Medical University of Vienna
Institute for Cancer Research (Head)
Department of Medicine IBorschkegasse 8a
1090 Vienna, Austria
Phone: +43 1 40160-57502
Fax: +43 1 40160-957502
» Website; » Sibilia-Lab
Our laboratory is interested in understanding the molecular mechanisms leading to inflammatory diseases and cancer using the mouse as a model system. We investigate the cell-specific role of EGFR signaling in cancer and tumor stromal cells and their complex interaction. Moreover, we aim to understand how inflammatory cells affect tumor development and regression and exploit novel concepts to modulate tumors to become more sensitive to current anti-cancer treatments. The ultimate goal is to translate this knowledge to patients to develop more effective personalized treatments for human cancer.
Role of EGFR positive myeloid cells in Ras-mediated resistances.
Metastatic colorectal cancer (CRC) patients are treated with chemotherapy combined with targeted anti-EGFR therapy whereby the presence of a mutated Ras/Raf is a negative predictive biomarker for therapy response. We have recently found that the EGFR is upregulated in myeloid cells infiltrating human CRC samples and that the presence of these cells is associated with poor prognosis in patients. By employing GEMMs, we demonstrated that, EGFR deletion in myeloid cells impaired CRC development, whereas EGFR deletion in tumor cells did not reduce tumor growth.
Supposing that tumor cells are not the primary targets responding to anti-EGFR treatment in CRC, it is unclear why the presence of oncogenic mutations in tumor cells confer resistance to anti-EGFR therapies. This projects will therefore aim at elucidating how the presence of Ras mutations affect the composition of the tumor microenvironment focusing on the role of EGFR positive tumor-associated myeloid cells. We will employ genetically engineered CRC organoids and mouse models of CRC. The results of these experiments will not only be important for a better understanding of the mechanism of action of targeted anti-EGFR drugs and related resistances, but also to provide better stratification parameters predicting response to anti-EGFR treatment considering that 50% of eligible patients still do not respond to this treatment.
- Linder M, Glitzner E, Srivatsa S, Bakiri L, Matsuoka K, Shahrouzi P, Dumanic M, Novoszel P, Mohr T, Langer O, Wanek T, Mitterhauser M, Wagner EF, Sibilia M. EGFR is required for FOS-dependent bone tumor development via RSK2/CREB signaling. EMBO Mol Med. 2018 Nov;10(11). pii: e9408. doi: 10.15252/emmm.201809408.
- Srivatsa S, Paul MC, Cardone C, Holcmann M, Amberg N, Pathria P, Diamanti MA, Linder M, Timelthaler G, Dienes HP, Kenner L, Wrba F, Prager GW, Rose-John S, Eferl R, Liguori G, Botti G, Martinelli E, Greten FR, Ciardiello F, Sibilia M. EGFR in Tumor-Associated Myeloid Cells Promotes Development of Colorectal Cancer in Mice and Associates With Outcomes of Patients. Gastroenterology. 2017 Jul;153(1):178-190.e10. doi: 10.1053/j.gastro.2017.03.053.
- Lanaya, H., A. Natarajan, K. Komposch, L. Li, N. Amberg, L. Chen, S. K. Wculek, M. Hammer, R. Zenz, M. Peck-Radosavljevic, W. Sieghart, M. Trauner, H. Wang, and M. Sibilia. 2014. EGFR has a tumour-promoting role in liver macrophages during hepatocellular carcinoma formation. Nature cell biology 16: 972-981, 971-977.
- Lichtenberger, B. M., P. A. Gerber, M. Holcmann, B. A. Buhren, N. Amberg, V. Smolle, H. Schrumpf, E. Boelke, P. Ansari, C. Mackenzie, A. Wollenberg, A. Kislat, J. W. Fischer, K. Rock, J. Harder, J. M. Schroder, B. Homey, and M. Sibilia. 2013. Epidermal EGFR controls cutaneous host defense and prevents inflammation. Science translational medicine 5: 199ra111.
- Drobits, B., M. Holcmann, N. Amberg, M. Swiecki, R. Grundtner, M. Hammer, M. Colonna, and M. Sibilia. 2012. Imiquimod clears tumors in mice independent of adaptive immunity by converting pDCs into tumor-killing effector cells. The Journal of clinical investigation 122: 575-585.
- Lichtenberger, B. M., P. K. Tan, H. Niederleithner, N. Ferrara, P. Petzelbauer, and M. Sibilia. 2010. Autocrine VEGF signaling synergizes with EGFR in tumor cells to promote epithelial cancer development. Cell 140: 268-279.