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Dotto Gian-Paolo, Full Professor

HUMAN EPITHELIAL STEM CELL SIGNALING AND CARCINOGENESIS | Publications | Group members
 


Gian-Paolo 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. After postdoctoral training at the Whitehead Institute/MIT in Cambridge, Mass., 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.

Paolo.Dotto@unil.ch

HUMAN EPITHELIAL STEM CELL SIGNALING AND CARCINOGENESIS

Self-renewal of human epithelial stem cells versus their commitment to differentiation are closely linked. Understanding this process is of great potential impact for new therapeutic approaches to human tumors, which are mostly of epithelial origin. Our main interest is the interplay between intra- and inter-cellular signaling pathways involved in control of epithelial tissue homeostasis and tumor development. Our present research is focused on two main topics : (i) intrinsic control mechanisms underlying the balance between epithelial stem cell renewal and differentiation; (ii) role of underlying mesenchymal cells in control of epithelial cell fate determination and tumorigenesis. For a general overview of our research efforts and their impact, see the enclosed interview article.

pdf   Article_interview_Research_Media.pdf  (3029 Kb)

1) The gene regulatory network involved in intrinsic keratinocyte growth/differentiation control.

Keratinocytes and skin provide an attractive experimental system to study the connection between growth/differentiation potential of epithelial cells and transformation. Notch signalling is an important form of cell-cell communication with a function that is highly context-dependent. A substantial body of evidence (reviewed in1) has confirmed and expanded our original findings that this pathway plays a key role in promoting epidermal cell differentiation and suppressing tumor development 2,3. We showed that the Notch1 gene, which plays the most critical function in keratinocytes, is a direct target of p53 and that down-modulation of Notch1 expression in keratinocyte-derived tumors can be explained by mutation of p53 4 or down-modulation of p53 expression by increased EGFR activation 5 or calcineurin inhibition 6. Notch activation, in turn, suppresses p63, a p53-related transcription factor with an essential role in maintenance of keratinocyte self renewing populations 7. The cross-talk between Notch, p53/EGFR and p63 is at the core of a genetic network with key role in keratinocyte growth/differentiation control and tumor development. Another components of this network with an essential role in epidermal development and differentiation is IRF6, a transcription factor of the IRF (Interferon Responsive Factors) family that we have recently established as Notch target 8. Importantly, deep sequencing analysis of oral, skin and lung squamous cell carcinomas (SCCs) by a number of other laboratories has revealed that one or more components of the Notch/p53/p63 network can be inactivated by mutations in human SCCs, confirming their key role in the disease 9-12. We are currently further exploring regulation and function of this gene network in the skin.

Summary diagram of the Notch-connected network involved in keratinocyte differentiation and tumor suppression. A set of representative genes with a known or likely role in keratinocyte differentiation and Notch signalling is indicated. For explanation and more complete specification of network elements and connections, see the text above and indicated references.

2) The dermal fibroblast gene regulatory network involved in skin field cancerization.

While great attention has been paid to the role of Notch signalling in the epithelial compartment of the skin, we have started to explore the role of this pathway in the underlying mesenchyme. We have developed a genetic mouse model with loss of Notch signalling in the mesenchymal compartment of the skin, finding that this pathway is essential for cell fate maintenance of overlying hair follicle keratinocytes 13. More importantly, by combined analysis of the mouse model and clinically-derived skin samples, we have uncovered a novel essential role of mesenchymal Notch signalling in field cancerization in the skin 14. Epithelial tumours are usually thought to result from genetic changes in a discrete group of cells, originating from a single initial progenitor, and of changes in immediately surrounding normal cells. The field cancerization process refers instead to pro-tumourigenic changes, in both epithelial cells and surrounding stromal cells, that occur in larger areas, or "fields", of target organs like the skin, oral cavity, lung, prostate and breast. The widespread changes help explaining the frequent multifocality of epithelial tumors and the fact that, after removal, these tumors often recur. Field cancerization has been linked to the presence of genetic pro-tumourigenic changes in apparently normal ‘patches’ of epithelial cells that expand over time. Our recent findings indicate that compromised Notch signalling in the underlying dermal fibroblasts is likely to play an equally important primary role, resulting in tissue alterations (stromal atrophy and inflammation) that precede premalignant and malignant epithelial tumor development 14. Mechanistically, Notch signaling in dermal fibroblasts of both murine and human origin results in intrinsically increased expression of diffusible growth factors and inflammatory cytokines, cancer-associated matrix components and matrix remodeling enzymes, which are amenable to up-regulation of AP1 levels and activity 14. The findings are of likely clinical significance, as suppression of Notch/CSL signaling and associated gene expression events occur in stromal fields adjacent to cutaneous premalignant lesions (actinic keratosis), and can be induced by UVA exposure, a major cause of skin chronic and cancer-predisposing alterations 14. We have established an intensive research effort to further explore the molecular and cellular basis of field cancerization in the skin. 

 

Summary diagram of the Notch-connected network involved in dermal fibroblast activation and skin field cancerization. The genes in the network are partially overlapping with those involved in the keratinocyte network illustrated above. The diagram is based on our recent findings that UVA exposure of human skin / dermal fibroblasts induces down-modulation of Notch expression and activity through specific mechanisms like increased DNA methylation of the Notch2 promoter 14. Notch suppression leads to up-regulated expression of AP1 family members and of AP1 target genes with a role in inflammation, promotion of cancer development and/or aging 14.

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Publications

Cited publications

  1. Dotto, G.P. Notch tumor suppressor function. Oncogene. 2008 Sep 1;27(38):5115-23. doi: 10.1038/onc.2008.225.
  2. Nicolas, M., et al. Notch1 functions as a tumor suppressor in mouse skin. Nat Genet. 2003 Mar;33(3):416-21. Epub 2003 Feb 18.
  3. Rangarajan, A., et al. Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J. 2001 Jul 2;20(13):3427-36.
  4. Lefort, K., et al. Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCKalpha kinases. Genes Dev. 2007 Mar 1;21(5):562-77.
  5. Kolev, V., et al. EGFR signalling as a negative regulator of Notch1 gene transcription and function in proliferating keratinocytes and cancer. Nat Cell Biol. 2008 Aug;10(8):902-11. doi: 10.1038/ncb1750. Epub 2008 Jul 6.
  6. Wu, X., et al. Opposing roles for calcineurin and ATF3 in squamous skin cancer. Nature. 2010 May 20;465(7296):368-72. doi: 10.1038/nature08996.
  7. Nguyen, B.C., et al. Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation. Genes Dev. 2006 Apr 15;20(8):1028-42.
  8. Restivo, G., et al. IRF6 is a mediator of Notch pro-differentiation and tumour suppressive function in keratinocytes. EMBO J. 2011 Nov 16;30(22):4571-85. doi: 10.1038/emboj.2011.325.
  9. Agrawal, N., et al. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science. 2011 Aug 26;333(6046):1154-7. doi: 10.1126/science.1206923. Epub 2011 Jul 28.
  10. Durinck, S., et al. Temporal Dissection of Tumorigenesis in Primary Cancers. Cancer Discov. 2011 Jul;1(2):137-43. doi: 10.1158/2159-8290.CD-11-0028. Epub 2011 Jun 29.
  11. Stransky, N., et al. The mutational landscape of head and neck squamous cell carcinoma. Science. 2011 Aug 26;333(6046):1157-60. doi: 10.1126/science.1208130. Epub 2011 Jul 28.
  12. Wang, N.J., et al. Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma. Proc Natl Acad Sci U S A. 2011 Oct 25;108(43):17761-6. doi: 10.1073/pnas.1114669108. Epub 2011 Oct 17.
  13. Hu, B., et al. Control of hair follicle cell fate by underlying mesenchyme through a CSL-Wnt5a-FoxN1 regulatory axis. Genes Dev. 2010 Jul 15;24(14):1519-32. doi: 10.1101/gad.1886910.
  14. Hu, B., et al. Multifocal epithelial tumors and field cancerization from loss of mesenchymal CSL signaling. Cell. 2012 Jun 8;149(6):1207-20. doi: 10.1016/j.cell.2012.03.048.

 

Honors and Awards

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
2002 -2003 NIH study section member (GMA-1)
2005/2007 Vice Chair/Chair Gordon Conference on Epithelial Differentiation
2010 Lecturing Professor, “Oncology at the Limits”, Cape Town, South Africa
2010 “Irwin Blank Symposium Lecture”, Society of Investigative Dermatology Meeting, Atlanta, Georgia
2011 Elected EMBO membership
2012 American Skin Association Lifetime Achievement Award
2013 European Research Council Panel Member, in “Physiology, Pathophysiology and Endocrynology”.

 

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Group members

Dania Al Labban Ph.D student
Pino Bordignon Ph.D student
Raissa Bortolotto Erasmus student
Elisa Cora Postdoctoral fellow
Dong Eun Kim Ph.D student
Csaba Laszlo Postdoctoral fellow
Karine Lefort Project leader
Elena Menietti Ph.D student
Corentin Pasche Technician
Maria Procopio Ph.D student

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