Interaction of purinergic signaling receptors P2Y2 and P2X7 and its consequences on neuroblastoma chemoresistance

• Grant number: 24/20595-3
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: May 01, 2025
• End date: April 30, 2026
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Claudiana Lameu
• Grantee: Rafael de Oliveira Faria
• Supervisor: Francico Ciruela
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Universitat de Barcelona (UB), Spain
• Associated to the scholarship: 21/04769-3 - Purinergic signaling mediated by exosomes in the plasticity of the tumor microenvironment and chemoresistance of Neuroblastoma, BP.DD

Abstract

Neuroblastoma has high recurrence rates and is often resistant to traditional treatments. Advanced cases, especially those involving metastasis, face poor survival outcomes, largely due to drug resistance. Such resistance significantly limits effective treatment options and underscores the urgent need to understand and target mechanisms driving chemoresistance in neuroblastoma. A promising focus for addressing resistance in neuroblastoma lies in purinergic signaling pathways, specifically involving the P2X7 and P2Y2 receptors. The P2X7 receptor exists in two main isoforms, P2X7A and P2X7B. P2X7A, capable of forming large membrane pores, has a cytotoxic function, whereas P2X7B functions as a smaller ion channel with pro-tumor properties. The balance between these two isoforms appears to be crucial in regulating neuroblastoma cell survival and resistance to therapy. Recent studies from our group have shown that chemoresistant neuroblastoma cells exhibit reduced P2X7 expression and increased P2Y2 receptor expression. The P2Y2 receptor, is linked to cell migration, proliferation, and chemoresistance in multiple cancers. Our findings indicate a complex, isoform-dependent interaction between P2X7 and P2Y2 receptors, and this interaction may also depend on the cellular context (chemoresistant or not), resulting in different roles for the P2Y2 in the chemioresistance of neuroblastoma. Notably, studies in other cancer models have shown that P2Y2 can modulate P2X7's function, indicating a potentially cooperative role in drug resistance and cellular adaptation to chemotherapy. Understanding this cross-talk between P2X7 and P2Y2 could reveal specific therapeutic targets. Our collaboration with Professor Francisco Ciruela, who has pioneered fluorescence-based receptor oligomerization techniques, will allow us to study these receptor interactions in detail. By employing advanced oligomerization and protein-protein interaction assays, we aim to study the interaction between P2Y2 and P2X7 receptors, both in cellular models and in situ, and to understand the functional consequences of this interaction, as well as whether the P2X7 isoforms A and B influence these outcomes. This project could lay the foundation for new pharmacological strategies targeting receptor interactions to improve therapeutic outcomes in neuroblastoma and potentially other cancers characterized by high drug resistance.