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Abstract

Pancreatic ductal adenocarcinoma (PDAC) stands as a formidable challenge in oncology due to its high mortality rate (5-year survival < 11%1 ) and neurotropic characteristics. The presence of hypertrophied nerves and neural invasion in virtually all patients correlates with worsened prognosis and severe pain. While tumour-nerve interactions and cancer metabolism are two prominent emerging fields, only few studies so far have set to understand how nerves can sustain or reprogram cancer metabolism. This study unravels the nerve-triggered metabolic reprogramming of PDAC cancer cells using spatial metabolomics at near single-cell level. Calcitonin Gene-Related Peptide (CGRP) and Substance P (SP) – key sensory neurotransmitters – increased triglycerides storage while glutamate – the most abundant excitatory neurotransmitter – promoted γ-glutamyl amino acid synthesis and downregulation of glutathione synthesis pathway. I developed a protocol for co-culture of cancer cells and primary neurons compatible with a state-of-the-art technology of spatial near single-cell metabolomics and could validate the γ-glutamyl amino acid-related findings, suggesting that cancer cells are able to use neurotransmitters for their own metabolism, and found other small molecule markers expressed only by cancer cells in presence with neurons. While spatial metabolomics was for a long time only used for tissue imaging, I show here the relevance of this tool to address complex mechanistic questions in advanced and pharmacologically relevant co-culture systems at the near single-cell level. This research shows the importance of spatial metabolomics towards understanding PDAC's neurotropism, paving the way for targeted therapies that disrupt nerve-driven metabolic reprogramming in cancer cells, alleviate patient suffering, and improve clinical outcomes. The structural changes of nerves within the tumour environment and their role in PDAC and pain management are unknown. Here, I showed that nerves in PDAC patients present unique ultrastructural features resembling nerve injury and defective repair mechanisms using targeted Correlative Light and Electron Microscopy (t-CLEM). I found that PDAC nerves contained less myelinated axons but more and smaller unmyelinated axons that presented bundling defects per Remak Schwann cell. Finally, this study provided the first high resolution characterisation of cancer cells invading nerves in PDAC patient tissue. These results open avenues for new perspectives on approaching neural alterations in PDAC, improving pain and quality of life management in patients, and further understanding neural plasticity.