Complex Cell- and Tissue Culture Models for High Content Screening & Drug Discovery

​Description of Research

Our laboratory aims for the development of complex, three-dimensional cell and tissue culture techniques that recapitulate the architecture of solid cancers. The focus is on tumor-host interactions, like communication between cancer and stromal cells (tumor microenvironment TME), and the ex-tracellular matrix (ECM). Both cell lines and primary cell cultures, extracted from patient biopsies, are used to recreate tissue structures in vitro as miniaturized microtissues. These are optimized for high content screening in early stage drug discovery, lead development, and functional validation of diagnostic or prognostic biomarkers. They mimic multicellular processes such as epithelial differenti-ation and maturation, cell motility and tumor invasion. Many of these dynamic effects are the result of tumor cell plasticity, leading to spontaneous transformation of differentiated into de-differentiated and increasingly aggressive states; including EMT (epithelial to mesenchymal transition). Based on microscopic imaging and automated image analysis tools, we have developed phenotypic assays that quantitatively address short- or long-term effects of small-molecule inhibitors, biologicals (peptides and antibodies), siRNAs and miRNAs on tissue architecture and invasive properties. To monitor tumor cell motility and invasion and assess the effects of tumor-stroma interactions on the aggressive behavior of cancers, specific assays simultaneously track the movement of both tumor and stromal cells into the surrounding ECM. We further study the molecular mechanisms and signaling pathways involved in invasion, including GPCR- and transcription factor signaling on organization and function of the actin cytoskeleton. To meet the analytic demands for these complex data, considerable effort has been placed into developing efficient, robust and automated image analysis methodology. The adapted approaches encompass the complete analysis chain from image processing with machine vision methods, to the statistical modeling of the drug effects based on biologically relevant morphometric features. In combination, these tools allow us to explore highly relevant model systems in phenotypic high content screens.

List of Personnel

Mervi Toriseva, PhD
Johanna Björk, PhD
Malin Åkerfelt, PhD
Ilmari Ahonen, MSc, doctoral candidate
Sean Robinson, MSc, doctoral candidate (jointly with CEA Grenoble/France)
Maria Laura Bellone, BSc, MSc candidate and Erasmus exchange student
Former lab members:
Ville Härmä, PhD; Mari Björkman, PhD;  Johannes Virtanen, technician

Selected Publications

Åkerfelt M, Bayramoglu N, Robinson S, Toriseva M, Schukov HP, Härmä V, Virtanen J, Sormunen R, Kaakinen M, Kannala J, Eklund L, Heikkilä J, Nees M.: Automated tracking of tumor-stroma morphology in microtissues identifies functional targets within the tumor microenvironment for therapeutic in-tervention. Oncotarget. 2015 Oct 6;6(30):30035-56.

Björk JK, Åkerfelt M, Joutsen J, Puustinen MC, Cheng F, Sistonen L, Nees M.: Heat-shock factor 2 is a suppressor of prostate cancer invasion. Oncogene. 2015 Jun 29.

Härmä V, Haavikko R, Virtanen J, Ahonen I, Schukov HP, Alakurtti S, Purev E, Rischer H, Yli-Kauhaluoma J, Moreira VM, Nees M, Oksman-Caldentey KM.: Optimization of Invasion-Specific Effects of Betulin Derivatives on Prostate Cancer Cells through Lead Development.
PLoS One. 2015 May 12;10(5):e0126111.

Härmä V, Schukov HP, Happonen A, Ahonen I, Virtanen J, Siitari H, Åkerfelt M, Lötjönen J, Nees M. (2014): Quantification of dynamic morphological drug responses in 3D organotypic cell cultures by automated image analysis. PLoS One (2014) 9:e96426.

Härmä V, Knuuttila M, Virtanen J, Mirtti T, Kohonen P, Kovanen P, Happonen A, Kaewphan S, Ahonen I, Kallioniemi O, Grafström R, Lötjönen J, Nees M. (2012): Lysophosphatidic acid and sphingosine-1-phosphate promote morphogenesis and block invasion of prostate cancer cells in three-dimensional organotypic models. Oncogene 19;31(16):2075-89.

Björkman M, Östling P, Härmä V, Virtanen J, Mpindi JP, Rantala J, Mirtti T, Vesterinen T, Lundin M, Sankila A, Rannikko A, Kaivanto E, Kohonen P, Kallioniemi O, Nees M: Systematic knockdown of epigenetic enzymes identifies a novel histone demethylase PHF8 overexpressed in prostate cancer with an impact on cell proliferation, migration and invasion. Oncogene. 2012 Jul 19;31(29):3444-56.

Härmä, V., Virtanen, J., Mäkelä, R.; Happonen, A.; Mpindi, J.P.; Knuuttila, M.; Kohonen, P.; Lötjönen, J.; Kallioniemi, O.; Nees, M. (2010): A comprehensive panel of three-dimensional models for studies of prostate cancer growth, invasion and drug responses. PloS One 5, 5 e10431