Neurons Release Serine to Support mRNA Translation in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) tumors have a nutrient-poor, desmoplastic, and highly innervated tumor microenvironment. Although neurons can release stimulatory factors to accelerate PDAC tumorigenesis, the metabolic contribution of peripheral axons has not been explored. We found that peripheral axons release serine (Ser) to support the growth of exogenous Ser (exSer)-dependent PDAC cells during Ser/Gly (glycine) deprivation. Ser deprivation resulted in ribosomal stalling on two of the six Ser codons, TCC and TCT, and allowed the selective translation and secretion of nerve growth factor (NGF) by PDAC cells to promote tumor innervation. Consistent with this, exSer-dependent PDAC tumors grew slower and displayed enhanced innervation in mice on a Ser/Gly-free diet. Blockade of compensatory neuronal innervation using LOXO-101, a Trk-NGF inhibitor, further decreased PDAC tumor growth. Our data indicate that axonal-cancer metabolic crosstalk is a critical adaptation to support PDAC growth in nutrient poor environments. [Display omitted] •Nerves secrete amino acids, such as serine, to support PDAC growth and survival•PDAC cells exhibit metabolic plasticity, but protein synthesis is a bottleneck•Serine deprivation decreases mitochondria activity by affecting mRNA translation•Serine deprivation decreases mRNA translation of TCC and TCT serine codons The high level of innervation seen in pancreatic ductal adenocarcinoma tumors supplies serine and serine-deprived conditions promote tumor innervation to support growth in nutrient poor environments.