Interdisciplinary research, exchange and education in cancer prevention
Gian-Paolo Dotto, MD, PhD
Prof. Gian-Paolo Dotto is director of the Laboratory of Skin Aging and Cancer Prevention, in the Dermatology Department at Massachusetts General Hospital and Harvard Medical School, director of the Personalised Cancer Prevention Program, University Hospital (CHUV) in Lausanne (CH) and President of the international Cancer Prevention Institute (iCPI). He is an elected member of the European Molecular Biology Organization (2011), the Academia Europaea (2012), the Leopoldina German National Academy of Sciences (2014) and an Overseas Fellow of the Royal Society of Medicine (2018). He is the recipient of a number of awards, including the American Skin Association Achievement Award (2012), an ERC Advanced investigator grant award (2013) the Jurg Tschopp Award for Excellence in Biological Sciences (2015) and the Life Time Achievement Award from the University of Lausanne, School of Medicine and Biology (2020). He has been a contributor for the Osservatore Romano, the official newspaper of the Holy See, as well as the Science and Society section of EMBO Reports.
Education, training and positions Dr. Dotto was educated at the University of Turin, Italy, where he received his MD in 1979. He then earned his PhD in bacteriophage genetics at the Rockefeller University, New York, in 1983. He moved for his postdoctoral training at the Whitehead Institute/MIT in Cambridge Mass. and subsequently joined Yale University, New Haven, Connecticut, as assistant professor of Pathology in 1987. He was promoted to the rank of associate professor in 1992 and soon after moved to Harvard Medical School, in the newly established Cutaneous Biology Research Center. In 2000 he obtained the full professorship at Harvard Medical School and a Biologist position at Massachusetts General Hospital. In 2002 he accepted a position of Professor in the Department of Biochemistry at the University of Lausanne (UNIL), while retaining his position of Biologist at Massachusetts General Hospital.
He has been directing the UNIL PhD program in Cancer and Immunology from 2007 to 2019 and has been responsible for Biochemistry teaching to Medical Students since 2004. Since Aug. 1st 2021 he is honorary professor of the Department of Biochemistry at UNIL. He is founder and director of the International Cancer Prevention Institute, established in Epalinges/Lausanne in 2016.
Scientific contributions The PI has opened major new perspectives on the complex balance that presides tissue homeostasis and tumorigenesis. His laboratory has been studying the interplay between intracellular and intercellular cell communication pathways that operate in this context, focusing on early steps of skin cancer development as a model.
Dr. Dotto has opened major new perspectives with his studies of the interplay between intracellular and intercellular cell communication pathways in control of normal tissue homeostasis and carcinogenesis, using skin as a model. He has focused on how alterations in this equilibrium lead to keratinocyte cancer development, specifically squamous cell carcinoma (SCC). A key concept that stems from Dr. Dotto’s work is that pro-differentiation signals can be beneficial in exhausting SCC stem cell populations that are quiescent and resistant to conventional chemotherapy. Until Dr. Dotto’s work, no cell cycle regulatory mechanisms were known that are specifically involved in differentiation control of normal epithelial cells. His laboratory established that induction of the cyclin dependent kinase inhibitor p21CDKN1A occurs as a very early event in keratinocyte differentiation and that, besides its role in the cell cycle, it plays an essential role in maintenance of keratinocyte stem cell populations while, at the same, suppressing late stages of differentiation.
Notch activation in mammalian cells was commonly thought to enhance stem cell potential and promote tumorigenesis. Dr. Dotto’s group showed for the first time that, in keratinocytes of both mouse and human origin, Notch activation is a key determinant of keratinocyte differentiation and tumor suppression, under direct transcriptional control of p53 and with p21CDKN1A and p63 as targets. They further established an interplay between Notch and the EGFR signaling pathway and, more recently, estrogen receptor ß, in control of squamous cell cancer (SCC). Clinical deep sequencining studies have provided a striking validation of the importance of the Notch-centered network in SCCs originating at various body sites, within a unified perspective of this cancer types pioneered by the Dotto group .
Field cancerization is a condition of major clinical significance consisting of multiple and recurrent cancer lesions associated with widespread changes of surrounding tissues. In this context, Dr. Dotto’s group established that activation of Cancer Associated Fibroblasts (CAFs) can play a primary triggering role. By a combination of mouse and human genetic studies, they showed that specific genetic/epigenetic changes in dermal fibroblasts, resulting from compromised Notch/CSL signaling, can trigger multifocal skin cancer development, with chronic inflammation as an important link. They further unveiled a multistep process of CAF activation at the intersection between transcription / chromatin control and telomere / genomic stability, with converging transcription and DNA damage repair pathways.
More recently, Dr. Dotto extended his field of investigation to sex-related differences in cancer susceptibility, focusing on the role of the androgen receptor (AR) in cancer of non-reproductive organs, a rather unexplored topic. His group established that AR plays a two-edged role in skin cancer development. They showed that downmodulation of AR expression in dermal fibroblasts, as it occurs in premalignant actinic keratosis lesions and skin SCCs, results in cellular senescence together with a senescence associated secretory phenotype (SASP) that promotes tumorigenesis of neighboring cancer cells. In melanoma cells, they found that loss of AR activity induces also cellular senescence, which is accompanied by genomic DNA breakage, leakage into the cytoplasm and a STING dependent inflammatory cascade that suppresses tumorigenesis. AR functions in this context by anchoring the DNA repair Ku70/Ku80 to RNA-Pol II and preventing transcription-associated DNA damage.
Melanoma provides a primary benchmark for targeted drug therapy. Most melanomas with BRAFV600 mutations regress in response to BRAF/MEK inhibitors (BRAFi/MEKi). However, nearly all relapse within the first two years, and there is a connection between BRAFi/MEKi-resistance and poor response to immune checkpoint therapy. Besides being required for sustained melanoma cell proliferation and tumorigenesis, the Dotto’s group has very recently shown that AR expression is markedly increased in BRAFi-resistant melanoma cells and that increased AR expression is sufficient to render melanoma cells BRAFi-resistant. Importantly, inhibition of AR expression or activity blunts changes in gene expression of BRAFi-resistant melanoma cells and in vivo promotes clusters of CD8+ T cells infiltration and cancer cells killing. Given the connection between BRAFi resistance and poor immune response, AR targeting compounds could be employed as co-adjuvants to improve current melanoma therapeutic approaches.
Outreach activities Dr. Dotto is founder and director of the International Cancer Prevention Institute (IPCI) (www.cancerprev.ch), a new paradigm of teaching / research institute and global forum for educators, policy makers and the general public for development of joint interdisciplinary efforts in primary, secondary and tertiary cancer prevention. He has organized several courses and workshops dedicated to this topic (including a recent EMBO meeting in 2018) and has been a driving force for a new collaborative PhD program on cancer prevention (Marie Curie Innovative Training Network, CANCERPREV).
He has brought to the attention the importance of differences in cancer susceptibility related to sex and ethnic background, two sensitive topics that can be tackled beneficially by rigorous scientific hypotheses and approaches.
More broadly, he is dedicating significant efforts to foster communication between natural sciences and humanities, with general opinion articles and a dedicated website (www.nature-thought-society.com). He has recently published a book entitled “Death and Resurrection: An experiment in progress” in which he tackles the conundrum raised by the historical claims of the Christian faith facing the inescapable tenets of Biology and Medicine.
Missero C, Calautti E, Eckner R, Chin J, Tsai L-H, Livingston DM, Dotto GP. Involvement of the cell cycle inhibitor Cip1/WAF1 and the Ela-associated p300 protein in terminal differentiation. Proc Natl Acad Sci USA 1995; 92:5451-55
Di Cunto F, Topley G, Calautti E, Hsiao J, Ong L, Seth PK, Dotto GP. Inhibitory function of p21Cip1/WAF1 in differentiation of primary mouse keratinocytes independent of cell cycle control. Science, 1998; 280: 1069-1072
Rangarajan, A., C. Talora, M. Nicolas, R. Okuyama, C. Mammucari, H. Oh, J. C. Aster, S. Krishna, D. Metzger, P. Chambon, L. Miele, M. Aguet, F. Radtke and G. P. Dotto. Notch signaling functions as a direct determinant of the exit of keratinocytes from the cell cycle and entry into differentiation. The EMBO Journal, 2001; 20:3427-3436
Nguyen B-C, Lefort K, Mandinova A, Antonini D, Devgan V, Della Gatta G, Koster MI, Zhang Z, Wang J, Tommasi di Vignano A, Kitajewski J, Chiorino G, Roop DR, Missero C and Dotto GP, Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation. Genes & Dev. 2006; 20, 1028-42
Wu, X., Nguyen, B.C., Dziunycz, P., Chang, S., Brooks, Y., Lefort, K., Hofbauer, G.F., and Dotto, G.P. (2010). Opposing roles for calcineurin and ATF3 in squamous skin cancer. Nature 465, 368-372
Hu, B, Castillo, E., Harewood, L., Ostano, P., Reymond, A., Dummer, R., Raffoul, W., Hoetzenecker, W., Hofbauer, G.F.L. and Dotto, G.P. (2012) Multifocal Epithelial Tumors and Field Cancerization from Loss of Mesenchymal CSL Signaling. Cell, 149, 1207–1220
Dotto, G.P. Multifocal epithelial tumors and field cancerization: stroma as a primary determinant. J Clin Invest. 2014; 124 :1 446-53. doi: 10.1172/JCI72589
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., Lefort1, 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, and Rustgi, A., Squamous cell cancers: a unified perspective on biology and genetics. Cancer Cell 2016; 29, 622-637
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. doi:10.1038/s41467-020-18919-2
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
Xu, X., Tassone, B., Ostano, P., Katarkar, A., Proust, T., Joseph, J.M., Riganti, C., Chiorino, G., Kutalik, Z., Lefort, K., and Dotto, G.P. (2021). HSD17B7 gene in self-renewal and oncogenicity of keratinocytes from Black versus White populations. EMBO Mol Med 13, e14133.
Opinion articles (mostly in Italian, full text in English provided by links):
