methylome; squamous cell carcinoma; cancer treatment; organ transplant recipients; RNA sequencing; polymorphisms; epigenetics; skin cancer; large nested project (STCS)
Kuzmanov Aleksandar, Johansen Pål, Hofbauer Günther (2020), FBXO25 Promotes Cutaneous Squamous Cell Carcinoma Growth and Metastasis through Cyclin D1, in Journal of Investigative Dermatology
, 140(12), 2496-2504.
Kuzmanov A, Qi W, Stenz N, Bochud P, Kutalik Z, Wojtowicz A, Hofbauer G (2019), rs34567942 a Novel Susceptibility Single Nucleotide Polymorphism for Cutaneous Squamous Cell Carcinoma in Organ Transplant Recipients, in Acta Dermato Venereologica
Bordignon Pino, Bottoni Giulia, Xu Xiaoying, Popescu Alma S., Truan Zinnia, Guenova Emmanuella, Kofler Lukas, Jafari Paris, Ostano Paola, Röcken Martin, Neel Victor, Dotto G. Paolo (2019), Dualism of FGF and TGF-β Signaling in Heterogeneous Cancer-Associated Fibroblast Activation with ETV1 as a Critical Determinant, in Cell Reports
, 28(9), 2358-2372.e6.
Skin cancers and skin inflammations like eczema or psoriasis are common skin diseases. Among those, actinic keratoses (AKs) are intraepithelial lesions that develop on sun-exposed surfaces of the skin such as the face, scalp or lower arms. These lesions result from UV-induced alterations in the epidermal part of the skin, and more specifically in keratinocytes. AKs may develop into invasive squamous cell carcinoma of the skin (SCC) which is the second most common form of skin cancer worldwide. It is thus a major source of morbidity and cost overall. The incidence (number of new cases arising in a given period expressed as a rate per 100,000 persons per year) for SCC over the last 40 years is increasing at an impressive pace in Western European countries and particularly in Switzerland. Switzerland has the highest SCC incidence rate among all countries in mainland Europe. It has also the fastest increase from 14.2/100 000 person-years in 1978 to 28.9/100 000 person-years in 1997 and keeps increasing in numbers, both medically and economically.Some populations are at a greatly elevated risk for SCC of the skin. Organ transplant recipients (OTRs) achieve maintenance of their graft by immunosuppressive medication which suppresses transplant rejection. Calcineurin inhibition is the cornerstone of most immunosuppressive regimes. This success of modern transplantation medicine is, however, countered by an increased cancer risk in this population. SCC is the most frequent complication in organ transplant recipients at a risk increased 60- to 100-fold compared to the general population. SCC in OTR is characterized by a higher risk of metastasis in up to 20% of cases and shows a more aggressive course than SCC in the general population. Not infrequently, successfully transplanted patients suffer a great burden in their quality of life and sometimes even a vital threat by the formation of SCC. The commonly used calcineurin inhibitor, cyclosporine A (CsA), directly induces tumor growth in murine models and in humans via transcription factor ATF3 and increases the secretion of transforming growth factor-ß and vascular endothelia growth factor conductive to SCC formation. While some mechanisms for this greatly increased risk of squamous cell carcinoma of the skin have been elucidated, open questions remain. However, not all patients undergoing immunosuppressive treatment develop SCC, some are heavily affected, others hardly. Therefore, this project proposes to integrate transcriptome with epigenetic and functional analysis to understand genetic predisposition to cancer, with SCC in OTR as a focus. Generally, the possible role of genetic/epigenetic modifications of gene networks in SCC predisposition is largely unexplored. Thus, identifying patient- and tumor-specific differences will provide a comprehensive landscape of actionable targets. As a consequence, this expanding knowledge has implications for all aspects of cancer management, including prevention, screening, and treatment.We will address two main aims: 1)To test the hypothesis that different susceptibility of OTR patients to skin SCC is linked to different expression of genes with key regulatory function in keratinocytes and skin homeostasis.2)To assess in primary keratinocytes derived from OTRs the difference in their tumor forming/yielding capability in a manner that can be explained by different genetic and/or epigenetic control of key regulatory genes.