title: Molecular deconstruction, detection, and computational prediction of microenvironment-modulated cellular responses to cancer therapeutics.
abstract: The field of bioengineering has pioneered the application of new precision fabrication technologies to model the different geometric, physical or molecular components of tissue microenvironments on solid-state substrata. Tissue engineering approaches building on these advances are used to assemble multicellular mimetic-tissues where cells reside within defined spatial contexts. The functional responses of cells in fabricated microenvironments have revealed a rich interplay between the genome and extracellular effectors in determining cellular phenotypes and in a number of cases have revealed the dominance of microenvironment over genotype. Precision bioengineered substrata are limited to a few aspects, whereas cell/tissue-derived microenvironments have many undefined components. Thus, introducing a computational module may serve to integrate these types of platforms to create reasonable models of drug responses in human tissues. This review discusses how combinatorial microenvironment microarrays and other biomimetic microenvironments have revealed emergent properties of cells in particular microenvironmental contexts, the platforms that can measure phenotypic changes within those contexts, and the computational tools that can unify the microenvironment-imposed functional phenotypes with underlying constellations of proteins and genes. Ultimately we propose that a merger of these technologies will enable more accurate pre-clinical drug discovery.
authors.affiliation: Life Science Division of Lawrence Berkeley National Laboratory, University of California, 1 Cylcotron Rd, MS977, Berkeley, CA 94720, USA. Electronic address: MALabarge@lbl.gov.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Labarge
authors.affiliation: Life Science Division of Lawrence Berkeley National Laboratory, University of California, 1 Cylcotron Rd, MS977, Berkeley, CA 94720, USA. Electronic address: B_Parvin@lbl.gov.
authors.forename: Bahram
authors.initials: B
authors.lastname: Parvin
authors.affiliation: Department of Biomedicine and Center for Cancer Biomarkers, University of Bergen, Jonas Lies vei 91, NO-5020 Bergen, Norway. Electronic address: Jim.Lorens@biomed.uib.no.
authors.forename: James B
authors.initials: JB
authors.lastname: Lorens
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D060833:Cellular Microenvironment / Q000187:drug effects* / Q000502:physiology; D020650:Combinatorial Chemistry Techniques / Q000379:methods / Q000639:trends; D019295:Computational Biology / Q000379:methods* / Q000639:trends; D005544:Forecasting; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D059016:Tumor Microenvironment / Q000187:drug effects* / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents
keywords: Cancer; Computation; Microenvironment; Therapeutic response