Psychological stress-induced ALKBH5 deficiency promotes tumour innervation and pancreatic cancer progression via extracellular vesicle transfer of m6A-modified RNAs

Pathological role and the mechanism of psychological stress in cancer progression are little known. Here, we show in a mouse model that psychological stress drives pancreatic ductal adenocarcinoma (PDAC) progression via stimulating tumor nerve innervation. We demonstrate that nociception and other stressors activate sympathetic nerve to release Noradrenaline, downregulating tumor cell RNA demethylase alkB homolog 5 (Alkbh5). Alkbh5 deficiency causes cancer cell aberrant m6A modification of RNAs, which are packed to extracellular vesicles and delivered to neurons in the tumor microenvironment, enhancing hyperinnervation and PDAC progression. ALKBH5 levels are reversely correlated with tumor innervation and survival time in PDAC patients. Animal experiments identify a natural flavonoid Fisetin preventing neurons from taking in m6A-RNA contained EVs and suppress PDAC tumor excessive innervation and progression. Together, our study shed light on a novel molecular mechanism for neuro-cancer crosstalk linking psychological stress and cancer progression and raise a potential strategy for PDAC therapy. Overall design: We performed RNA sequencing data, proteomics data and assay for transposase-accessible chromatin with sequencing data obtained from isolated PADC cells to elucidate the mechanism for the stress to induce tumor progression. We performed RNA m6A-sequencing to elucidate RNA m6A methylation change in cell RNA and EV RNA after NA treatment or Alkbh5 KO. To evaluate the effects of EV-RNAs on neuronal transcriptional profiles, we performed RNA sequencing of neurons after transfection of EV-RNAs from Alkbh5-KO or control KPC cells. We also separated m6A-modified RNAs and non-m6A-modified RNAs extracted from Alkbh5-KO KPC cell produced EVs by RNA immunoprecipitation and then delivered them into neurons to elucidate the change of neuronal transcriptional profiles. This dataset includes RNA-seq of isolated tumor cell from orthotopic tumor tissue.