Division of Viral Transformation Mechanisms

Prof. Dr. Frank Rösl

A) Induction of autophagy (red) in HPV immortalized human keratinocytes (blue: stained nuclei). B) Mitochondria staining in primary keratinocytes (Green)
Courtesy of Dr. B. Rincon Orozco (F030)
© dkfz.de

  1. Mechanisms of human papillomavirus (HPV)-induced carcinogenesis: Here we are investigating how transcription and viral RNA splicing of high-risk HPV is regulated during the different steps towards malignant transformation. Another focus is on the function of epigenetic mechanisms (e.g. de novo methylation, nucleosomal organization) in HPV-positive cells and their impact on viral-host interaction during persistence.

  2. Immunological surveillance: In this context, we are studying the interferon/chemokine pathway to understand the innate response against viral and bacterial infections. Moreover, with respect to the role of inflammation in cancer, we are examining the function of individual HPV oncoproteins on the NALP3 inflammasome.

  3. A natural rodent model system for papillomavirus (PV)-induced skin cancer: In this project we study the whole infection pathway, starting from primary infection until the final manifestation of a skin tumor in molecular and serological terms. We have also developed a “virus-like particle” (VLP) based vaccine to prevent PV-induced skin lesions. This vaccine is efficient both under normal and immunocompromised conditions and may provide the basis for the clinical development of potent immunization strategies against cutaneous HPV infections and HPV-induced tumors, especially in patients awaiting organ transplantation.

  4. Virus-Cell Interactome: Considering a cell as a functional regulatory network, tumorviruses always attack central hubs to overcome intracellular surveillance. It is therefore necessary to understand these viral-host interactions using both systems biology approaches and high-throughput strategies. In particular, potential co-infections (e.g. with bacteria), their communication pathways and cross-talks are under investigation.

FUTURE OUTLOOK

Besides the current projects which will be followed up in greater detail, we will focus our future interest on the following topics:

  1. Metabolism and cancer: Here we will especially determine the function of viral oncoproteins on the metabolic pathway. We have already mapped the regulatory region of the LKB1 tumor suppressor gene, a central master kinase that controls the intracellular energy status. This gene is found to be dysregulated in HPV-positive cells. We have also dissected the mechanism whereby tumor cells sense their own metabolism. We will further analyze the innate immune response under hypoxic and energy-deprived conditions.

  2. Cellular escape mechanisms: This study aims to understand the spatial and temporal interaction of immunological effector cells of the innate defense system with non-tumorigenic HPV-positive cells, in direct comparison with their tumorigenic counterparts in immunocompromised animals. In addition, we designed experiments that allow for the characterization of genes and intracellular regulatory pathways in transplanted HPV-positive cells responsible for tumor suppression.

  3. Resistance mechanisms: Cancer cells are robust and highly adaptive against various therapeutic approaches. Although most of the tumor mass can be eradicated in vivo and in vitro, there are still cells which survive. Whether these represent cancer stem cells will be studied in further detail.

Contact

Prof. Dr. Frank Rösl
Viral Transformation Mechanisms (F030)
Tel: +49 6221 42 4900

Selected Publications

  • Hasche D, Stephan S, Braspenning-Wesch I, Mikulec J, Niebler M, Gröne H-J, Flechtenmacher C, Akgül B, Rösl F, and Vinzón SE (2017). The Interplay of UV and Cutaneous Papillomavirus Infection in Non-Melanoma Skin Cancer Development in the animal model Mastomys coucha. PLoS Pathog 13(11): e1006723. doi: 10.1371/journal.ppat.1006723 [in press].
  • Higareda-Almaraz JC, Ruiz-Moreno JS, Klimentova J, Barbieri D, Salvador-Gallego R, Ly R, Valtierra-Gutierrez IA, Dinsart C, Rabinovich GA, Stulik J, Rösl F, Rincon-Orozco B. (2016). Systems-level effects of ectopic galectin-7 reconstitution in cervical cancer and its microenvironment. BMC Cancer. 2016 Aug 24;16:680. doi: 10.1186/s12885-016-2700-8.
  • Niebler, M., Qian, X., Höfler, D., Kogosov, V., Kaewprag, J., Kaufmann, A.M., Ly, R., Böhmer, M., Zawatzky, R., Rösl, F., and Rincon-Orozco, B. (2013). Post-Translational Control of IL-1? via the Human Papillomavirus Type 16 E6 Oncoprotein: A Novel Mechanism of Innate Immune Escape Mediated by the E3-Ubiquitin Ligase E6-AP and p53. PLoS Pathogens, DOI: 10.1371/journal.ppat.1003536.
  • Vinzon, S.E., Braspenning-Wesch, I., Müller, M., Geissler, E.K., Nindl, I., Gröne, H-J., Schäfer, K., and Rösl, F. (2014). Protective Vaccination against Papillomavirus-Induced Skin Tumors under Immunocompetent and Immunosuppressive Conditions: A Preclinical Study Using a Natural Outbred Animal Model. PLoS Pathogens, Feb 20; 10 (2): e1003924.
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