A novel neuro-oncogenic mechanism involved in colorectal cancer progression

Introduction: The rising incidence of colorectal cancer (CRC) among young adults worldwide underscores the urgency to understand its underlying mechanisms and identify potential therapeutic targets. Similar to other cancers that are innervated, CRC cells are apposed to innervation from the neurons of the enteric nervous system (ENS) as well as from other gut-innervating neurons. However, the role of innervation in progression of CRC remains unknown. Here, we aim to identify an Opiod Growth Factor Receptor (OGFR)-Met Enkephalin (M-ENK)-PCSK1 based molecular mechanism through which enteric innervation may modulate CRC behavior. Methods: Single cell RNAseq data was used to identify OGFR expression by epithelial stem cells, and proenkephalin (PENK) expression by enteric neurons. Immunohistochemistry was used to observe proprotein convertase subtilisin/kexin-1 (PCSK1) expression by enteric neurons. Dexamethasone, to simulate stress response, was used to test the effect of stress on PCSK1 expression (by western blot and RT-PCR) and on PCSK1-mediated catalysis of PENK to the OGFR ligand M-ENK (by western blot). Results: Epithelial stem cells, and CRC cells expressed M-ENK receptor OGFR and ENS neurons expressed PENK and PCSK1. Dexamethasone significantly reduced expression of PCSK1 and M-ENK. Treatment of MC38 colon cancer cell with naloxone and recombinant M-ENK led to a significant reduction in cell replication. Conclusions: While stress is known to contribute to cancer progression, the neuronal mechanisms through which this occurs in CRC is not known. We show that stress significantly reduces neuronal expression of PCSK1, and the catalysis of PENK to the OGFR ligand M-ENK. Since reduced OGFR signaling has been associated with increased CRC progression, our data suggests that the OGFR – M-ENK – PCSK1 pathway is a potentially novel neuro-oncogenic mechanism that drives CRC progression. Our studies were supported by the National Institute of Aging R01AG66767 (SK), Deutsche Forschungsgemeinschaft SE 528835020 (PS), and Harvard Digestive Disease Center (SK). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.