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 envents, 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 PR0X1 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 netword 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 netword 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/calcineurin pathway contributes to lymphatic vascular development. Current research in the lab focuses on identificaion 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.
Mouse molecular genetics, ex-vivo organ culture, molecular imaging, gene expression profiling, genome wide ChIP-chip and ChIP-seq.
Transcription, differentiation, cancer stem cells, intestinal and vascular development, lymphedema, cancer.
Full list of publications
- Ivanov KI, Agalarov Y, Valmu L, Samuilova O, Liebl J, Houhou N, Maby-El Hajjami H, Norrmén C, Jaquet M, Miura N, Zangger N, Ylä-Herttuala S, Delorenzi M, Petrova TV. Phosphorylation Regulates FOXC2-Mediated Transcription in Lymphatic Endothelial Cells. Mol Cell Biol. 2013 Oct;33(19):3749-61. doi: 10.1128/MCB.01387-12. Epub 2013 Jul 22.
- Norrmén C, Ivanov KI, Cheng J, Zangger N, Delorenzi M, Jaquet M, Miura N, Puolakkainen P, Horsley V, Hu J, Augustin HG, Ylä-Herttuala S, Alitalo K, Petrova TV. FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1. J Cell Biol. 2009 May 4;185(3):439-57. doi: 10.1083/jcb.200901104. Epub 2009 Apr 27.
- Petrova TV*, Nykänen A, Norrmén C, Ivanov KI, Andersson LC, Haglund C, Puolakkainen P, Wempe F, von Melchner H, Gradwohl G, Vanharanta S, Aaltonen LA, Saharinen J, Gentile M, Clarke A, Taipale J, Oliver G, Alitalo K*. Transcription factor PROX1 induces colon cancer progression by promoting the transition from benign to highly dysplastic phenotype. Cancer Cell. 2008 May;13(5):407-19. doi: 10.1016/j.ccr.2008.02.020.
- Alitalo K, Tammela T, Petrova TV. Lymphangiogenesis in development and human disease. Nature. 2005 Dec 15;438(7070):946-53.
Kari Alitalo University of Helsinki, Finland
Mauro Delorenzi Swiss Institute of Bioinformatics in Lausanne, Switzerland
Stefan Schulte-Merker Hubrecht Institute, Netherlands
Seppo Ylä-Herttuala University of Kuopio, Finland