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Open AccessArticle
BRAF Inhibition and UVB Light Synergistically Promote Mus musculus Papillomavirus 1-Induced Skin Tumorigenesis
by
Sonja Dorfer
Sonja Dorfer 1,†
,
Julia Maria Ressler
Julia Maria Ressler 1,†
,
Katharina Riebenbauer
Katharina Riebenbauer 1,
Stefanie Kancz
Stefanie Kancz 1,
Kim Purkhauser
Kim Purkhauser 1,
Victoria Bachmayr
Victoria Bachmayr 1,
Christophe Cataisson
Christophe Cataisson
Prof. Christophe Cataisson is a Staff Scientist at the Laboratory of Cancer Biology and Genetics, He [...]
Prof. Christophe Cataisson is a Staff Scientist at the Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute. He received his Ph.D. from Université d'Auvergne. Dr. Cataisson’s research expertise is centered on skin carcinogenesis (cutaneous squamous cell carcinoma) following two-stage chemical carcinogenesis (DMBA-TPA). He also uses primary mouse keratinocytes to define phenotypic changes caused by oncogenic RAS. He uses genetically modified mouse models to study pathways contributing to carcinogenesis (PKC, MyD88, CXCR2, EGFR, MET, MTOR). Using an in vivo grafting model on a syngeneic host has allowed Dr. Cataisson to probe the respective contribution of cancer cells and their stroma to tumor formation. Dr. Cataisson’s integrated research takes advantage of the ability to use primary cells transformed by a single hit (oncogenic RAS) and exploring their phenotype in vivo in a relevant context.
2
,
Reinhard Kirnbauer
Reinhard Kirnbauer
Reinhard Kirnbauer is the chief of the Laboratory of Viral Oncology and a Professor at the of in He [...]
Reinhard Kirnbauer is the chief of the Laboratory of Viral Oncology and a Professor at the Department of Dermatology in Vienna. He has a strong interest in translational research and in the pathobiology of papillomaviruses. He is recognized for over 30 years of pioneering work on the development of prophylactic human papillomavirus (HPV) vaccines, seroepidemiology, and basic aspects of papillomavirus infection. As co-inventor of HPV16 virus-like particle (VLP) technology with Drs Schiller and Lowy, in 1992, he was the first to describe the assembly from L1 into morphologically correct VLPs and the induction of high-level neutralizing antisera. In preclinical animal models, he then demonstrated VLP vaccine efficacy in rabbits and cows, which formed the basis for clinical HPV vaccine development. His inventions were licensed by MSD and GSK to permit them to develop and produce the current HPV vaccines, Gardasil (-9) and Cervarix. He also developed a VLP-based ELISA that has been widely used in seroepidemiology and vaccination trials. Besides basic work on the cellular papillomavirus receptor, he has developed a vaccine platform based on papillomavirus VLPs that carry foreign peptides on their surface to combat diseases like Alzheimer's disease or prion-related diseases. More recently he has developed chimeric HPV16 VLPs for cross-protection against a broad spectrum of HPV types that will be tested shortly in a phase I first-in-human clinical trial.
1
,
Peter Petzelbauer
Peter Petzelbauer 1
,
Markus Wiesmueller
Markus Wiesmueller 1,
Maximilian Egg
Maximilian Egg 1,
Christoph Hoeller
Christoph Hoeller
Prof. Dr. Christoph Hoeller (MD, PhD) is a Professor of Dermatology and Head of the Skin Cancer He a [...]
Prof. Dr. Christoph Hoeller (MD, PhD) is a Professor of Dermatology and Head of the Skin Cancer Center. He is a Professor of Medicine at the Medical University of Vienna. He currently leads the melanoma study team and the outpatient center for melanoma treatment and manages the skin cancer center at the Medical University of Vienna. He is a board member of EADO and ADO as well as a member of the EORTC and ESMO melanoma groups. Prof. Dr. Hoeller received his education from the Medical University of Vienna, where he earned both his medical and doctoral degrees, and he also completed his specialty training in dermatology and venereology from the university's Department of Dermatology. During this time, Dr. Hoeller began his work in melanoma research, which earned him a scholarship from the Max Kade Foundation, and he spent 2 years abroad working as a faculty member at the Wistar Institute in Philadelphia. He is a dermatology specialist, and his research is focused on the treatment of melanoma and other dermatologic malignancies.
1
and
Alessandra Handisurya
Alessandra Handisurya 1,*
1
Department of Dermatology, Medical University of Vienna, 1090 Vienna, Austria
2
Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to the work.
Cancers 2024, 16(18), 3133; https://doi.org/10.3390/cancers16183133 (registering DOI)
Submission received: 7 August 2024
/
Revised: 4 September 2024
/
Accepted: 10 September 2024
/
Published: 11 September 2024
Simple Summary
Outgrowth of skin tumors in cancer patients who receive therapies with BRAF inhibitors is frequently observed as an undesired side effect. Infection with certain human papillomaviruses may play a role in BRAF-inhibitor-associated skin tumor development. In this study, the impact of BRAF inhibitors and Ultraviolet B (UVB) light on tumor growth was investigated in laboratory mice after infection of their skin with a murine papillomavirus. We could show that the combination of BRAF inhibitor treatment and UVB exposure resulted in higher numbers of virus-induced tumors compared with virus-infected mice that had received only BRAF inhibitors, only UVB irradiation or no additional treatment. This shows that BRAF inhibitors, particularly when combined with UVB light, support skin tumor growth in mice and may represent a novel way by which BRAF inhibitors contribute to skin cancer development.
Abstract
The development of keratinocytic skin tumors, presumably attributable to paradoxical activation of the MAPK pathway, represents a relevant side effect of targeted therapies with BRAF inhibitors (BRAFis). The role of cutaneous papillomavirus infection in BRAFi-associated skin carcinogenesis, however, is still inconclusive. Employing the Mus musculus papillomavirus 1 (MmuPV1) skin infection model, the impact of BRAFis and UVB exposure on papillomavirus induced skin tumorigenesis was investigated in immunocompetent FVB/NCrl mice. Systemic BRAF inhibition in combination with UVB light induced skin tumors in 62% of the MmuPV1-infected animals. In contrast, significantly fewer tumors were observed in the absence of either BRAF inhibition, UVB irradiation or virus infection, as demonstrated by lesional outgrowth in 20%, 5% and 0% of the mice, respectively. Combinatory exposure to BRAFis and UVB favored productive viral infection, which was shown by high numbers of MmuPV1 genome copies and E1^E4 spliced transcripts and an abundance of E6/E7 oncogene mRNA and viral capsid proteins. BRAF inhibition, but not viral infection or UVB light, activated ERK1/2, whereas gH2AX expression, inducible by UVB light, remained unaltered by BRAFis. These results provide experimental evidence that BRAF inhibition and UVB irradiation synergistically promote MmuPV1-induced skin tumor development in vivo. This indicates an alternative pathway by which papillomavirus skin infection may contribute to BRAFi-associated skin tumorigenesis.
Share and Cite
MDPI and ACS Style
Dorfer, S.; Ressler, J.M.; Riebenbauer, K.; Kancz, S.; Purkhauser, K.; Bachmayr, V.; Cataisson, C.; Kirnbauer, R.; Petzelbauer, P.; Wiesmueller, M.;
et al. BRAF Inhibition and UVB Light Synergistically Promote Mus musculus Papillomavirus 1-Induced Skin Tumorigenesis. Cancers 2024, 16, 3133.
https://doi.org/10.3390/cancers16183133
AMA Style
Dorfer S, Ressler JM, Riebenbauer K, Kancz S, Purkhauser K, Bachmayr V, Cataisson C, Kirnbauer R, Petzelbauer P, Wiesmueller M,
et al. BRAF Inhibition and UVB Light Synergistically Promote Mus musculus Papillomavirus 1-Induced Skin Tumorigenesis. Cancers. 2024; 16(18):3133.
https://doi.org/10.3390/cancers16183133
Chicago/Turabian Style
Dorfer, Sonja, Julia Maria Ressler, Katharina Riebenbauer, Stefanie Kancz, Kim Purkhauser, Victoria Bachmayr, Christophe Cataisson, Reinhard Kirnbauer, Peter Petzelbauer, Markus Wiesmueller,
and et al. 2024. "BRAF Inhibition and UVB Light Synergistically Promote Mus musculus Papillomavirus 1-Induced Skin Tumorigenesis" Cancers 16, no. 18: 3133.
https://doi.org/10.3390/cancers16183133
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