Gian Paolo Dotto

Full professor

email: paolo.dotto@unil.ch
phone: 00416925720
building: F
room: 511

BIOGRAPHICAL SKETCH
NAME: Gian Paolo Dotto

EDUCATION/TRAINING

Turin Medical School, Italy M.D. 1979 Medicine
The Rockefeller University, New York NY Ph.D. 1983 Genetics
The Rockefeller University, New York NY Res. Fellow 1983 Genetics
Cancer Center & Whitehead Institute, Cambridge MA Postdoc 2010 Biology

A. Personal Statement
Dr. Dotto's main research interest has been control of epithelial tissue homeostasis and carcinogenesis, using skin as model system. His earlier work focused on the biochemical and cell-cell communication events underlying the onset of keratinocyte differentiation, elucidating the role that specific tyrosine kinase activation and gap junction communication play in this process. His other major research contributions are summarized in section C below. The concepts that he developed for the dermatological field are universally applicable to a wide variety of tissues and organs, bearing on other specialties, in particular, those related to normal and abnormal tissue development, inflammation, aging and cancer. Recently published and ongoing results have substantial translational implications. In fact, Dr. Dotto’s research is poised to provide novel treatments, which have the potential to transform procedural dermatology as well as other specialties.

B. Positions and Honors
Positions and Employment
1987 Assistant Professor; Dept. of Pathology & Biology, Yale University School of Medicine, New Haven CT
1992 Associate Professor; Dept. of Pathology & Biology, Yale University School of Medicine, New Haven CT
1992-2000 Associate Professor, Harvard Medical School, Dept. of Dermatology, Boston, MA
1992-2000 Associate Biologist (Dermatology), Massachusetts General Hospital, Boston MA
2000- Biologist (Dermatology), Massachusetts General Hospital, Boston MA
2000-2004 Professor, Harvard Medical School, Department of Dermatology, Boston, MA
2002- Professor, Institute of Biochemistry, University of Lausanne, Switzerland

Other Experience and Professional Memberships
1999- Member, Dana-Farber/Harvard Cancer Center, Boston, MA
2007 - Director, International PhD Program in Cancer and Immunology, UNIL-ISREC, University of
Lausanne, Switzerland 2007 - Director, International PhD Program in Cancer and Immunology,
UNIL-ISREC, University of Lausanne, Switzerland

Honors
1982 Grant-in-Aid of Research of the Sigma Xi, The Scientific Research Society, New Haven, CT
1984 Fellow; The Jane Coffin Childs Memorial Fund, New Haven CT
1987 Hull Cancer Research Award
1988 Swebilius Cancer Research Award
2001 Honorary Masters’ degree, Harvard University
2004-2006 Permanent member, NIH ACTS study section
2005-2007 Vice Chair/Chair Gordon Research Conference on Epithelial Differentiation
2011 Elected EMBO member
2012 Academia Europaea elected member
2012 American Skin Association Achievement Award
2013- Member, European Research Council Review Panel “Physiology/Pathophysiology/Endocrinology”
2013- German National Academy of Sciences, Leopoldina, Elected Member
2013- Advanced European Research Council investigator award
2015 Jurg Tschopp Award for Excellence in Biological Sciences
2018 Overseas Fellow of the Royal Society of Medicine


C. Contribution to Science
Dr. Dotto has opened major new perspectives on the complex balance that presides over epithelial stem cell renewal and tumorigenesis. He is known widely in tumor biology for his studies of the interplay between intracellular and intercellular cell communication pathways that control normal tissue homeostasis, using skin as a model. He has focused on how alterations in this equilibrium lead to epithelial 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. Countering these effects, his research group has also shown that in tumor cells, squamous differentiation can be a reversible process, so that differentiated cells may be a quiescent reservoir of cancer initiating populations. More recently, they showed that genetic or epigenetic alterations of stromal fibroblasts can play a primary role in field cancerization, a condition of major clinical significance in skin and many internal organs. Dr. Dotto’s laboratory has been responsible for the following major contributions:

1) His group was the first to implicate the cyclin/CDK inhibitor p21WAF1/Cip1 in control of keratinocyte differentiation, showing that p21WAF1/Cip1 can directly control gene transcription independently of the cell cycle, suppressing specific Wnt family members with a key role in keratinocyte stem cell renewal
a. 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. PMID: 9582119
b. Devgan, V., Rajashekara V, Mammucari C, Millar SE, Brisken C and Dotto G.P. p21WAF1/Cip1 is a negative transcriptional regulator of Wnt4 expression downstream of Notch1 activation. Genes & Dev 2005; 19:1485-1495. PCMID: PMC1151665.

2) Notch activation in mammalian cells is commonly thought to enhance stem cell potential and promote tumorigenesis. Dr. Dotto’s group was the first to show that Notch signalling can also function as a positive determinant of differentiation and tumor suppression, in keratinocytes of both mouse and human origin and with p21 waf1/cip1 and p63 as critical targets.
a. Rangarajan A,Talora C, Nicolas M, Okuyama R, Mammucari C, Oh H, Aster JC, Krishna S, Metzger D, Chambon P, Miele L, Aguet M, Radtke F, Dotto GP. 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. PMCID: PMC125257.
b. Nicolas M, Wolfer A, Raj K, Kummer JA, Mill P, Van Noort M, Hui CC, Clevers H, Dotto GP, Radtke F. Notch1 functions as a tumor suppressor in mouse skin. Nat Genet., 2003; 33:416-21 PMID: 12590261
c. Nguyen, B. C., Lefort, K., Mandinova, A., Antonini, D., Devgan, V., Della Gatta, G., Koster, M. I., Zhang, Z., Wang, J., di Vignano, A. T., Kitajewski, J., Chiorino, G., Roop, D. R., Missero, C. & Dotto, G. P. Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation. Genes & Dev, 2006; 20, 1028-42. PMCID: PMC1472299
d. Dotto, G.P, and Rustgi, A., (2016) Squamous cell cancers: a unified perspective on biology and genetics. Cancer Cell; 29, 622-637 PMCID: PMC4870309
e. 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. PCMID: PMC5983322

3) Surprisingly little is known regarding expression control of the Notch1 gene, in keratinocytes as in other cell types. The Dotto laboratory established Notch1 as a direct target of p53, downstream of UV activation and in antagonism to EGFR signalling, thereby providing an explanation for the down-modulation of Notch1 expression in squamous cell carcinoma in which p53 is mutated and EGFR activated. Recent deep sequencing analysis has provided a striking validation of the importance of the Notch-centered network pioneered by the Dotto group in oral, skin, lung and esophageal SCCs. More recently, and rather excitingly for possible novel translational approaches, they established the Notch1 gene as a direct positive target of Estrogen Receptor ß (ER-ß) in keratinocytes, with ER-ß selective agonists exerting a significant pro-differentiation and tumor suppressive function.
a. Lefort K., Mandinova A, Ostano P., Kolev V., Calpini V., Kolfschoten I., Devgan V, Lieb J, Raffoul W, Hohl D, Neel V, Garlick J, Chiorino G, and Dotto GP. (2007) Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCKa kinases. Genes & Dev.; 21, 562-77 PMCID: PMC1820898
b. Kolev V, Mandinova A, Guinea-Viniegra J, Hu B, Lefort K, Lambertini , Neel V, Dummer R, Wagner EF and Dotto GP. (2008) EGFR signaling as negative regulator of Notch1 gene transcription and function in proliferating keratinocytes and cancer. Nature Cell Biology, , 10 : 902-911. PMCID: 2747621
c. Brooks YS, Ostano P, Jo SH, Dai J, Getsios S, Dziunycz P, Hofbauer GF, Cerveny K, Chiorino G, Lefort K, Dotto GP. (2014) Multifactorial ERβ and NOTCH1 control of squamous differentiation and cancer. J Clin Invest.; 124 :2260-76. doi: 10.1172/JCI72718. Epub 2014 Apr 17. PMCID: PMC4002597
d. Clocchiatti, A., Cora, E.,, Zhang, Y. and Dotto, G.P. Sexual dimorphism in cancer. Nature Reviews Cancer 2016 16: p. 330-9. PMID: 27079803

4) Calcineurin/NFAT signaling is intensely studied for its role in the immune system. The Dotto group established that this pathway plays an unexpected pro-differentiation and tumor suppressing function in keratinocytes, in interconnection with Notch and p53. While calcineurin inhibitors such as cyclosporine are used as immunosuppressive agents (eg to prevent kidney allograft rejection), these patients experience an extraordinarily high incidence of cutaneous Squamous Cell Carcinomas. The Dotto group reported in Nature that calcineurin inhibition stimulated tumorigenesis within keratinocytes harbouring single-hit Ras mutations (which were otherwise clinically insignificant). These findings are of major importance for the many patients requiring systemic immunosuppression, for whom the development of squamous cell carcinoma is a very frequent and sometimes deadly complication.
a. Wu, X., Nguyen, B.C., Dziunycz, P., Chang, S., Brooks, Y., Lefort, K., Hofbauer, G.F.L., and Dotto, G.P. (2010) Calcineurin and ATF3: opposite role in keratinocyte cancer development versus senescence.: Nature 20, 465, 368-372. PMCID: PMC3050632

5) The Dotto group has recently discovered a novel and unexpected role for Notch/CSL signaling in the mesenchymal compartment of the skin: control of hair follicle cell fate and field cancerization, a condition of major clinical significance, which involves multifocal and recurrent epithelial tumors and surrounding epithelial and stromal tissue alterations. Changes in tumor stroma are most frequently viewed as secondary to changes in the epithelium. However, the Dotto’s laboratory provided the first demonstration that specific genetic/epigenetic changes in dermal fibroblasts, resulting from compromised Notch/CSL signaling, lead to a Cancer Associated Fibroblast (CAF) phenotype and can play a primary role in keratinocyte tumor development. They further implicated inflammation as an important link between stromal fibroblast alterations and field cancerization and showed that anti-inflammatory agents can be used to substantially retard this process. Further, they unveiled direct functional and biochemical interactions between the CSL and p53 proteins that are at the basis of stromal cell senescence as a fail safe mechanism against full CAF activation and cancer/stromal cell expansion. More recently, they obtained evidence of a nuclear super-repressor complex of CAF activation, with CSL associating with the stress responsive transcription factor ATF3 and Androgen Receptor in negative control of CAF effector genes and metabolic reprogramming (through induction of the autophagic process).

a. Hu, B., Lefort, K., Qiu, W., Nguyen, B.C., Rajaram, R.D., Castillo, E., He, F., Chen, Y., Angel, P., Brisken,C., and Dotto, G.P. (2010) Control of hair follicle cell fate by underlying mesenchyme through a CSL - Wnt5a-FoxN1 regulatory axis. Genes & Dev., 24, 1519-1532 PMCID: PMC2904942
b. 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) Loss of mesenchymal CSL signaling leads to field cancerization and multifocal epithelial tumor development. Cell, 149, 1207–1220 PMCID: PMC3578441
c. Dotto, G.P. Multifocal epithelial tumors and field cancerization: stroma as a primary determinant. J Clin Invest. (2014); 124 :1 446-53. PMCID: PMC3973113
d. Procopio MG, Laszlo C, Al Labban D, Kim DE, Bordignon P, Jo SH, Goruppi S, Menietti E, Ostano P, Ala U, Provero P, Hoetzenecker W, Neel V, Kilarski WW, Swartz MA, Brisken C, Lefort K, Dotto GP. (2015) Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation. Nat Cell Biol. , 17:1193-204. doi: 10.1038/ncb3228. Epub 2015 Aug 24. PMCID: PMC4699446
e. Menietti, E., Xu, X., Ostano, P., Joseph, J.M., Lefort, K. and Dotto G.P. (2016) Negative control of CSL gene transcription by stress/DNA damage response and p53. Cell Cycle, 15, 1767-1778 PMCID: PMC4957600
f. Jo, S.H., Kim, D.E., Clocchiatti, A. and G.P. Dotto. (2016) PDCD4 is a CSL associated protein with a transcription repressive function in cancer associated fibroblast activation. Oncotarget : PMCID: PMC5312270
g. Clocchiatti, A., Cora, E.,, Zhang, Y. and Dotto, G.P. Sexual dimorphism in cancer. Nature Reviews Cancer 2016 16: p. 330-9PMID: 27079803
h. Ozdemir, B. 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. PMCID: PMC5518637
i. 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. 214:2349-2368. PMCID: PMC5551580
l. 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. PMCID: PMC5616185
m. 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
n. 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. In press doi: 10.1172/JCI99159

Complete List of Published Work in MyBibliography:
https://applicationspub.unil.ch/interpub/noauth/php/Un/UnPers.php?PerNum=49320&LanCode=37&menu=pub


© Università degli Studi di Roma "La Sapienza" - Piazzale Aldo Moro 5, 00185 Roma