Prof. G.Paolo Dotto (MD PhD)

Full Professor of Biochemistry, University of Lausanne, Switzerland

Biologist, Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School

 

 

ABOUT

Dr. Dotto received his MD from the University of Turin, Italy, in 1979, and his PhD in Genetics from the Rockefeller University, New York, in 1983, followed by postdoctoral training with Robert A. Weinberg at the Whitehead Institute/MIT in Cambridge, Massachusetts.

In 1987 Dr. Dotto joined Yale University, New Haven, Connecticut, as assistant professor of Pathology. In 1992 he was promoted to the rank of associate professor and soon after moved to Harvard Medical School, as associate professor of Dermatology in the newly established Cutaneous Biology Research Center. In 2000 he was promoted to the rank of Professor at Harvard Medical School and Biologist at Massachusetts General Hospital.

In 2002 he accepted a position of Professor in the Department of Biochemistry at the University of Lausanne, while retaining his position of Biologist at Massachusetts General Hospital.

He has been elected to the European Molecular Biology Organization (2011), the Academia Europaea (2012) and the Leopoldina German National Academy of Sciences (2014) and is the recipient of a number of awards, including the American Skin Association Achievement Award (2012) and an Advanced ERC investigator grant award (2013).

 

Links:

University of Lausanne

Massachusetts General Hospital

  • Field cancerization 70%
  • Squamous cell differentiation and cancer prevention 60%
  • Epithelial-mesenchymal interactions 40%
  • Notch, p53 and Estrogen signaling 40%

RESEARCH INTERESTS

Our main research efforts are focused on control of epithelial tissue homeostasis and carcinogenesis, using skin as model system. We are focusing on two key questions:

1) the intracellular regulatory mechanisms that control the balance between squamous cell differentiation and tumorgenesis;

2) the role of mesenchymal stromal cells in control of tissu aging, inflammation and keratinocyte tumor development.

Currently, Prof. Dotto is the principle investigator of a major ICPI-supported development initiative on cervical cancer prevention in Cameroon. This project aims to invest in the sustainable development of the local public health care system while extracting valuable epidemiological data and novel molecular science.

RELEVANT PUBLICATIONS (of >110 total)

  1. 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.
  2. Cabodi S, Calautti E, Talora C, Kuroki T, Stein PL, Dotto GP. A Protein Kinase C-eta/ƒyn dependent pathway leading to keratinocyte growth arrest and differentiation. Mol. Cell 2000; 6:1121-1129.
  3. 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.
  4. Calautti E, Grossi M, Mammucari C, Aoyama Y, Pirro M, Ono Y, Li J, Dotto GP. Fyn tyrosine kinase is a downstream mediator of Rho/PRK2 function in keratinocyte cell-cell adhesion. J Cell Biol., 2002; 156:137-48.
  5. Talora C, Sgroi, DC, Crum CP, Dotto GP. Specific down-modulation of Notch1 signaling in cervical cancer cells is required for sustained HPV-E6/E7 expression and late steps of malignant transformation. Genes & Dev. 2002; 16:2252-63.
  6. 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.
  7. Okuyama R, Nguyen C, Talora T, Ogawa E, Tommasi di Vignano A, Lioumi M, Chiorino G, Tagami H, Woo M, and Dotto GP. High commitment of embryonic keratinocytes to terminal differentiation through a Notch1 – caspase 3 regulatory mechanism. Dev. Cell, 2004; 6:551-62.
  8. Mammucari, C., Tommasi di Vignano, A., Sharov, A. A., Havrda, M. C., Roop, D. R., Botchkarev, V. A., Crabtree, G. R. & Dotto, G. P., Integration of Notch1 and Calcineurin/NFAT signaling pathways in keratinocyte growth and differentiation control. Dev Cell 2005; 8:665-76.
  9. 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.
  10. 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.
  11. 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. Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCKa kinases. Genes & Dev. 2007; 21, 562-77.
  12. Mandinova A, Lefort K, Tommasi di Vignano A, Stonely W, Ostano P, Chiorino G, Iwaki H, Nakanish J, and Dotto GP. The FoxO3a gene is a key negative target of canonical Notch signaling in the keratinocyte UVB-response. EMBO J. 2008, 27:1243-54. PMCID: PMC2367396
  13. Kolev V, Mandinova A, Guinea-Viniegra J, Hu B, Lefort K, Lambertini , Neel V, Dummer R, Wagner EF and Dotto GP. EGFR signaling as negative regulator of Notch1 gene transcription and function in proliferating keratinocytes and cancer. Nature Cell Biology, 2008, 10 : 902-911. PMC2747621
  14. Dotto GP, Notch tumor suppressor function. Oncogene, 2008, 27: 5115-5123. PMC2747622
  15. Mandinova A, Kolev V, V Neel, B Hu, W Stonely, J Lieb, X Wu, C Colli, R Han, M Pazin, P Ostano, R Dummer, JL Brissette, and Dotto GP. An FGFR3/FOXN1 positive loop underlies benign skin keratosis versus squamous cell carcinoma formation. J Clin Invest. 2009: 119 : 3127-3137. PMC2752067
  16. Dotto GP. Crosstalk of Notch with p53 and p63 in cancer growth control. Nature Reviews Cancer 2009; 9: 587-595 PMID: 19609265
  17. Wu, X., Nguyen, B.C., Dziunycz, P., Chang, S., Brooks, Y., Lefort, K., Hofbauer, G.F.L., and Dotto, G.P. Calcineurin and ATF3: opposite role in keratinocyte cancer development versus senescence. 2010: Nature 465, 368-372. PMCID: PMC3050632
  18. 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
  19. Dotto GP. Calcineurin signaling as a negative determinant of keratinocyte cancer stem cell potential and carcinogenesis. Cancer Res. 2011; 6: 2029-2033. PMID: 21406393
  20. Restivo, G., Nguyen, B.C., Dziunycz, P., Ristorcelli, E., Ryan, R.J., Ozuysal, O.Y., Di Piazza, M., Radtke, F., Dixon, M.J., Hofbauer, G.F., Lefort, K. and Dotto, G.P. (2011). IRF6 is a mediator of Notch pro-differentiation and tumour suppressive function in keratinocytes. EMBO J., 30, 4571-85. PMCID: PMC3243593
  21. 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
  22. Lefort, K, Brooks, Y, Ostano, P, Cario-André, M, Calpini, V, Guinea-Viniegra, J, Albinger-Hegyi, A, Hoetzenecker, W, Kolfschoten, I, Wagner, EF, Werner, S, Dotto, GP. (2013) A miR-34a-SIRT6 axis in the squamous cell differentiation network. EMBO J., 32: 2248-63 PMCID: PMC3746195
  23. Goruppi, S. and Dotto, G.P. Mesenchymal stroma: primary determinant and therapeutic target for epithelial cancer. Trends Cell Biol. 2013; 23 : 593-602. doi: 10.1016/j.tcb.2013.08.006
  24. 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
  25. Brooks, Y., Ostano, P., Jo, S.-H., Dai, J., Getsios, S., Dziunycz, P., Hofbauer, G.F.L. Chiorino, G., Lefort, K. and Dotto G.P. (2014) Multifactorial ERß and Notch1 Control of Squamous Differentiation and Cancer. 2014, 124:2260-76. doi: 10.1172/JCI72718