Prof. Gian-Paolo Dotto

Keywords

Field cancerization, squamous cell carcinoma, cancer associated fibroblasts, Notch/CSL signaling, androgen receptor

What we investigate

We focus on field cancerization, a major clinical condition with multifocal recurrent neoplastic lesions associated with widespread changes of surrounding tissues. 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.

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 underlined:

  • Clocchiatti A., Ghosh S, Procopio MG, Mazzeo L, Bordignon P, Ostano P, Goruppi S, Bottoni G, Katarkar A, Levesque M, Kölblinger P, Dummer R, Neel V, Ozdemir BC, and Dotto GP (2018). Androgen receptor functions as transcriptional repressor of cancer associated fibroblast activation. J Clin Invest 128: 5531-5548.
  • 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 29: 3884.
  • Bordignon P, Bottoni G, Xu X, Popescu A, Truan Z, Guenova E, Kofler L, Jafari P, Ostano P, Röcken M, Neel V, and Dotto GP (2019). Dualism of FGF and TGF-β Signaling in Heterogeneous Cancer-Associated Fibroblast Activation with ETV1 as a Critical Determinant. Cell Rep 28: 2358-2372.
  • 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, in press.
  • 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, in press.