Epithelial-mesenchymal interactions are key for organ morphogenesis, tissue homeostasis and carcinogenesis. Notch signaling is an important form of cell-cell communication with an essential pro- differentiation function in the epithelial compartment of the skin. Our main goal is to explore the role of this pathway in the underlying mesenchyme. We will test the following specific hypotheses: 1) Notch/CSL signaling in dermal fibroblasts may play an essential function in intrinsic control of proliferation potential versus senescence. We will expand on our preliminary findings that deletion of the CSL/RBP-J: gene, the key effector of Notch signaling, results in cell senescence and assess to what extent the Notch1 and/or Notch2 genes are involved. We will explore the underlying mechanisms and assess the significance of the findings for control of dermal aging in vivo. 2) Notch/CSL signaling in dermal cells may be involved in control of keratinocyte proliferation and tumor formation in the overlying epidermis. We will expand on our initial findings that mice with mesenchymal deletion of the CSL/RBP- J: gene exhibit epidermal hyperplasia followed by spontaneous multifocal keratinocyte tumor formation, and test whether these mice have also increased susceptibility to UVB-induced carcinogenesis. We will further explore the underlying mechanisms focusing, in particular, on specific diffusible factor(s) that are under Notch/CSL control in dermal fibroblasts and mitogenic for keratinocytes. 3) Mesenchymal Notch/CSL may play a similar role in human skin. We will assess the consequences of suppression of Notch/CSL signaling on senescence control mechanisms of human dermal fibroblasts and on the capability of these cells to affect proliferation and tumor formation of neighboring keratinocytes. By analysis of clinical samples, we will assess to what extent premalignant versus malignant keratinocytic lesions are linked to down-modulation of mesenchymal Notch signaling and associated molecular and cellular events. We will further investigate whether endogenous Notch signaling in the dermis of human skin is down-modulated as a consequence of UV exposure, a major etiological agent of aging and cancer.

Public Health Relevance

Notch signaling is an important form of cell-cell communication with an essential role in development, tissue homeostasis and cancer development. Our main working hypothesis is that this pathway plays an essential role in the mesenchymal compartment of the skin, with an impact on dermal fibroblast senescence and dermal aging- associated changes, as well as on paracrine control of keratinocyte proliferation and tumor development.)

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR039190-25
Application #
8459430
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Baker, Carl
Project Start
1988-07-01
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
25
Fiscal Year
2013
Total Cost
$431,247
Indirect Cost
$183,404
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Goruppi, Sandro; Jo, Seung-Hee; Laszlo, Csaba et al. (2018) Autophagy Controls CSL/RBPJ? Stability through a p62/SQSTM1-Dependent Mechanism. Cell Rep 24:3108-3114.e4
Al Labban, Dania; Jo, Seung-Hee; Ostano, Paola et al. (2018) Notch-effector CSL promotes squamous cell carcinoma by repressing histone demethylase KDM6B. J Clin Invest 128:2581-2599
Ă–zdemir, Berna C; Dotto, Gian-Paolo (2017) Racial Differences in Cancer Susceptibility and Survival: More Than the Color of the Skin? Trends Cancer 3:181-197
Goruppi, Sandro; Procopio, Maria-Giuseppina; Jo, Seunghee et al. (2017) The ULK3 Kinase Is Critical for Convergent Control of Cancer-Associated Fibroblast Activation by CSL and GLI. Cell Rep 20:2468-2479
Kim, Dong Eun; Procopio, Maria-Giuseppina; Ghosh, Soumitra et al. (2017) Convergent roles of ATF3 and CSL in chromatin control of cancer-associated fibroblast activation. J Exp Med 214:2349-2368
Jo, Seung-Hee; Kim, Dong Eun; Clocchiatti, Andrea et al. (2016) PDCD4 is a CSL associated protein with a transcription repressive function in cancer associated fibroblast activation. Oncotarget 7:58717-58727
Menietti, Elena; Xu, Xiaoying; Ostano, Paola et al. (2016) Negative control of CSL gene transcription by stress/DNA damage response and p53. Cell Cycle 15:1767-78
Dotto, G Paolo; Rustgi, Anil K (2016) Squamous Cell Cancers: A Unified Perspective on Biology and Genetics. Cancer Cell 29:622-637
Lefort, Karine; Ostano, Paola; Mello-Grand, Maurizia et al. (2016) Dual tumor suppressing and promoting function of Notch1 signaling in human prostate cancer. Oncotarget 7:48011-48026
Procopio, Maria-Giuseppina; Laszlo, Csaba; Al Labban, Dania et al. (2015) Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation. Nat Cell Biol 17:1193-204

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