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.
Congratulations to Professor Alec C Kimmelman and co-authors from New York University, M.D. Anderson Cancer Center, and Dana-Farber Cancer Institute for their outstanding work published in Cell (IF=67)!
InvivoChem is proud to provide Professor Alec C Kimmelman’s team with our high-quality product Larotrectinib sulfate (LOXO-101; ARRY-470) (Cat #: V2599; CAS #: 1223405-08-0, TRK inhibitor) for this research.
References: Cell. 2020 Nov 25;183(5):1202-1218.e25. doi: 10.1016/j.cell.2020.10.016.
