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.
['Banh|Robert S|RS|', 'Biancur|Douglas E|DE|', 'Yamamoto|Keisuke|K|', 'Sohn|Albert S W|ASW|', 'Walters|Beth|B|', 'Kuljanin|Miljan|M|', 'Gikandi|Ajami|A|', 'Wang|Huamin|H|', 'Mancias|Joseph D|JD|', 'Schneider|Robert J|RJ|', 'Pacold|Michael E|ME|', 'Kimmelman|Alec C|AC|']
D000230:Adenocarcinoma D000368:Aged D000818:Animals D001369:Axons D021441:Carcinoma, Pancreatic Ductal D045744:Cell Line, Tumor D049109:Cell Proliferation D003062:Codon D005260:Female D005998:Glycine D006801:Humans D008297:Male D051379:Mice D008875:Middle Aged D008928:Mitochondria D009417:Nerve Tissue D009474:Neurons D010101:Oxygen Consumption D010190:Pancreatic Neoplasms D014176:Protein Biosynthesis D011720:Pyrazoles D011743:Pyrimidines D012333:RNA, Messenger D012343:RNA, Transfer D051381:Rats D012694:Serine
neurons serine mRNA translation pancreatic cancer metabolic crosstalk