolz
authors.forename: Donald
authors.initials: D
authors.lastname: Taylor
authors.forename: Theresa
authors.initials: T
authors.lastname: Ulrich
authors.forename: Raman
authors.initials: R
authors.lastname: Venkataramanan
authors.forename: Alan
authors.initials: A
authors.lastname: Wells
authors.forename: Carissa
authors.initials: C
authors.lastname: Young
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity; D019149:Bioreactors; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D005260:Female; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy / Q000556:secondary*; D046210:Microfluidic Analytical Techniques / Q000295:instrumentation / Q000379:methods; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines