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Role of collagen receptors DDR in mechanosignaling and therapeutic resistance in melanoma

Grant number: 22/05133-8
Support Opportunities:Scholarships abroad - Research Internship - Doctorate (Direct)
Effective date (Start): November 01, 2022
Effective date (End): October 31, 2023
Field of knowledge:Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
Principal Investigator:Leticia Veras Costa Lotufo
Grantee:Amanda Soares Hirata
Supervisor: Sophie Tartare-Deckert
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Research place: Université Côte d'Azur, France  
Associated to the scholarship:20/06613-8 - Characterization of seriniquinone mechanism of action in vemurafenibe resistant Melanoma cells, BP.DD

Abstract

Melanoma is the one of the most aggressive and refractory type of cancer, with a remarkable ability to adapt to microenvironmental influences. Its high cellular plasticity and consequent acquired resistance is due by genetic and non-genetic mechanisms, resulting in a heterogeneous tumor with a phenotypic cell spectrum. Non-genetic alterations are associated with transcriptional reprogramming, which melanoma cells change from a differentiated melanocytic and proliferative state to a dedifferentiated slow-cycling mesenchymal-like state. This process is called phenotypic switching and contributes to alternative survival pathways, invasive potential and, consequently, therapy evasion. Tumor cells have an intimate crosstalk with the surrounding microenvironment. The tumor microenvironment is characterized by a dynamic remodeling of the extracellular matrix (ECM) leading to increased collagen linearization and ECM stiffening. Discoidin domain receptors (DDR) are collagen receptors that contribute to various aspects of tumor progression and aggression. Tartare-Deckert's team described their role in mediating resistance to targeted therapy and revealed an original mechanosignaling loop that confers resistance in response to ECM rigidity. The present project aims to explore DDRs contribution, through gain and loss of DDR function, in phenotypic switching of melanoma cells in response to mechanical signals from the ECM and evaluate the influence of DDR-dependent signaling in drug evasion. Understanding these mechanisms will be important for the development of innovative treatments targeting the mechanical interplay associated with resistance and relapse. (AU)

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