Photo of G. Paolo Dotto,  MD, PhD

G. Paolo Dotto, MD, PhD

Massachusetts General Hospital

Massachusetts General Hospital
Phone: (617) 724-9538
Fax: (617) 726-4453


gdotto@partners.org

G. Paolo Dotto, MD, PhD

Massachusetts General Hospital

EDUCATIONAL TITLES

  • Biologist, Cutaneous Biology Research Center, Massachusetts General Hospital

DF/HCC PROGRAM AFFILIATION

Research Abstract

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. His group was the first to implicate the cyclin/CDK inhibitor p21WAF1/Cip1 in control of keratinocyte differentiation and cancer formation, showing that this molecule can directly impact on gene transcription independently of the cell cycle. Notch activation in mammalian cells is commonly thought to enhance stem cell potential and promote tumorigenesis. Dr. Dotto showed instead that in keratinocytes Notch signaling is an important determinant of differentiation and tumor suppression, with p21 WAF1/Cip1 and p63 as critical targets. Little is known on control of Notch1 gene expression. His laboratory established this gene as a direct p53 target in antagonism to EGFR signaling, validating these findings for cancer development in the clinical setting. They also discovered a novel pro-differentiation and tumor suppressing function of calcineurin signaling in keratinocytes, with the ATF3 transcription factor as a critical target. This is of major clinical significance for the many patients under treatment with calcineurin inhibitors as immunosuppressants, who develop squamous cell carcinoma as a very frequent and often deadly complication. Epithelial-mesenchymal interactions play a key role in epithelial organ morphogenesis and homeostasis. In this context, the Dotto's group has pioneered research on an entirely novel and unexpected role of the Notch pathway in the mesenchymal compartment of the skin. His group showed that this pathway is critically required in dermal papilla cells for control and maintenance of the hair follicle cell fate. More recently, they showed that dermal fibroblast alterations can play a primary role in cutaneous field cancerization, with loss of Notch/CSL signaling and associated AP1 activation as underlying mechanisms.

Publications

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  • Brooks YS, Ostano P, Jo SH, Dai J, Getsios S, Dziunycz P, Hofbauer GF, Cerveny K, Chiorino G, Lefort K, Dotto GP. Multifactorial ER硫 and NOTCH1 control of squamous differentiation and cancer. J Clin Invest 2014; 124:2260-76. PubMed
  • Dotto GP. Multifocal epithelial tumors and field cancerization: stroma as a primary determinant. J Clin Invest 2014; 124:1446-53. PubMed
  • Dotto GP, Karine L. miR-34a/SIRT6 in squamous differentiation and cancer. Cell Cycle 2014; 13:1055-6. PubMed
  • Dziunycz PJ, Lefort K, Wu X, Freiberger SN, Neu J, Djerbi N, Iotzowa-Weiss G, French LE, Dotto GP, Hofbauer GF. The Oncogene ATF3 Is Potentiated by Cyclosporine A and Ultraviolet Light A. J Invest Dermatol 2014. PubMed
  • Goruppi S, Dotto GP. Mesenchymal stroma: primary determinant and therapeutic target for epithelial cancer. Trends Cell Biol 2013; 23:593-602. PubMed
  • 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. A miR-34a-SIRT6 axis in the squamous cell differentiation network. EMBO J 2013; 32:2248-63. PubMed
  • Kim JE, Won CH, Bak H, Kositratna G, Manstein D, Dotto GP, Chang SE. Gene Profiling Analysis of the Early Effects of Ablative Fractional Carbon Dioxide Laser Treatment on Human Skin. Dermatol Surg 2013. PubMed
  • Hu B, Castillo E, Harewood L, Ostano P, Reymond A, Dummer R, Raffoul W, Hoetzenecker W, Hofbauer GF, Dotto GP. Multifocal epithelial tumors and field cancerization from loss of mesenchymal CSL signaling. Cell 2012; 149:1207-20. PubMed
  • Dotto GP. p63 and FGFR: when development meets proliferation. EMBO Mol Med 2012; 4:165-7. PubMed
  • Ferrándiz N, Caraballo JM, García-Gutierrez L, Devgan V, Rodriguez-Paredes M, Lafita MC, Bretones G, Quintanilla A, Muñoz-Alonso MJ, Blanco R, Reyes JC, Agell N, Delgado MD, Dotto GP, León J. p21 as a transcriptional co-repressor of S-phase and mitotic control genes. PLoS ONE 2012; 7:e37759. PubMed
  • Restivo G, Nguyen BC, Dziunycz P, Ristorcelli E, Ryan RJ, Ozuysal OY, Di Piazza M, Radtke F, Dixon MJ, Hofbauer GF, Lefort K, Dotto GP. IRF6 is a mediator of Notch pro-differentiation and tumour suppressive function in keratinocytes. EMBO J 2011. PubMed
  • Dotto GP. Calcineurin signaling as a negative determinant of keratinocyte cancer stem cell potential and carcinogenesis. Cancer Res 2011; 71:2029-33. PubMed
  • Hu B, Lefort K, Qiu W, Nguyen BC, Rajaram RD, Castillo E, He F, Chen Y, Angel P, Brisken C, Dotto GP. Control of hair follicle cell fate by underlying mesenchyme through a CSL-Wnt5a-FoxN1 regulatory axis. Genes Dev 2010; 24:1519-32. PubMed
  • Kang J, Yoo J, Lee S, Tang W, Aguilar B, Ramu S, Choi I, Otu HH, Shin JW, Dotto GP, Koh CJ, Detmar M, Hong YK. An exquisite cross-control mechanism among endothelial cell fate regulators directs the plasticity and heterogeneity of lymphatic endothelial cells. Blood 2010; 116:140-50. PubMed
  • Lyubimova A, Garber JJ, Upadhyay G, Sharov A, Anastasoaie F, Yajnik V, Cotsarelis G, Dotto GP, Botchkarev V, Snapper SB. Neural Wiskott-Aldrich syndrome protein modulates Wnt signaling and is required for hair follicle cycling in mice. J Clin Invest 2010; 120:446-56. PubMed
  • Wu, X. Nguyen, B. C. Dziunycz, P. Chang, S. Brooks, Y. Lefort, K. Hofbauer, G. F. Dotto, G. P.. Opposing roles for calcineurin and ATF3 in squamous skin cancer Nature 2010; 465:368-72.
  • Mandinova A, Kolev V, Neel V, Hu B, Stonely W, Lieb J, Wu X, Colli C, Han R, Pazin MJ, Pazin M, Ostano P, Dummer R, Brissette JL, Dotto GP. A positive FGFR3/FOXN1 feedback loop underlies benign skin keratosis versus squamous cell carcinoma formation in humans. J Clin Invest 2010; 119:3127-37. PubMed
  • Dotto GP. Notch tumor suppressor function. Oncogene 2008; 27:5115-23. PubMed
  • Kolev V, Mandinova A, Guinea-Viniegra J, Hu B, Lefort K, Lambertini C, Neel V, Dummer R, Wagner EF, Dotto GP. EGFR signalling as a negative regulator of Notch1 gene transcription and function in proliferating keratinocytes and cancer. Nat Cell Biol 2008; 10:902-11. PubMed
  • Mandinova A, Lefort K, Tommasi di Vignano A, Stonely W, Ostano P, Chiorino G, Iwaki H, Nakanishi J, Dotto GP. The FoxO3a gene is a key negative target of canonical Notch signalling in the keratinocyte UVB response. EMBO J 2008; 27:1243-54. PubMed
  • 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. PubMed
  • 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. PubMed
  • Oh H, Mammucari C, Nenci A, Cabodi S, Cohen SN, Dotto GP. Negative regulation of cell growth and differentiation by TSG101 through association with p21(Cip1/WAF1). Proc Natl Acad Sci U S A 2002; 99:5430-5. PubMed
  • 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. PubMed
  • Cabodi S, Calautti E, Talora C, Kuroki T, Stein PL, Dotto GP. A PKC-eta/Fyn-dependent pathway leading to keratinocyte growth arrest and differentiation. Mol Cell 2000; 6:1121-9. PubMed
  • Topley GI, Okuyama R, Gonzales JG, Conti C, Dotto GP. p21(WAF1/Cip1) functions as a suppressor of malignant skin tumor formation and a determinant of keratinocyte stem-cell potential. Proc Natl Acad Sci U S A 1999; 96:9089-94. PubMed
  • Calautti E, Cabodi S, Stein PL, Hatzfeld M, Kedersha N, Paolo Dotto G. Tyrosine phosphorylation and src family kinases control keratinocyte cell-cell adhesion. J Cell Biol 1998; 141:1449-65. PubMed
  • 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; 280:1069-72. PubMed
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