Exploring perineural invasion (PNI) mechanisms in Pancreatic Cancer using hyperpolarized 13C NMR

ongoing

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with 5-year survival rate of less than 7%. Existing treatments are limited because 90-100% of patients develop perineural invasion (PNI). PNI is associated with severe pain, poor prognosis, poor survival, and tumor recurrence, and involves nerve invasion by cancer cells, as a result of dynamic interactions between them and other cells in the tumor microenvironment (TME). Schwann cells (SCs) are part of this TME and are activated by cancer cells to become PNI promoters. To date, the question of how metabolic dysregulation generated by cancer cells, characterized by different levels of lactate and an acidic TME drives SCs-mediated-PNI remains unanswered. Taking account that PNI is still poorly understood and that there are no PNI-targeted diagnosis methods or effective therapies, this project pursues the study of the role of metabolic alterations induced by PDAC cells on SCs, and how that drives SCs activation and PNI. To achieve this goal, nuclear magnetic resonance (NMR) mediated hyperpolarization of metabolites as contrast agents that could be used later in clinical diagnosis without adverse effects will be used. Hyperpolarization by Para-Hydrogen-Induced-Polarization (PHIP) boosts the detectable NMR and magnetic resonance image (MRI) metabolites signals by a factor of >10000, it allows obtaining precise kinetic data on metabolites’ inter-conversion on short timescales, and the insights from cells can be directly translated into in vivo studies. All of this represents an advantage over standard biological studies, which often struggle to capture these types of events. Using NMR-PHIP technology with cellular and molecular biology-based techniques on SCs-PDAC cells co-cultures and on an in vivo PNI model, this project will contribute to identifying new predictive biomarkers for future monitoring and early diagnosis of PNI, as well as to the potential development of PNI-targeted therapies.