The vast majority of cell-based assays used for testing cancer drug efficacy are based on growing cells as two-dimensional (2D) monolayers on plastic, or as three-dimensional (3D) floating spheroids in suspension. The challenge is to develop cell culture models that better resemble cancer tissues, and more faithfully recapitulate the complex architecture of tumors in vivo. The major difficulty when developing cancer therapeutics is the limited availability of biologically relevant and predictive in vitro models for chemosensitivity tests, target validation and high content phenotypic screening.
These results highlight the advantage of our approach, which recapitulates tumor histology and can significantly improve cancer target validation in vitro. This complex phenotype was not detected in other standard in vitro models. focal adhesion kinase (FAK) inhibitors specifically blocked tumor growth and invasion concurrently with fibroblast spreading and motility. Interestingly, certain inhibitors selectively disrupted tumor-CAF interactions, e.g. We utilized the platform to determine the efficacy of inhibitors in prostate cancer and the associated tumor microenvironment as a functional unit. Tracking of fibroblast dynamics revealed that CAFs guided the way for tumor cells to invade and increased the growth and invasiveness of tumor organoids. The platform consists of microtissues from prostate cancer cells, combined with CAFs in extracellular matrix that allows biochemical perturbation.
Here, we have developed a novel automated pipeline to model tumor-stroma interplay, track motility and quantify morphological changes of 3D co-cultures, in real-time live-cell settings. Although the importance of including CAFs into three-dimensional (3D) cell cultures has been acknowledged, computational support for quantitative live-cell measurements of complex cell cultures has been lacking. Received: MaAccepted: AugPublished: September 03, 2015Ĭancer-associated fibroblasts (CAFs) constitute an important part of the tumor microenvironment and promote invasion via paracrine functions and physical impact on the tumor.
Keywords: 3D co-culture, cancer associated fibroblast (CAF), phenotypic screening, invasion, focal adhesion kinase (FAK) Malin Åkerfelt 1, 2, Neslihan Bayramoglu 3, Sean Robinson 4, 5, 6, 7, Mervi Toriseva 1, 2, 8, Hannu-Pekka Schukov 8, Ville Härmä 2, Johannes Virtanen 2, Raija Sormunen 9, Mika Kaakinen 10, Juho Kannala 3, Lauri Eklund 10, Janne Heikkilä 3, Matthias Nees 1, 2ġTurku Centre for Biotechnology, University of Turku, Turku, FI-20520, FinlandĢVTT Technical Research Centre of Finland, Turku, FI-20521, FinlandģCentre for Machine Vision Research, University of Oulu, Oulu, FI-90014, FinlandĤDepartment of Mathematics and Statistics, University of Turku, Turku, FI-20014, FinlandĥUniversity Grenoble Alpes, iRTSV-BGE, Grenoble, F-38000, FranceĦCEA, iRTSV-BGE, Grenoble, F-38000, FranceĨInstitute of Biomedicine, University of Turku, Turku, FI-20520, FinlandĩBiocenter Oulu and Department of Pathology, University of Oulu and Oulu University Hospital, Oulu, FI-90220, Finlandġ0Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, FI-90014, Finland
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