Research

Research > Research areas > Cell Adhesion and Cancer

Cell Adhesion and Cancer

Group leader

Johanna Ivaska, Academy of Finland Researcher
VTT Medical Biotechnology
johanna.ivaska [at] vtt.fi

Contact information

Turku Centre for Biotechnology
P.O. Box 123, Biocity
(Street adr. Tykistökatu 6 B)
FIN-20521 Turku, Finland

Background

Invasive and metastatic behaviour of malignant cells is the major cause of mortality in all cancer patients. Migration of cancer cells is critically regulated by physical adhesion of cells to each other and to their non-cellular surroundings (i.e. extracellular matrix). Cell-matrix interactions are mediated by a class of proteins called the integrins. Adhesion dependent migration in tissue is a prerequisites for lymphatic or hematogenous cancer cell dissemination. Epithelial tissue is the source of more than 80% of human cancers and epithelial-to-mesenchymal transition (EMT), where epithelial cells loose polarization is an important event during tumor progression and metastasis. Integrin mediated adhesion regulates in part epithelial cell polarity. The endo-exocytic traffic of integrins is important for directional cell motility of transformed cells. However, the molecular mechanisms regulating this process are still poorly characterized. In addition, it is unknown whether integrin traffic plays a role in the homeostasis of epithelial cells and if alterations in integrin traffic are necessary for cell transformation to occur

In the past few years, we have performed genome-wide screens to identify integrin-binding intracellular proteins and HTS RNAi screens to investigate regulators of integrin activity and endocytosis. The novel protein-protein interactions studied thus far regulate receptor tyrosine kinase (RTK) signalling and cell proliferation as well as integrin traffic and motility of cancer cells.

Our RNAi screens have highlighted SHARPIN as a novel inhibitor of integrin activity in vitro and in vivo. Our aim is to extend our studies on SHARPIN to better understand the exact molecular mechanism of SHARPIN mediated integrin inhibition and its biological role in human cancer and inflammatory conditions.

We are actively involved in RNAi screens to characterize the molecular mechanisms regulating integrin traffic in different cell types and their relevance to metastasis. Cross-talk between integrins and receptor tyrosine kinases is also an important focus area with respect to endosomal traffic and signalling of the integrins and RTKs.

In addition, we have recently studied in detail cell migration and EMT. We have shown that a novel interaction between a5 integrin and ZO-1 tight junction protein functions in the lamellipodia of transformed cells to support cell migration and EMT in vitro and in vivo. We have also investigated the role of mesenchymal protein vimentin in EMT.

Group Members

Johanna Ivaska (PI), Elina Mattila (Post-doc), Stefan Veltel (Post-doc), Jeroen Pouwels (Post-doc), Ghaffar Muharram (Post-doc), Saara Tuomi (Post-doc-maternity leave), Antti Arjonen (PhD student), Anja Mai (PhD student), Gunilla Högnäs (PhD student), Reetta Virtakoivu (PhD student), Jonna Alanko (PhD student), Nicola De Franceschi (PhD student), Riina Kaukonen (PhD student), Jenni Siivonen (Technician), Laura Lahtinen (Technician) Markku Saari (Microscopy expert)

: From left to right: Back: Antti Arjonen, Jeroen Pouwels, Jarkko Heiskanen, Saara Tuomi, Elina Mattila, Stefan Veltel, Gunilla Högnäs, Laura Lahtinen, Jonna Nevo, Anja Mai; Front: Ghaffar Muharram, Johanna Ivaska and Reetta Virtakoivu

Projects

Selected Publications

Mattila E., Pellinen, T., Nevo, J., Vuoriluoto, K. Arjonen, A. and Ivaska, J (2005) Negative regulation of EGFR signalling via integrin a1b1-mediated activation of protein tyrosine phosphatase TCPTP. Nature Cell Biol. 7:78-85.

Pellinen T, Arjonen A, Vuoriluoto K, Kallio K, Fransen JA, Ivaska J. (2006) Small GTPase Rab21 regulates cell adhesion and controls endosomal traffic of beta1-integrins. J. Cell Biol. 173:767-80.

Pellinen T., Tuomi, S., Arjonen, A., Wolf, M., Edgren, H., Meyer, H., Grosse, R., Kitzing, T., Rantala, JK., Kallioniemi O., Fässler, R., Kallio, M., and Ivaska, J. (2008) Integrin traffic regulated by Rab21 is necessary for cytokinesis. Dev. Cell, 15:371-385.

Tuomi, S., Mai, A., Nevo, J., Laine, JO, Vilkki, V., Öhman, TJ., Gahmberg, CG., Parker, PJ. and Ivaska, J. (2009) PKCe Regulation of an a5 Integrin–ZO-1 Complex Controls Lamellae Formation in Migrating Cancer Cells. Science Signaling, 2(77): ra32

Nevo, J., Mai, A., Tuomi, S., Pellinen, T., Pentikäinen, O.T., Heikkilä, P., Lundin, J., Joensuu, H.,Bono, P.and Ivaska, J. (2010) Mammary derived growth inhibitor (MDGI) interacts with integrin α-subunits and suppresses integrin activity and invasion. Oncogene. 29:6452-63

Vuoriluoto, K., Haugen, H., Kiviluoto, S., Mpindi, J-P, Nevo, J., Gjerdrum, C., Lorens, J.B. and Ivaska, J.(2011) Vimentin regulates EMT induction and migration by governing Axl expression in breast cancer. Oncogene. 30(12):1436-1448.

Mai, A., Veltel, S., Pellinen, T., Padzik, A., Coffey, E., Marjomäki, V. and Ivaska, J. (2011)Competitive binding of Rab21 and p120RasGAP to integrins regulates receptor trafficking in migrating cancer cells. J. Cell Biol. 194:291-306.

Rantala, J.K., Pouwels, J., Pellinen, T., Veltel, S., Laasola, P., Mattila, E., Potter, C., Duffy, T., Sundberg, J.P., Askari, J.A.-. Humphries, M., Kallioniemi, O., Parsons, M., Salmi, M. and Ivaska, J. (2011) Sharpin is an endogenous inhibitor of beta1-integrin activation. Nature Cell. Biol.

Pellinen, T., Rantala, J.K., Arjonen, A., Mpindi, J-P., Kallioniemi, O. and Ivaska, J. (2011) A functional genetic screen reveals new regulators of b1-integrin activity. In press J. Cell. Sci.