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Control of Notch1 Gene Transcription in skin homeostasis and carcinogenesis

English title Control of Notch1 Gene Transcription in skin homeostasis and carcinogenesis
Applicant Dotto Gian-Paolo
Number 138653
Funding scheme Project funding (Div. I-III)
Research institution Département de Biochimie Faculté de Biologie et Médecine Université de Lausanne
Institution of higher education University of Lausanne - LA
Main discipline Experimental Cancer Research
Start/End 01.10.2011 - 30.09.2014
Approved amount 832'782.00
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All Disciplines (2)

Discipline
Experimental Cancer Research
Physiology : other topics

Keywords (4)

Notch; p53; Transcription factors; Differentiation

Lay Summary (English)

Lead
Lay summary

Epithelial-mesenchymal interactions play a determining function in organ morphogenesis, tissue homeostasis and carcinogenesis. Notch signaling is an important form of cell-cell communication with a key role in control of cell fate commitment. The role of this pathway in the epithelial cell compartments of organs like the skin is by now well established. In our most recent work funded by the SNF over the last three years, we have demonstrated that it plays an equally important function in the skin mesenchymal compartment.  In particular, we have found that down-modulation of the Notch1 gene plays an equally important tumor suppressing function in both keratinocytes and fibroblasts.  As a continuation of our work, we are now planning to dissect the molecular mechanisms involved in transcriptional control of the Notch1 gene, and test the hypothesis that restoration of normal mechanisms of Notch regulation in cancer cells and/or surrounding stroma will have substantial effects in promoting commitment to differentiation and suppressing tumor development.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Multifactorial ERbeta and NOTCH1 control of squamous differentiation and cancer
Brooks Y. S., Ostano P., Jo S. H., Dai J., Getsios S., Dziunycz P., Hofbauer G. F., Cerveny K., Chiorino G., Lefort K., Dotto G. P. (2014), Multifactorial ERbeta and NOTCH1 control of squamous differentiation and cancer, in J Clin Invest, 124, 2260-76.
Multifocal epithelial tumors and field cancerization: stroma as a primary determinant
Dotto G. P. (2014), Multifocal epithelial tumors and field cancerization: stroma as a primary determinant, in J Clin Invest, 124, 1446-53.
Small GTPase RhoE/Rnd3 is a critical regulator of Notch1 signaling
Zhu Z., Todorova K., Lee K. K., Wang J., Kwon E., Kehayov I., Kim H. G., Kolev V., Dotto G. P., Lee S. W., Mandinova A. (2014), Small GTPase RhoE/Rnd3 is a critical regulator of Notch1 signaling, in Cancer Res, 74, 2082-93.
The oncogene ATF3 is potentiated by cyclosporine A and ultraviolet light A
Dziunycz P. J., Lefort K., Wu X., Freiberger S. N., Neu J., Djerbi N., Iotzowa-Weiss G., French L. E., Dotto G. P., Hofbauer G. F. (2014), The oncogene ATF3 is potentiated by cyclosporine A and ultraviolet light A, in J Invest Dermatol, 134, 1998-2004.
A miR-34a-SIRT6 axis in the squamous cell differentiation network
Lefort K., Brooks Y., Ostano P., Cario-Andre M., Calpini V., Guinea-Viniegra J., Albinger-Hegyi A., Hoetzenecker W., Kolfschoten I., Wagner E. F., Werner S., Dotto G. P. (2013), A miR-34a-SIRT6 axis in the squamous cell differentiation network, in EMBO J, 32, 2248-63.
Gene profiling analysis of the early effects of ablative fractional carbon dioxide laser treatment on human skin
Kim J. E., Won C. H., Bak H., Kositratna G., Manstein D., Dotto G. P., Chang S. E. (2013), Gene profiling analysis of the early effects of ablative fractional carbon dioxide laser treatment on human skin, in Dermatol Surg, 39, 1033-43.
Mesenchymal stroma: primary determinant and therapeutic target for epithelial cancer
Goruppi S., Dotto G. P. (2013), Mesenchymal stroma: primary determinant and therapeutic target for epithelial cancer, in Trends Cell Biol, 23, 593-602.
The retinoid-related orphan receptor RORalpha promotes keratinocyte differentiation via FOXN1
Dai J., Brooks Y., Lefort K., Getsios S., Dotto G. P. (2013), The retinoid-related orphan receptor RORalpha promotes keratinocyte differentiation via FOXN1, in PLoS One, 8, 70392-70392.
Multifocal epithelial tumors and field cancerization from loss of mesenchymal CSL signaling
Hu B., Castillo E., Harewood L., Ostano P., Reymond A., Dummer R., Raffoul W., Hoetzenecker W., Hofbauer G. F., Dotto G. P. (2012), Multifocal epithelial tumors and field cancerization from loss of mesenchymal CSL signaling, in Cell, 149, 1207-20.
p63 and FGFR: when development meets proliferation
Dotto G. P. (2012), p63 and FGFR: when development meets proliferation, in EMBO Mol Med, 4, 165-7.
Calcineurin signaling as a negative determinant of keratinocyte cancer stem cell potential and carcinogenesis
Dotto G. P. (2011), Calcineurin signaling as a negative determinant of keratinocyte cancer stem cell potential and carcinogenesis, in Cancer Res, 71, 2029-33.
IRF6 is a mediator of Notch pro-differentiation and tumour suppressive function in keratinocytes
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., Dotto G. P. (2011), IRF6 is a mediator of Notch pro-differentiation and tumour suppressive function in keratinocytes, in EMBO J, 30, 4571-85.
p63 and epithelial metaplasia: a gutsy choice
Lefort K., Dotto G. P. (2011), p63 and epithelial metaplasia: a gutsy choice, in Cell, 145, 1003-5.

Collaboration

Group / person Country
Types of collaboration
Universitätsspital Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Notch Signaling in Development, Regeneration & Disease Talk given at a conference Notch and CSL in Cancer Fields 20.07.2014 Bates College, Lewiston, ME, United States of America Dotto Gian-Paolo;
Epithelial Differentiation and Keratinization Talk given at a conference Notch Signaling at the Interconnection between Skin Aging and Cancer 12.05.2013 Il Ciocco, Italy Dotto Gian-Paolo;
EMBO Members Meeting 2012 Talk given at a conference Homeostatic control of epithelial differentiation and carcinogenesis 24.10.2012 Heidelberg, Germany Dotto Gian-Paolo;
The Notch meeting V Talk given at a conference Loss of mesenchymal Notch/CSL signalling leads to field cancerization and epithelial tumor development 02.10.2011 Athens, Greece Dotto Gian-Paolo;


Awards

Title Year
Germany National Academy of Sciences, Leopoldina, elected member 2014
Advanced ERC investigator award 2013
Honorary Lecture, Turin University Doctoral Day ("D" Day) 2013
Academia Europaea elected Member 2012
American Skin Association Achievement Award 2012
Elected EMBO Member 2011

Associated projects

Number Title Start Funding scheme
150837 MicroSPECT/PET/CT for preclinical molecular imaging 01.12.2013 R'EQUIP
144001 Role of poly(ADP-ribose) polymerase-1 (PARP-1) during development of squamous cell carcinoma (SCC) 01.06.2012 International short research visits
122281 Notch signaling as a key determinant of Epithelial-Mesenchymal interactions in the skin 01.10.2008 Project funding (Div. I-III)
130576 miRNAs as integrative determinants of the keratinocyte response to UVB. 01.08.2010 Sinergia

Abstract

Epithelial-mesenchymal interactions play a determining function in organ morphogenesis, tissue homeostasis and carcinogenesis. Notch signaling is an important form of cell-cell communication with a key role in control of cell fate commitment. The role of this pathway in the epithelial cell compartments of organs like the skin is by now well established. In our most recent work funded by the SNF over the last three years, we have demonstrated that it plays an equally important function in the skin mesenchymal compartment. In particular, we have found that down-modulation of the Notch1 gene plays an equally important tumor suppressing function in both keratinocytes and fibroblasts. As a continuation of our work, we are now planning to dissect the molecular mechanisms involved in transcriptional control of the Notch1 gene, and test the hypothesis that restoration of normal mechanisms of Notch regulation in cancer cells and/or surrounding stroma will have substantial effects in promoting commitment to differentiation and suppressing tumor development.
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