Prof. Gian-Paolo Dotto is professor of Dermatology at Harvard Medical School, director of the Laboratory of Skin Aging and Cancer Prevention, in the Dermatology Department at Massachusetts General Hospital, emeritus professor of Biochemistry at the University of Lausanne, director of the Personalized 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.
Dr. Dotto has pioneered work on the interplay between cell cycle and developmental signaling pathways in tissue homeostasis and cancer susceptibility across individuals of different age, sex, and ancestry. His research has primarily focused on how disruptions in this balance lead to the development of skin cancer, particularly squamous cell carcinoma (SCC) and melanoma. Dr. Dotto’s work emphasizes that cancer does not arise solely from a single deregulated cell or group of cells, but from broader alterations in the surrounding tissues.
In this context, his group demonstrated that the activation of Cancer-Associated Fibroblasts (CAFs) is a multistep process, initially linked to fibroblast senescence. Through studies combining mouse genetic models and clinical samples, they established that CAF activation can play a triggering role in field cancerization, a condition of major clinical significance characterized by multiple and recurrent cancer lesions along with widespread changes in the surrounding tissues.Recently, Dr. Dotto expanded his research to explore the differences in cancer susceptibility between male and female populations and people of different ancestries, focusing on the influence of sex hormones, particularly androgen signaling. His group found that the androgen receptor (AR) has a dual role in cancer development: it suppresses stromal fibroblast senescence and CAF activation while promoting melanoma cell proliferation, tumorigenesis, and resistance to targeted therapy.
Dr. Dotto has opened major new perspectives with his studies on 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 the co-founder and president of the International Cancer Prevention Institute (CancerPrev) (https://cancerprev.com), an innovative teaching and research institute and global forum for educators, policymakers, and the public. CancerPrev focuses on fostering interdisciplinary efforts in personalized cancer prevention. He has organized several international conferences on this topic, emphasizing the need to bridge cutting-edge research and diversity. Dr. Dotto is deeply committed to link science and society and has published numerous opinion articles and a book on a variety of topics. He has founded a cultural hub to promote outreach efforts (http://www.studium1.com) through workshops, summer courses, and a residence/hospitality program.
Representative Scientific Publications (for a complete list see bibliography)
Dotto, G.P., Buckinx, A., Özdemir, B.C. et al. Androgen receptor signalling in non-prostatic malignancies: challenges and opportunities. Nat Rev Cancer (2024). https://doi.org/10.1038/s41568-024-00772-w
Ghosh, S., Isma, J., Ostano, P., Mazzeo, L., Toniolo, A., Das, M., White, J.R., Simon, C. and G. Paolo Dotto. “Nuclear Lamin A/C Phosphorylation by Loss of Androgen Receptor Leads to Cancer-Associated Fibroblast Activation.” Nature Communications 2024; DOI : 10.1038/s41467-024-52344-z
Mazzeo, Luigi, Soumitra Ghosh, Emery Di Cicco, Jovan Isma, Daniele Tavernari, Anastasia Samarkina, Paola Ostano, Markus K. Youssef, Christian Simon, and G. Paolo Dotto. “ANKRD1 Is a Mesenchymal-Specific Driver of Cancer-Associated Fibroblast Activation Bridging Androgen Receptor Loss to AP-1 Activation.” Nature Communications 2024 : 1038. https://doi.org/10.1038/s41467-024-45308-w.
Samarkina, Anastasia, Markus Kirolos Youssef, Paola Ostano, Soumitra Ghosh, Min Ma, Beatrice Tassone, Tatiana Proust, et al. “Androgen Receptor Is a Determinant of Melanoma Targeted Drug Resistance.” Nature Communications 14, no. 1 (October 14, 2023): 6498. https://doi.org/10.1038/s41467-023-42239-w.
Ma, M., S. Ghosh, D. Tavernari, A. Katarkar, A. Clocchiatti, L. Mazzeo, A. Samarkina, et al. “Sustained Androgen Receptor Signaling Is a Determinant of Melanoma Cell Growth Potential and Tumorigenesis.” J Exp Med 218, no. 2 (February 1, 2021). https://doi.org/10.1084/jem.20201137.
Clocchiatti, A., S. Ghosh, M. G. Procopio, L. Mazzeo, P. Bordignon, P. Ostano, S. Goruppi, et al. “Androgen Receptor Functions as Transcriptional Repressor of Cancer-Associated Fibroblast Activation.” J Clin Invest 128, no. 12 (December 3, 2018): 5531–48. https://doi.org/10.1172/JCI99159.
Clocchiatti, A., E. Cora, Y. Zhang, and G. P. Dotto. “Sexual Dimorphism in Cancer.” Nat Rev Cancer 16, no. 5 (May 2016): 330–39. https://doi.org/10.1038/nrc.2016.30.
Dotto, G. P., and A. K. Rustgi. “Squamous Cell Cancers: A Unified Perspective on Biology and Genetics.” Cancer Cell 29, no. 5 (May 9, 2016): 622–37. https://doi.org/10.1016/j.ccell.2016.04.004.
Dotto, G. P. “Multifocal Epithelial Tumors and Field Cancerization: Stroma as a Primary Determinant.” J Clin Invest 124, no. 4 (April 1, 2014): 1446–53. https://doi.org/10.1172/JCI72589.
Hu, B., E. Castillo, L. Harewood, P. Ostano, A. Reymond, R. Dummer, W. Raffoul, W. Hoetzenecker, G. F. Hofbauer, and G. P. Dotto. “Multifocal Epithelial Tumors and Field Cancerization from Loss of Mesenchymal CSL Signaling.” Cell 149, no. 6 (June 8, 2012): 1207–20. https://doi.org/S0092-8674(12)00535-1 [pii] 10.1016/j.cell.2012.03.048.
Wu, X., B. C. Nguyen, P. Dziunycz, S. Chang, Y. Brooks, K. Lefort, G. F. Hofbauer, and G. P. Dotto. “Opposing Roles for Calcineurin and ATF3 in Squamous Skin Cancer.” Nature 465, no. 7296 (May 20, 2010): 368–72. https://doi.org/nature08996 [pii] 10.1038/nature08996.
Dotto, G. P. “Crosstalk of Notch with P53 and P63 in Cancer Growth Control.” Nat Rev Cancer 9, no. 8 (August 2009): 587–95. https://doi.org/nrc2675 [pii] 10.1038/nrc2675.
Di Cunto, F., G. Topley, E. Calautti, J. Hsiao, L. Ong, P. K. Seth, and G. P. Dotto. “Inhibitory Function of p21Cip1/WAF1 in Differentiation of Primary Mouse Keratinocytes Independent of Cell Cycle Control.” Science 280, no. 5366 (1998): 1069–72.
Opinion articles (English translation of the Italian articles provided in links):
Dotto, G. P. “Ambassadors of Peace: The Anthropology of War and How to Overcome the Human Killing Instinct.” EMBO Reports, August 19, 2024. https://doi.org/10.1038/s44319-024-00231-5.
Dotto, G. P. “To Be or Not to Be: The Second Law of Thermodynamics and the Flow of Life and Death.” EMBO Reports 21, no. 7 (July 3, 2020): e50861. https://doi.org/10.15252/embr.202050861.
Dotto, G. P. “Conjectures, Refutations and the Search for Truths: Science, Symbolic Truths and the Devil.” EMBO Reports 21, no. 2 (February 5, 2020): e49924. https://doi.org/10.15252/embr.201949924.
