Purinergic signaling mediated by exosomes in the plasticity of the tumor microenvironment and chemoresistance of Neuroblastoma

• Grant number: 21/04769-3
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Effective date (Start): February 01, 2022
• Effective date (End): January 31, 2027
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Claudiana Lameu
• Grantee: Rafael de Oliveira Faria
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

As the most common solid extracranial tumor in children, Neuroblastoma is responsible for 15% of infant mortality related to Cancer. Children older than one year with Neuroblastoma have a low chance of surviving (only 34%), with recurrence in more than 50% of the cases, and recurrent tumors are resistant to treatments. Chemotherapy is the standard treatment to fight Cancer, however, resistance to this therapy is present in 90% of invasive Cancers. One of the ways that tumor cells acquire tolerance to drugs is through dynamic changes in the Tumor Microenvironment (TME) during treatment. There is a cross-talk between tumor cells and their microenvironment that can occur through the secretion of biomarkers, such as ATP or through the transfer of molecules carried by exosomes. Purinergic signaling has gained attention in cell communication, since extracellular ATP and Adenosine (ADO), the main purinergic receptor agonists, are present at high levels in the TME. In addition, P2X7 and P2Y2 receptors are being linked to chemoresistance mechanisms in many types of Cancer, including Neuroblastoma. Another abundant component in TME are the Tumor-Associated Macrophages (TAM), although their presence correlates with poor prognosis due to involvement with immunosuppression, neovascularization, invasion, metastasis, and poor response to treatment, it is still unclear how TAMs acquire a pro-tumor phenotype. Thus, the objective of this project is to study the crosstalk between P2X7 and P2Y2 in tumor resistance. The exosomal content of Neuroblastoma will also be analyzed, using the in vitro chemoresistance model standardized by our group. The focus will be to quantify in the exosomes the expression of the ABC transporters and enzymes that control the levels of ATP and ADO. Besides to study how the chemoresistant cells-derived exosomes interfere in the polarization of TAMs and influence the fate of cells sensitive to resistance in the TME, correlating with the levels of ATP and ADO in the extracellular medium and expression of ABC transportes. (AU)