National Center of Competence in Research - NCCR Molecular Oncology

Prof. Tatiana Petrova

Tatiana Petrova received her M.Sc in chemistry from Moscow State Univeristy in 1990 and a Ph.D. in biochemistry from the University of Geneva in 1996. She did a post-doctoral work at Northwestern University in Chicago from 1997 to 1999, and then moved to a second postdoctoral position at the University of Helsinki, Finland. In 2004 she became a group leader at Molecular Cancer Biology Program at the Univerisity of Helsinki, and in 2008 joined the Division of Experimental Oncology at CePO, CHUV and University of Lausanne as an SNF assistant professor.

Division of Experimental Oncology
CePO, CHUV and University of Lausanne

Transcriptional networks in colon and small cell lung cancer

The group of Tatiana Petrova is interested in understanding the mechanistic bases for the cell type- and cancer –specific responses, and using this knowledge to develop novel treatment approaches. More specifically, we focus our efforts on transcription factors, which, as it has been now spectacularly demonstrated in the case of iPS cells, are at the heart of cell decisions to differentiate and to form a specific cell type, or, on the contrary, to acquire the pre-malignant and malignant changes. Transcription factors act by interacting with multiple cis-regulatory regions, in a combinatorial fashion with other transcription factors, and in accordance with a chromatin modification landscapes in a given cell type. One of the major challenges in the field of cancer functional genomics is to understand the changes introduced in these parameters upon oncogenic transformation and how they affect the tumor cell properties, such as cell proliferation, apoptosis, metastasis and interaction with the surrounding stromal cells.

We use mouse models of intestinal tumorigenesis to address these questions, and in the coming years we would like to extend our analysis to other human cancers, for which few therapeutic approaches have been developed so far, such as small cell lung cancer. Colon cancer is an interesting model to study because there is a large body of knowledge regarding the tumor initiating events, such as activation of oncogenic Wnt signaling and acquisition on intestinal stem cell properties, yet our recent results show that with time Wnt program in colon cancer is modified as compared to the one active in normal intestinal stem cells. Better understanding of such cancer-specific responses will be important for the development of targeted approach, which at the same time will spare normal stem cells. In addition to mouse genetics tools, we also employ other methods, such as ChIP-seq, gene expression profiling, and ex-vivo organ cultures.

Figure 1. Increased expression of transcription factor Prox1 (green) is intestinal tApcmin/+ tumor cells from mouse model of familial intestinal polyposis. ß-catenin is stained in red (Petrova et al., Cancer Cell, 2008).

List of publications

Norrmén, C., Vandevelde, W., Ny, A., Saharinen, P., Gentile, M., Haraldsen, G., Puolakkainen, P., Lukanidin, E., Dewerchin, M., Alitalo, K.* & Petrova, T.V.* Liprin ß1 is highly expressed in lymphatic vasculature and is important for lymphatic vessel integrity. *-corresponding authors, Blood, DOI 10.1182/blood-2009-03-212274. (2009)

Mouta-Bellum C, Kirov A, Miceli-Libby L, Mancini ML, Petrova TV, Liaw L, Prudovsky I, Thorpe PE, Miura N, Cantley LC, Alitalo K, Fruman DA, Vary CP. Organ-specific lymphangiectasia, arrested lymphatic sprouting, and maturation defects resulting from gene-targeting of the PI3K regulatory isoforms p85alpha, p55alpha, and p50alpha. Dev Dyn. 238, 2670-9 (2009)

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. J. Cell. Biol., 185, 439-57 (2009)

Kirjavainen, A., Sulg, M., Heyd, F., Alitalo, K., Ylä-Herttuala, S., Möröy, T., Petrova, T.V., Pirvola, U. Prox1 interacts with Atoh1 and Gfi1, and regulates cellular differentiation in the inner ear sensory epithelia. Dev Biol., 322, 33-45 (2008)

Petrova, T.V., Bono, P., Holnthoner,W., Chesnes, J.,Pytowski, B., Sihto, H., Laakkonen, P., Heikkilä, P., Joensuu, H.,&Alitalo, K. VEGFR-3 expression is restricted to blood and lymphatic vessels in solid tumors, Cancer Cell, 13, 554-56 (2008)

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.* Homeobox transcription factor PROX1 induces progression of colon cancer by promoting the transition from benign to highly dysplastic phenotype, Cancer Cell, 13, 407-19 *-corresponding authors (2008)

Tammela T., Saaristo A., Holopainen T., Lyytikkä J., Kotronen A., Pitkonen M., Abo-Ramadan U., Ylä-Herttuala S., Petrova T.V. & Alitalo K. Therapeutic differentiation and maturation of lymphatic vessels after lymph node dissection and transplantation. Nature Medicine, 13, 1458-66. (2007)

Takemoto M, He L, Norlin J, Patrakka J, Xiao Z, Petrova T, Bondjers C, Asp J, Wallgard E, Sun Y, Samuelsson T, Mostad P, Lundin S, Miura N, Sado Y, Alitalo K, Quaggin SE, Tryggvason K, Betsholtz C. Large-scale identification of genes implicated in kidney glomerulus development and function. EMBO J. 25, 1160-74 (2006)

Kreuger J, Nilsson I, Kerjaschki D, Petrova T, Alitalo K, Claesson-Welsh L. Early Lymph Vessel Development From Embryonic Stem Cells. Arterioscler Thromb Vasc Biol., 26,1073-78 (2006)

Baluk, P., Tammela, T., Ator,E., Lyubinskaya, N., Achen, M.G., Hicklin, D.J., Jeltsch, M., Petrova, T.V., Pytkowski, B., Stacker, S.A., Ylä-Herttuala, S.,Jackson, D.G., Alitalo, K., and McDonald, D.M. Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation, J. Clin. Invest., 115, 247-257 (2005)

Petrova TV, Karpanen T, Norrmen C, Mellor R, Tamakoshi T, Finegold D, Ferrell R, Kerjaschki D, Mortimer P, Yla-Herttuala S, Miura N, Alitalo K. Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis. Nature Medicine, 10, 974-981 (2004)

Kerjaschki, D., Regele, H.M., Moosberger, I., Nagy-Bojarski, K., Watschinger, B., Soleiman, A., Birner , P., Krieger, S., Hovorka, A., Silberhumer, G., Laakkonen, P., Petrova, T., Langer, B., Raab, I. Lymphatic neoangiogenesis in human kidney transplants is associated with immunologically active lymphocytic infiltrates. J. Am. Soc Nephrol., 15, 603-12 (2004)

Karkkainen, M. J., Haiko, P., Sainio, K., Partanen, J., Taipale, J., Petrova, T., Jeltsch, M., Jackson, D. G., Talikka, M., Rauvala, H., Betsholtz, C., and Alitalo, K. VEGF-C is required for sprouting of the first lymphatic vessels from embryonic veins. Nature Immunology (journal cover), 5, 74-80 (2004)

Veikkola,T., Lohela, M., Ikenberg, K., Mäkinen, T., Korff, T.,Saaristo, Petrova T., A., Jeltsch,M., Augustin, H.G., and Alitalo, K. Intrinsic versus microenvironmental regulation of lymphatic endothelial cell phenotype and function. FASEB J., 17, 2006-2013 (2004)

Reviews

Maby-El Hajjami H, & Petrova T.V. Developmental and pathological lymphangiogenesis: from models to human disease. Histochem Cell Biol. 130, 1063-78 (2008)

Makinen T, Norrmen C, & Petrova T.V. Molecular mechanisms of lymphatic vascular development. Cell Mol Life Sci., 64, 1915-29 (2007)

Alitalo, K., Tammela,T., and Petrova T.V. Lymphangiogenesis in development and human disease. Nature, 38, 946-953 (2005)

Tammela,T., Petrova T.V., and Alitalo, K. Molecular lymphangiogenesis: new players. Trends Cell Biol. 15, 434-441 (2005)

Saharinen,P., and Petrova T.V. Molecular regulation of lymphangiogenesis, Annals of New York Academy of Sciences, 1014, 76-87 (2004)