KRAS/ACTN4/p65-NR2A axis mediates glutamine-glutamate metabolic coupling between schwann cells and pancreatic cancer promoting perineural invasion.

INTRODUCTION

Pancreatic ductal adenocarcinoma (PDAC) exhibits aggressive perineural invasion (PNI), a hallmark of poor prognosis observed in 70-100% of cases. Schwann cells (SCs), key components of the tumor microenvironment, drive PNI via multiple pathways, yet the underlying mechanisms remain unclear.

OBJECTIVES

This study investigates the hypothesis that PDAC cells and SCs establish a glutamine-glutamate metabolic symbiosis to fuel PNI.

METHODS

Integrated approaches, including LC-MS metabolomics, isotopic tracing, co-culture systems, and in vivo models, were employed to analyze bidirectional metabolite exchange. Molecular assays and functional studies elucidated signaling pathways. The therapeutic potential of targeting glutamine transporters (SLC1A5/SLC7A5) and glutamate receptor NR2A was tested using inhibitors V9302 and PEAQX.

RESULTS

SCs secreted glutamine, which PDAC cells internalized via SLC1A5 and converted to glutamate. Glutamate activated SCs through NR2A, inducing ROS/NRF2-expression and upregulating glutamine synthetase (GS) and GLT-1, thereby regenerating glutamine to sustain the metabolic loop. KRAS-ACTN4-p65 signaling amplified this cycle by transcriptionally activating SLC1A5/SLC7A5 and GLS, while leucine uptake via SLC7A5 activated mTORC1 to promote invasion and PNI. In vivo, dual inhibition of SLC1A5/SLC7A5 (V9302) and NR2A (PEAQX) synergistically reduced tumor growth, PNI length, and improved sciatic nerve function in mice.

CONCLUSION

This study identifies a reciprocal glutamine-glutamate metabolic symbiosis between PDAC cells and SCs as a driver of PNI, orchestrated by KRAS-ACTN4-NF-κB signaling and glutamate-NR2A-ROS-NRF2 pathways. Disrupting this axis with V9302 and PEAQX offers a novel therapeutic strategy to target PDAC's metabolic adaptability and neurotrophic microenvironment.