Laboratory of Skin Aging and Cancer Prevention
Research Program Overview :
Cancer risk is exponentially increasing with aging and aging-related diseases. Cumulative exposure to environmental agents are connected with increased cancer risk. There are significant sex-related differences in aging that may contribute to sexual dimorphism in cancer susceptibility.
Aging has been connected with senescence of cells, which can function both as a fail safe mechanism against cancer development but also facilitate this process. The dual tumor-suppressing and -promoting function of cellular senescence depends on cell types and cell-cell interactions.
Cancers do not arise solely from a single deregulated group of cells but rather as a combined result of alterations in tissues and organs associated with the aging and cellular senescence processes in widespreading cancer fields.
Within this context, 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 connected with widespread aging-associated changes of surrounding tissues.
We focus on field cancerization of the skin, as a benchmark of major clinical significance. We are exploring genetic and epigenetic determinants of squamous cell carcinoma and melanoma development, with a specific focus on precursor lesions and their risk of malignant conversion.
In this context, we are exploring genetic and epigenetic determinants of cancer variability across gender and race. This is a topic of great interest as there are significant differences in cancer susceptibility between individuals of different sex and race that cannot solely be attributed to socioeconomic and behavioural factors and instead, are the likely result of an interplay with biological factors.
Field Cancerization : bad seed / bad soil hypothesis. Environmental insults, like UV irradiation or smoke, can target both epithelial and stromal compartments of organs such as skin, head/neck, lung, bladder or breast, with ensuing genetic and/or epigenetic changes. Establishment and spreading of “cancer fields” is the likely result of an interplay between epithelial and stromal alterations, with the latter playing an equally important and possibly primary role. The situation leading to multifocal and recurrent neoplastic lesions may be analogous to that of a bad plant difficult to eradicate. This may be due to roots deeply embedded in the terrain or the spreading of bad multiple seeds, growing in the presence of a permissive or favorable soil. An alternative possibility with important conceptual implications is that the main problem is the soil itself. A bad soil could corrupt properties of otherwise perfectly good plants or seeds. According to this view, unless the soil is corrected, various forms of prevention and intervention would be of little or no use.
Esther Revai Lechtich
Markus Kirolos Youssef
Representative papers (out of 111)
Ma, M., Ghosh,S., Tavernari, D., Katarkar, A., Clocchiatti, A., Mazzeo,L., Samarkina, A., Epiney, Yu, Y._R. Ho, P.-C., Levesque, M.P. Özdemir, B.C., Ciriello, G., Dummer, R. and G.P. Dotto(2020) Sustained Androgen Receptor signaling is a determinant of melanoma cell growth potential and tumorigenesis. J. Exp. Med. 218. PMID: 33112375
Katarkar, A., Bottoni, G., Clocchiatti, A., Goruppi, S., Bordignon, P., Lazzaroni, F., Gregnanin, I., Ostano, P., Neel,V., and G.P. Dotto (2020) NOTCH1 gene amplification promotes expansion of Cancer Associated Fibroblast populations in human skin. Nature Comm. In press. doi:10.1038/s41467-020-18919-2
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 G.P. Dotto (2019). CSL controls telomere maintenance and genome stability in human dermal fibroblasts. Nature Comm. 29;10(1):3884. doi: 10.1038/s41467-019-11785-7.
Bordignon, P., Bottoni, G., Xu, X., Popescu, A., Truan, Z., Guenova, E., Kofler, L., Jafari, P., Ostano, P., Röcken, M., Neel, V., and G.P. Dotto (2019). Dualism of FGF and TGF-β Signaling in Heterogeneous Cancer-Associated Fibroblast Activation with ETV1 as a Critical Determinant. Cell Rep 28(9): 2358-2372.e6. doi: 10.1016/j.celrep.2019.07.092.
Al Labban, D., Jo, S.H., Ostano, P., Saglietti, C., Bongiovanni, M., Panizzon, R., and Dotto, G.P. (2018). Notch-effector CSL promotes squamous cell carcinoma by repressing histone demethylase KDM6B. J. Clin. Invest. 128, 2581-2599, doi.org/10.1172/JCI96915.
Clocchiatti, A., S. Ghosh, M.G. Procopio, L. Mazzeo, P. Bordignon, P. Ostano, S. Goruppi, G. Bottoni, A. Katarkar, M. Levesque, P. Kölblinger, R. Dummer, V. Neel, B.C. Ozdemir, and G.P. Dotto. (2018). Androgen receptor functions as transcriptional repressor of Cancer Associated Fibroblast activation. J. Clin. Invest. 128(12): p. 5531-5548 doi: 10.1172/JCI99159.
Goruppi, S., Jo, S.H., Laszlo, C., Clocchiatti, A., Neel, V., and Dotto, G.P. (2018). Autophagy Controls CSL/RBPJkappa Stability through a p62/SQSTM1-Dependent Mechanism. Cell Rep 24, 3108-3114. PMID: 30231994
Goruppi, S., M.G. Procopio, S. Jo, A. Clocchiatti, V. Neel, and G.P. Dotto (2017). The ULK3 Kinase Is Critical for Convergent Control of Cancer-Associated Fibroblast Activation by CSL and GLI. Cell Rep 20:2468-2479, doi: 10.1016/j.celrep.2017.08.048
Kim, D.E, Procopio,M.G., Ghosh, S., Jo, S.H, Goruppi, S., Magliozzi, F., Bordignon, P., Neel, V., Angelino,P.and Dotto G.P. (2017) Convergent roles of ATF3 and CSL in chromatin control of cancer-associated fibroblast activation. J. Exp. Med. 214, 1-20, doi: 10.1084/jem.20170724
Procopio, M.G., Laszlo, C., Al Labban, D., Eun Kim, D., Bordignon, P., Jo, S., Goruppi, S., Menietti, E., Ostano, P., Ala, U., Provero, P., Hoetzenecker, W., Neel, V., Kilarski, W., Swartz, M.A., Brisken, C., Lefort, K. and Dotto, G.P. (2015) Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation. Nature Cell Bio. 17, 1193–1204 doi:10.1038/ncb3228
Dotto, G.P. (2019) Gender and sex—time to bridge the gap, EMBO Molecular Medicine,DOI: 10.15252/emmm.201910668
Özdemir, B.C. and Dotto, G.P. (2019) Sex hormones and anticancer immunity, Clinical Cancer Research, DOI:10.1158/1078-0432.CCR-19-0137
Goruppi, S., A. Clocchiatti, and Dotto, G.P. (2019). A role for stromal autophagy in cancer-associated fibroblast activation.Autophagy,15:4,738 739, DOI: 10.1080/15548627.2019.1569936
Özdemir, B.C. and Dotto, G.P., Racial Differences in Cancer Susceptibility and Survival: More Than the Color of the Skin? Trends in Cancer, 2017; 3, 181-197 http://dx.doi.org/10.1016/j.trecan.2017.02.002
Dotto, G.P, and Rustgi, A., Squamous cell cancers: a unified perspective on biology and genetics. Cancer Cell 2016; 29, 622-637
Clocchiatti, A., Cora, E.,, Zhang, Y. and Dotto, G.P. Sexual dimorphism in cancer. Nature Reviews Cancer 2016; 16: p. 330-9