National Center of Competence in Research - NCCR Molecular Oncology

Prof. Ivan Stamenkovic

Prof. Ivan Stamenkovic obtained his M.D. from the University of Geneva in 1978. Following a residency in Internal Medicine and a residency in Pathology, he moved to Boston for a post-doctoral fellowship in the laboratory of Dr. Brian Seed in the Department of Molecular Biology at the Massachusetts General Hospital and the Department of Genetics at Harvard Medical School. In 1988, he was appointed Assistant Professor of Pathology at Harvard Medical School and in 1990 he started his own laboratory in the Department of Pathology at the Massachusetts General Hospital, with a joint appointment at the MGH Cancer Center. In 1992 Prof. Stamenkovic was appointed to Associate Professor of Pathology at HMS and Director of the Molecular Pathology Unit within the MGH Cancer Center. In 2001, he accepted a position as Professor of Experimental Pathology at the University of Lausanne, and was nominated Vice-Dean for Research of the Faculty of Biology and Medicine in July 2007. 

Division of Experimental Pathology
Institut Universitaire de Pathologie

The role of the Tumor Stroma

Our group is focusing on understanding mechanisms that underlie transformation and tumor progression. We are particularly interested in the relationship between transformation and genetic reprogramming that leads to the emergence of cancer stem cells. In parallel, we are working on obtaining new insight into how reactive stroma supports primary and secondary tumor survival and growth.

To address the relationship between primary cell transformation and genetic reprogramming, we are using human sarcomas, and particularly Ewing sarcoma family tumors (ESFT), as models. We have shown that primary mouse mesenchymal progenitor cells (MPC) can undergo transformation as a result of expression of the EWS-FLI-1 fusion protein, associated with 85% of ESFT, in the absence of any other potential oncogenic events. These observations have helped identify mesenchymal progenitor cells as candidate cells of origin of ESFT and have uncovered several candidate target genes of the EWS-FLI-1 transcription factor that may be implicated in transformation. We have conducted the same studies on human mesenchymal stem cells (MSC) that have not only confirmed the observations in MPC but that have demonstrated EWS-FLI-1 reprogramming of MSC toward the neuroectodermal lineage, which may explain the dual mesenchymal/neuroectodermal phenotype of Ewing sarcoma cells. More recently, we isolated and characterized ESFT cancer stem cells.

Using both MSC and primary ESFT cancer stem cells, we are studying genetic reprogramming initiated by EWS-FLI-1 that conditions ESFT differentiation and governs MSC permissiveness for oncogene expression. This approach will serve as a model to elucidate the mechanisms whereby oncogenic events reprogram primary cells and endow them with stem cell features.

Our second major focus is on the effect of tumor cells on host tissues and vice-versa. Tumor-host interactions play an essential role in supporting tumor cell survival and growth. Our aim is to determine how tumor-reactive stroma may provide the equivalent of a stem cell niche for cancer stem cells and to elucidate the mechanisms that render a tissue permissive for or resistant to metastatic tumor growth. Using both human and mouse models of tumor invasion and metastasis, we have isolated several genes expressed in the tumor stroma that render host tissues permissive for tumor growth and that help maintain cancer stem cell plasticity. The function and therapeutic targetability of these genes are currently being investigated.

List of publications

Suvà, M-L*, Riggi N*, Janiszewska M., Radovanovic I., Provero P, Stehle J-C., Baumer K, Le Bitoux M-A., Marino D, Cironi L, Marquez VE, Clément V. and Stamenkovic I. EZH2 is essential for glioblastoma cancer stem cell maintenance. Cancer Res., in press (2009)

*Equal contribution

Mario-Luca Suvà*, Nicolò Riggi*, Jean-Christophe Stehle, Karine Baumer, Stéphane Tercier, Jean-Marc Joseph, Domizio Suvà, Virginie Clément, Paolo Provero, Luisa Cironi, Maria-Chiara Osterheld, Louis Guillou and Ivan Stamenkovic. Identification of cancer stem cells in Ewing’s sarcoma. Cancer Res., 69: 1776-1781 (2009)

*Equal contribution

Cironi L, Riggi N, Provero P, Wolf N, Suvà ML, Suvà D, Kindler V, Stamenkovic I. IGF1 is a common target gene of Ewing's sarcoma fusion proteins in mesenchymal progenitor cells. PLoS ONE. Jul 9;3(7):e2634 (2008)

Bacac, M., Provero, P., Stehle, J.-C., and Stamenkovic, I. A stromal gene expression signature in a model of multistage carcinogenesis is predictive of human cancer progression. PloSONE; e pub.Dec 20;1:e32 (2006)

Riggi, N., Cironi, L, Provero, P., Suva, M.L., Stehle, J.C., Baumer, K., Guillou, L., Stamenkovic, I. Expression of the FUS-CHOP fusion protein in primary mesenchymal progenitor cells gives rise to a model of myxoid liposarcoma, Cancer Res., 66(14):7016-23 (2006)

Bacac, M., Migliavacca, E., Mckee, T., Delorenzi, M., Coindre, J.-M., Guillou, L. and Stamenkovic, I. A gene expression signature that distinguishes desmoid tumours from nodular fasciitis, J. Pathol. 208(4):543-53 (2006)

Riggi, N., Cironi, L., Provero P., Suvà, M.L., Kaloulis, K., Garcia-Echeverria, C., Hoffmann, F., Trumpp, A. and Stamenkovic, I. Development of Ewing’s sarcoma from bone-marrow-derived mesenchymal progenitor cells. Cancer Res., 65(24):11459-68 (2005)

Meyer, E., Vollmer, J.Y., Bovey, R., Stamenkovic, I. Matrix metalloproteinases 9 and 10 inhibit protein kinase C-potentiated, p53-mediated apoptosis. Cancer Research, 65(10), 4261-72 (2005)

Lahav, R., Suva, M.L., Rimoldi, D., Patterson, P.H., Stamenkovic I. Endothelin receptor B inhibition triggers apoptosis and enhances angiogenesis in melanomas. Cancer Research 15, 64, 8945-53 (2004)

Yu, Q., Stamenkovic, I. Transforming Growth Factor-beta facilitates breast carcinoma metastasis by promoting tumor cell survival. Clinical & Experimental Metastasis 21, 235-42 (2004)

Fiore, E., Fusco, C., Romero, P., Stamenkovic, I. Matrix metalloproteinase 9 (MMP-9/gelatinase B proteolytically cleaves ICAM-1 and participates in tumor cell resistance to natural killer cell-mediated cytotoxicity. Oncogene 21, 5213-5223 (2002)

Yu, W.H., Woessner, F. Jr., McNeish, J.D., Stamenkovic, I. CD44 regulates female reproductive organ remodelling and anchors the assembly of matrilysin/MMP-7 with heparin-binding epidermal growth factor precursor and ErbB4. Genes and Development 16, 307-323 (2002)

Reviews

LeBitoux, M.-A. and Stamenkovic I. Tumor-host interactions: the role of inflammation. Histochem. Cell Biol.; 130: 1079-1090 (2008)

Bacac M. and Stamenkovic I. Metastatic cancer cell. Annu. Rev. Pathol., 3: 221-247 (2008)

Suva, M-L., Cironi, L., Riggi, N. and Stamenkovic I. Sarcomas: genetics, signaling and cellular origins: Part II. TET-independent fusion proteins and receptor tyrosine kinase mutations. J. Pathol.; 213: 117-130 (2007)

Riggi, N., Cironi, L., Suvà, M.L., Stamenkovic, I. Sarcomas: genetics, signalling, and cellular origins. Part 1: The fellowship of TET. J Pathol. 213(1):4-20 (2007)

Riggi, N. and Stamenkovic I. The biology of Ewing’s sarcoma. Cancer Lett. 254(1):1-10 (2007)

Riggi, N., Suvà, M.L., Stamenkovic, I. Ewing's Sarcoma-Like Tumors Originate from EWS-FLI-1-Expressing Mesenchymal Progenitor Cells. Cancer Res. 66(19):9786 (2006)

Stamenkovic, I. Extracellular matrix remodelling, the role of matrix metalloproteinases. Journal of Pathology 200, 448-64 (2003)