What we investigate
Our main research focuses on genetic and epigenetic determinants of field cancerisation, a very frequent condition consisting of multifocal and recurrent lesions at various stages of neoplastic progression associated with widespread aging-associated changes of surrounding tissues. More specifically, we focus on field cancerization of the skin, as a benchmark of major clinical significance. We dissect the role of the Notch/CSL and androgen receptor signaling pathways in cancer associated fibroblast (CAF) activation and their impact on skin squamous cell carcinoma and melanoma development.
KEYWORDS
field cancerization, squamous cell carcinoma, cancer associated fibroblasts, Notch/CSL signaling, androgen receptor
Our research in more detail
On the basis of a bad seed/bad soil hypothesis that we have proposed for field cancerization, we are addressing two main topics: (i) the role that genetic/epigenetic alterations leading to CAF activation play in this process; (ii) the reciprocal crosstalk between activated CAFs and cells of incipient squamous cell carcinoma and melanoma lesions. We are investigating the interplay between transcriptional/epigenetic control mechanisms and genomic stability in dermal fibroblasts and CAFs, focusing on CSL, the key effector of canonical Notch signaling endowed with intrinsic transcription repressive function, which we have found to be also an essential element of a telomere binding/protective complex. We are studying specific genomic alterations that occur in CAFs, focusing on the frequent amplification and overexpression of the Notch1 gene that render these cells resistant to the UVA-induced DNA damage response (DDR) and promote cancer/stromal cells expansion. Finally, we are investigating the dual role that androgen receptor (AR) signaling plays in suppressing CAF activation and, at the same time, promoting melanoma cell proliferation and tumorigenesis. We are exploring the translational potential of our findings by testing epigenetic modulatory compounds interfering with Notch/CSL and AR signaling in both CAFs and cancer cells.
Selected publications
SKINTEGRITY.CH Principal Investigators are in bold:
- Goruppi S, Clocchiatti A, Bottoni G, Di Cicco E, Ma M, Tassone B, Neel V, Demehri S, Simon C and Dotto GP (2023). The ULK3 kinase is a determinant of keratinocyte self-renewal and tumorigenesis targeting the arginine methylome. Nat Commun, 14(1), p. 887.
- Katarkar A, Bottoni G, Clocchiatti A, Goruppi S, Bordignon P, Lazzaroni, F, Gregnanin I, Ostano P, Neel V and Dotto GP (2020) NOTCH1 gene amplification promotes expansion of cancer associated fibroblast populations in human skin. Nat Commun, 11(1), p. 5126.
- Ma M, Ghosh S, Tavernari D, Katarkar A, Clocchiatti A, Mazzeo L, Samarkina A., Epiney, Yu Y-R, Ho P-C, Levesque MP, Özdemir BC, Ciriello G, Dummer R and Dotto GP (2020) Sustained Androgen Receptor signaling is a determinant of melanoma cell growth potential and tumorigenesis. J Exp Med, 218(2), p. e20201137.
- Bottoni G., Katarkar A, Tassone B, Ghosh S, Clocchiatti A, Goruppi S, Bordignon P, Jafari P, Tordini, F, Lunardi T, Hoetzenecker W, Nell V, Lingner J and Dotto GP (2019). CSL controls telomere maintenance and genome stability in human dermal fibroblasts. Nat Commun, 10(1), p. 3884.
- Clocchiatti A., Ghosh S, Procopio MG, Mazzeo L, Bordignon P, Ostano P, Goruppi S, Bottoni G, Katarkar A, Levesque MP, Kölblinger P, Dummer R, Neel V, Özdemir BC and Dotto GP (2018). Androgen receptor functions as transcriptional repressor of cancer associated fibroblast activation. J Clin Invest, 128(12), pp. 5531-5548.