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I. The molecular virus-host interplay in the development of skin cancer in the model Mastomys coucha

Model of the Interplay of MnPV and UV in SCC development. A) Virus replication and virion formation depends on differentiating squamous cells and is favored by UV-induced hyperproliferation. UV induces photoproducts, e.g. in Trp53. In uninfected cells, damages are repaired. In infected cells, MnPV reduces chromosomal stability and inhibits DNA repair. B) Mutations accumulate, altered squamous cells become neoplastic (light blue) and start forming a well-differentiated keratinizing SCC, still representing a permissive system that allows viral replication and formation of virions. C) When neoplastic squamous cells accumulate further mutations (dark blue), a spindle cell phenotype is acquired, forming a poorly differentiated non-keratinizing SCC. MnPV cannot replicate in dedifferentiated cells and viral DNA is subsequently lost. This is the first study providing evidence for a “hit-and-run” mechanism of cutaneous PVs in the development of NMSC. (Modified from Hasche et al. (2017), PloS Pathogens)

Cutaneous human papillomaviruses (HPVs) have been suggested as co-factors in the multi-step process of skin carcinogenesis. Especially immunosuppressed organ transplant recipients suffer from a highly increased risk of developing non-melanoma skin cancer (NMSC), the most frequent cancer in Caucasians.

The rodent Mastomys coucha is naturally and persistently infected with Mastomys natalensis papillomavirus (MnPV), which was shown to be the etiological agent for the spontaneous development of both benign and malignant skin lesions. With this unique natural animal model we try to decipher mechanisms of skin tumor development in the context of papillomavirus infection, starting from primary infection until manifestation of a tumor.

Recently, we mapped the complete MnPV transcriptome in MnPV-induced lesions and identified known and previously unknown transcripts that will be part of further investigations.

Currently, we could show that ultraviolet (UV)-irradiation and papillomavirus infection cooperate in the development of skin tumors. Under certain conditions that lead to a dedifferentiation of the tumors the viral DNA is lost as also frequently observed in human NMSC. Using in vivo and in vitro approaches, we try to identify the underlying reasons and the molecular virus-host interplay that favors tumor development in early stages and makes the virus indispensable in later stages.

  • 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.
  • Hasche D, Stephan S, Savelyeva L, Westermann F, Rösl F, Vinzón SE. (2016). Establishment of an Immortalized Skin Keratinocyte Cell Line Derived from the Animal Model Mastomys coucha. PLoS One. 2016 Aug 17;11(8):e0161283. doi: 10.1371/journal.pone.0161283. eCollection 2016.
  • Salvermoser M, Chotewutmontri S, Braspenning-Wesch I, Hasche D, Rösl F, Vinzón SE. (2016). Transcriptome analysis of Mastomys natalensis papillomavirus in productive lesions after natural infection. J Gen Virol. 2016 Jul;97(7):1658-69. doi: 10.1099/jgv.0.000471. Epub 2016 Apr 4.
  • Vinzon SE, Braspenning-Wesch I, Müller M, Geissler EK, 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. 10.1371/journal.ppat.1003924

II. Investigation of skin cancer prevention strategies in the model Mastomys coucha

MnPV viral load in skin biopsies. Panel A: The red color shows viral genomes in the suprabasal layers of normal skin visualized by DNA in situ hybridization. The dotted line marks the basal membrane. Panel B: MnPV DNA in situ hybridization of a papilloma. Panel C: qPCR analyses to detect viral DNA by amplifying a fragment of the L1 ORF. Tissue samples were taken from normal skin of animals from the naturally infected colony. (Modified from Vinzon et al. (2014), PloS Pathogens)

Although mortality rates of non-melanoma skin cancer (NMSC) are low, a considerable burden on health-care systems makes prevention or curative strategies desirable. While vaccines against mucosal HPV types are established in the clinic, vaccination against cutaneous papillomaviruses is hampered due to their high diversity.

In contrast to widely used transgenic model systems, naturally Mastomys natalensis papillomavirus (MnPV)-infected Mastomys coucha, are well-suited to perform serological follow-up studies and tests of vaccination strategies. The established virus-infected and virus-free colonies enable both natural infections and experimental infections at defined time points.

In the past, we developed a virus-like particle (VLP)-based vaccine that completely prevented skin tumor formation even in immunosuppressed animals. Currently, incorporated in the EU-funded project Infect-ERA and also in collaboration with group of Martin Müller (DKFZ) we test second generation, more cross-protective vaccines against cutaneous papillomaviruses.

Another project addresses the kinetics of seroconversion of infected animals and the underlying reason of these different immune responses, which putatively represent an immune escape mechanism.

  • Hasche D, Ahmels M, Braspenning-Wesch I, Stephan S, Cao R, Schmidt G, Müller M, Rösl F. Isoforms of the Papillomavirus Major Capsid Protein Differ in Their Ability to Block Viral Spread and Tumor Formation. Front Immunol. 2022 Mar 14;13:811094. doi: 10.3389/fimmu.2022.811094.
  • Fu Y, Cao R, Schäfer M, Stephan S, Braspenning-Wesch I, Schmitt L, Bischoff R, Müller M, Schäfer K,Vinzón S, Rösl F, Hasche D. Expression of different L1 isoforms of Mastomys natalensis papillomavirus as mechanism to circumvent adaptive immunity. eLife. 2020; 9: e57626. doi: 10.7554/eLife.57626.
  • Vinzon SE, Braspenning-Wesch I, Müller M, Geissler EK, 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. 10.1371/journal.ppat.1003924
  • Schäfer K, Neumann J, Waterboer T, Rösl F. (2011). Serological markers for papillomavirus infection and skin tumour development in the rodent model Mastomys coucha. J Gen Virol. 2011 Feb;92(Pt 2):383-94.

III. Virus-host interactions of high-risk human papillomaviruses and pathways of transformation

Human papillomaviruses (HPVs) are notorious for strongly interacting with central pathways of the infected host cell in order to favor viral persistence by inhibiting apoptosis, evading the immune system and promoting cell cycle progression. The identification of such pathways is important both for the early diagnosis and efficient treatment of HPV-induced (pre)cancerous lesions.

In previous studies we were able to demonstrate that one key mechanism employed by high-risk HPVs is the interference with innate immune responses (like cytokines and chemokines) whose inhibition ultimately favors viral persistence and therefore the likelihood of malignant cell transformation. In a recent approach we employed RNA sequencing to efficiently identify novel pathways of virus-host interference that might serve as diagnostic markers or therapeutic targets in patients.

The microenvironment at sites of viral infection can also have a tremendous impact on virus infectivity, cell homeostasis and at later stages tumor progression. We are therefore furthermore interested in the impact that acute hypoxia or a co-infection with the intracellular pathogen Chlamydia trachomatis might have on inhibiting or favoring virus-induced processes in the host cell. To address this question we employ a combination of high-throughput RNA sequencing in a newly developed cell line system in combination with SILAC analyses in order to identify factors that are differentially or synergistically influenced by either condition. Identifying such factors will allow a better assessment of putative cancer risk factors or the development of targeted treatment regimens for normoxic or hypoxic regions of solid tumors.

  • Yang R, Klimentová J, Göckel-Krzikalla E, Ly R, Gmelin N, Hotz-Wagenblatt A, Řehulková H, Stulík J, Rösl F, Niebler M. (2019). Combined Transcriptome and Proteome Analysis of Immortalized Human Keratinocytes Expressing Human Papillomavirus 16 (HPV16) Oncogenes Reveals Novel Key Factors and Networks in HPV-Induced Carcinogenesis. mSphere. 2019 Mar 27;4(2).
  • Hoppe-Seyler K, Bossler F, Lohrey C, Bulkescher J, Rösl F, Jansen L, Mayer A, Vaupel P, Dürst M, Hoppe-Seyler F (2017). Induction of dormancy in hypoxic human papillomavirus-positive cancer cells.Proc Natl Acad Sci U S A.,114(6):E990-E998. doi: 10.1073/pnas.1615758114. Epub 2017 Jan 23.
  • Niebler M, Qian X, Höfler D, Kogosov V, Kaewprag J, Kaufmann AM, Ly R, Böhmer G, Zawatzky R, Rösl F, Rincon-Orozco B (2013). Post-translational control of IL-1β 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 Pathog.9(8):e1003536. doi: 10.1371/journal.ppat.1003536. Epub 2013 Aug 1.
  • Hacke K, Rincon-Orozco B, Buchwalter G, Siehler SY, Wasylyk B, Wiesmüller L, Rösl F (2010). Regulation of MCP-1 chemokine transcription by p53. Mol Cancer. Apr 20;9:82. doi: 10.1186/1476-4598-9-82
  • Rincon-Orozco B, Halec G, Rosenberger S, Muschik D, Nindl I, Bachmann A, Ritter TM, Dondog B, Ly R, Bosch FX, Zawatzky R, Rösl F (2009). Epigenetic silencing of interferon-kappa in human papillomavirus type 16-positive cells. Cancer Res. Nov 15;69(22):8718-25. doi: 10.1158/0008-5472.CAN-09-0550. Epub 2009 Nov 3.

IV. Chlamydia trachomatis and HPV induced cervical cancer: a causal or coincidental interaction?

Immunofluorescence staining of Chlamydia trachomatis-infected HeLa cells. The Chlamydia major outer membrane protein (green) was stained 24 hours post infection.

Chlamydia trachomatis is the most prevalent sexual transmitted bacteria and is an obligatory intracellular pathogen which exhibits tropism in endocervical epithelial cells. Over the past decades, C. trachomatis has been widely studied as a potential co-factor in high-risk HPV induced cervical cancer. Meanwhile, emerging epidemiological researches indicate a strong association of C. trachomatis infection and HPV induced cervical while others suggest no correlation between these two events. The controversial conclusions from epidemiological studies and the absence of concrete evidence from basic researches lead us to ask the question: what’s the role of C. trachomatis infection in HPV induced cervical cancer.  

To answer the question, we stably expressed HPV16 E6 and E7 in spontaneously immortalized human keratinocytes and performed SILAC (Stable Isotope labeling by Amino Acids in cell culture) and RNAseq experiments under conditions with or without acute C. trachomatis infection. Our current interest is to analyze the transcriptomic and proteomic data in detail to decipher the possible role of C. trachomatis infection in HPV-induced cervical cancer. After thorough interrogations of all candidates in the most changed gene/protein lists, we are validating these hits using different method and thereby draw conclusions to the question. In the meantime, the cell model we established for chlamydia study is also an ideal model to study HPV itself and these high-throughput data also provide a new perspective in further defining the molecular mechanism of HPV-induced cellular transformation. Therefore, we are also expecting identification of new targets of HPV16 E6 and E7 oncogenes in this multi-omics study.

V. Micronutritional effects on papillomavirus-host interaction

Several epidemiological studies highlighted the importance of micronutrient intake in cancer development. Among these micronutrients, folate, a water soluble B vitamin, has been shown to exert a protective effect in carcinogenesis. Folate displays a central role in nucleotide synthesis and methylation reactions. Thus, variations in its availability might compromise these pathways. Its deficiency is associated with an increased incidence of several malignancies, including cervical cancer, which is etiologically linked to Human Papilloma Virus (HPV) infection.

This project identifies the molecular events upon folate modulation that can promote HPV-induced carcinogenesis. Using human keratinocytes immortalized by HPV16 E6 and E7, in vitro folate depletion and subsequent repletion had an impact on several cellular events such as: DNA damage, chromosomal stability, cellular proliferation, gene expression.

Further investigation is being conducted to characterize the molecular mechanisms underlying the observed events and dissect folate contribution in HPV-induced carcinogenesis.

  • Savini C, Yang R, Savelyeva L, Göckel-Krzikalla E, Hotz-Wagenblatt A, Westermann F, Rösl F. (2019). Folate Repletion after Deficiency Induces Irreversible Genomic and Transcriptional Changes in Human Papillomavirus Type 16 (HPV16)-Immortalized Human Keratinocytes. Int J Mol Sci. 2019 Mar 4;20(5). pii: E1100.
  • Bach M, Savini C, Krufczik M, Cremer C, Rösl F, Hausmann M. (2017). Super-   Resolution Localization Microscopy of γ-H2AX and Heterochromatin after Folate Deficiency. Int J Mol Sci. 2017 Aug 8;18(8). pii: E1726. doi: 10.3390/ijms18081726.

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