Division of Molecular thoracic Oncology

Prof. Dr. Rocio Sotillo

Primary lung epithelial cells from TetO-Mad2/CCSP-rtTA/H2B-GFP mice grown in 3D culture. Overexpression of Mad2 arrests cells in mitosis and leads to chromosome missegregation.
© dkfz.de

The Cooperation Unit Molecular Thoracic Oncology is a research collaboration with the Thoraxklinik within the Medical Faculty of Heidelberg University. Our main interest is to understand the molecular basis of lung tumor development and drug resistance. Chromosomal instability (CIN), the inability to correctly segregate sister chromatids during mitosis, is a hallmark of cancer cells. CIN is also associated with poor survival and therapeutic outcome in a number of malignancies, including lung cancer.
We discovered that overexpression of the mitotic checkpoint protein Mad2, commonly found in human tumors, leads to CIN and the development of aneuploid tumors in mouse models. In addition, CIN can facilitate escape from oncogene addiction (the dependence of tumor cells on their initiating lesion for survival) and may be responsible for tumor relapse after targeted therapies. These observations highlight early genetic instability and intra-tumor heterogeneity as cardinal characteristics of human cancer with key importance for efforts to control disease and overcome therapy resistance. However, very little is known about the mechanism of how and when CIN promotes tumor relapse. Using a combination of mouse genetics and highly innovative 3D in vitro culture systems, our lab focuses on understanding the molecular mechanisms that lead to CIN and the consequences it may have in tumor initiation, suppression and relapse.

The overall goal of the lab is to develop new mouse models that combine chromosomal instability with other genes that are known to be important in lung tumorigenesis. These models will serve to further our understanding of the role of CIN in tumor progression and relapse and identify new mechanisms of resistance to therapies. How CIN influences the response to these therapies will be crucial to determine the most efficient way of combating lung cancer. These animal models will also serve as preclinical models to study the most efficient combinational therapies in lung cancer.

Contact

Prof. Dr. Rocio Sotillo
Molecular thoracic Oncology (B220)
Deutsches Krebsforschungszentrum
Im Neuenheimer Feld 280
69120 Heidelberg
Tel: +49 6221 423691

Selected Publications

  • Rowald K, Mantovan M, Passos, J, Buccitelli C, Mardin BR, Korbel JO, Jechlinger M, Sotillo R.(2016) Negative selection and chromosome instability induced by Mad2 overexpression delay breast cancer but facilitate oncogene-independent outgrowth. Cell Rep.15(12): 2679-91.
  • Sotillo, R., Hernando, E., Diaz-Rodriguez, E., Teruya-Feldstein, J., Cordon-Cardo, C., Lowe, S.W., Benezra, R. (2007). Mad2 overexpression promotes aneuploidy and tumorigenesis in mice. Cancer Cell 1, 9-23.
  • Schvartzman, J.M., Duijf, P.H., Sotillo, R., Coker, C., Benezra, R. (2011). Mad2 is a critical mediator of the chromosome instability observed upon Rb and p53 pathway inhibition. Cancer Cell 19, 701-14.
  • Sotillo, R., Schvartzman, J.M., Socci, N.D., Benezra, R. (2010). Mad2-induced chromosome instability leads to lung tumor relapse after oncogene withdrawal. Nature 464, 436-440.
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