Recruited Nerves Supply Serine to Support Pancreatic Cancer Growth

Greater tumor innervation in pancreatic ductal adenocarcinoma (PDAC) is correlated with poor prognosis. Nerve cell–tumor cell interactions may promote PDAC via a variety of mechanisms—for example, nerve cells release neurotransmitters that may stimulate growth—but whether nerve cells within PDAC tumors contribute to the tumors' metabolic demands is not established. Banh and colleagues found that the axons of rat dorsal root ganglion cells secreted amino acids, including the often growth-limiting serine, into nutrient-depleted medium, suggesting that neurons may be able to supply serine in the tumor microenvironment. Additionally, about 40% of human PDAC cell lines were dependent on exogenous serine for proliferation, and a similar percentage of human PDAC tumors did not express the serine biosynthesis enzyme PHGDH at the protein level. The proliferation of exogenous serine–dependent PDAC cells in serine-depleted medium could be restored via coculture with axons, which raised serine levels in the growth medium under these conditions. Depriving exogenous serine–dependent PDAC cells of serine reduced mRNA translation, decreasing their demand for ATP and consequently lowering their mitochondrial oxygen consumption rate. Interestingly, PDAC cells dependent on exogenous serine exhibited specifically reduced translation of two of the six codons for serine in low-serine conditions. Notably, these two codons were found to be less commonly used in the gene encoding nerve growth factor (NGF) than in genes encoding other soluble factors. In vivo, mice with pancreatic tumors derived from orthotopically injected exogenous serine–dependent PDAC cells had increased tumor innervation with sympathetic nerves when fed a serine- and glycine-restricted diet. Further, administration of an inhibitor of the NGF receptor (TRK) reduced PDAC tumor innervation and decreased tumor burden. Collectively, these findings support a model in which PDAC tumors that are dependent on exogenous serine secrete NGF under serine-restricted conditions to recruit nerves that supply serine and support tumor growth.

Banh RS, Biancur DE, Yamamoto K, Sohn ASW, Walters B, Kuljanin M, et al. Neurons release serine to support mRNA translation in pancreatic cancer. Cell 2020;183:1202–18.E25.

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