Transcriptional control in lymphatic vascular development and cancer
We are interested in the transcriptional regulation of cell differentiation and the role of transcription factors in human diseases, such as cancer and lymphedema.
One of our projects deals with the mechanisms of cancer progression. The initiating events, such as loss of APC in colon cancer, frequently lead to the development of benign tumors, and in humans many years are required for the transition towards the malignant phenotype. We have shown recently that a transcription factor PROX1 plays an important role in this process via the regulation of cell adhesion and polarity program. We believe that this knowledge is important for our understanding of gastro-intestinal cancers and could provide novel targets for therapy in these diseases. We are currently working on the mechanistic understanding of PROX1-regulated transcriptional network in cancer and producing mouse models, which will be used to characterize normal and cancer intestinal progenitor and stem cells.
Second project concerns the mechanisms of lymphatic vascular development and remodelling. The lymphatic vascular system plays important roles in the removal of interstitial fluid, antigen presentation and the uptake of dietary fat. Damaged or absent lymph vessels lead to tissue swelling or lymphedema. Our main goal is to understand the processes of lymphatic vascular remodelling and formation of the mature lymphatic vascular network comprising capillaries and collecting vessels. We are studying the fork head transcription factor FOXC2, which plays an important role in specifying collecting or capillary lymphatic vessel type in mammals. FOXC2 occurs in a mutated form in humans with the hereditary lymphatic vessel disease lymphoedema-distichiasis (LD). LD is characterized by late onset swelling of the legs and a double row of eyelashes (distichiasis), which is sometimes combined with cardiovascular or other defects. In addition, we have recently discovered that NFAT/calciuneurin pathway contributes to lymphatic vascular development. Current research in the lab focuses on identification of FOXC2 target genes, analysis of in vivo models with tissue-specific inactivation of NFAT/calcineurin pathway and functional characterization of novel regulators of (lymph)angiogenesis.
Methods: mouse molecular genetics, ex-vivo organ culture, molecular imaging, gene expression profiling, genome wide ChIP-chip and ChIP-seq
Key words: transcription, differentiation, cancer stem cells, intestinal and vascular development, lymphedema, cancer
Kari Alitalo, University of Helsinki, Finland
Mauro Delorenzi, Swiss Institute of Bioinformatics, Lausanne, Switzerland
Stefan Schulte-Merker, Hubrecht Institute, Netherlands
Seppo Ylä-Herttuala, University of Kuopio, Finland
Selected publications :
Norrmén, C., Ivanov, K.I., Cheng, J., Zangger, N., Delorenzi, M., Jaquet, M., Miura, N., Puolakkainen, P., Horsley, V., Hu, J., Augustin, H.G., Ylä-Herttuala, S., Alitalo, K. & Petrova, T.V. FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1 (2009). J. Cell. Biol., 185, 439-57
Petrova, T.V.*, Nykänen, A., Norrmén,C., Ivanov, K.I., Andersson, L.C., Haglund, C., Puolakkainen, P.,Wempe, F., von Melchner, H., Gradwohl, G., Vanharanta, S., Aaltonen, L.A., Saharinen, J., Gentile, M., Clarke, A., Taipale, J., Oliver, G., & Alitalo, K.* (2008) Homeobox transcription factor PROX1 induces progression of colon cancer by promoting the transition from benign to highly dysplastic phenotype, Cancer Cell, 13, 407-19
Alitalo, K., Tammela,T., and Petrova T.V. (2005) Lymphangiogenesis in development and human disease. Nature, 38, 946-953