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Involvement of the photosensitive and temporal controlling systems in the development, progression, and metastasis of malignant melanoma: an investigation of novel therapeutic targets

Grant number: 18/16511-8
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): April 01, 2019
Effective date (End): March 31, 2021
Field of knowledge:Biological Sciences - Physiology
Principal Investigator:Ana Maria de Lauro Castrucci
Grantee:Leonardo Vinícius Monteiro de Assis
Home Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

The photosensitive system of the skin has been known for more than 20 years; however, only in 2011 a significant advance regarding its functionality started to be reported. Our research group has been working in a pioneering fashion in the field. Thus far we have demonstrated that the skin photosensitive system not only participates in UVA-induced immediate pigment darkening, but also as thermo-sensor, which feeds the molecular clock of normal and malignant melanocytes. Within this line, the temporal control system of the skin has an elegant working mechanism whose role is evident in the physiological scenario; however, its participation in pathological conditions - more specifically in cancer - is still poorly understood. We have provided strong evidence that the molecular components of the clock are downregulated in malignant melanocytes; thus, demonstrating the establishment of chronodisruption in melanoma cancer when compared to health tissue. We have also shown in a pioneering fashion that a non-metastatic melanoma leads to chronodisruption in distant organs, and that in patients BMAL1 is a positive prognostic factor that can be used as a tool to discriminate patients that could benefit from immunotherapy regimes. Taken altogether, this project has the goal to elucidate the participation of melanopsin in the development, progression, and metastases of melanoma cancer through the usage of melanopsin knockout cell line and/or animals and its putative interaction with the skin biological clock. Several experimental protocols will be employed to reach this goal. Bioinformatics analysis will be performed in public database in order to establish targets for in vitro validation. In addition, this project will evaluate the role of central and peripheral clocks in the development of melanoma through the usage of genetically modified animals. To reach its goal this project has a multidisciplinary, international, and collaborative team as well as it will use elegant cellular models and genetically modified animals whose physiological phenomena will be evaluated by advanced techniques of molecular biology. The ultimate aim is to establish the photosensitive and molecular clock systems of the skin as potential therapeutic targets for the treatment of melanoma cancer.