Pancreatic ductal adenocarcinoma (PDAC) cells have a nutrient-poor tumour microenvironment and are also highly innervated. In a new study published in Cell, researchers demonstrate both in vitro and in vivo that peripheral axons metabolically support PDAC cells by secreting amino acids such as serine in nutrient-deprived environments.
It has previously been shown that PDAC cells can upregulate nutrient scavenging pathways and use metabolites released from other cells such as stellate cells and macrophages to adapt to nutrient-deprived environments. “Although these processes can supply PDAC tumours with some metabolites, they may not supply sufficient levels of certain metabolites required for growth,” says Robert Banh, first author of the study. “As PDAC tumours are one of the most highly innervated cancers, we hypothesized that neurons could metabolically support PDAC cells in nutrient-deprived regions of the tumour.” To assess the contribution of innervation, the researchers first grew rat dorsal root ganglion (DRG) cells in microfluidic devices to isolate peripheral axons from the neuronal body. This set-up is similar to the in vivo setting, in which tumours in nutrient-deprived environments are exposed to peripheral axons but not to neuronal bodies, which have access to the nutrient-rich circulation. In the in vitro model, axonal media had increased levels of amino acids such as serine and glycine compared with non-axonal media, which suggests that axons release amino acids into nutrient-deprived environments.
The researchers found that a subset of human PDAC cell lines depend on exogenous serine for proliferation and lack expression of phosphoglycerate dehydrogenase (PHGDH), a key enzyme in the serine biosynthesis pathway. In addition, co-culturing axons with exogenous serine-dependent PDAC cells in serine and glycine-deprived media restored tumour growth. Further in vitro experiments established that serine is required for efficient mRNA translation in PDAC cells and that serine deprivation reduces mRNA translation rates, thereby lowering demand for ATP and consequently decreasing mitochondrial activity. In addition, generation of green fluorescent protein reporters of the serine codons identified two codons, TCT and TCC, whose translation efficiencies decreased during serine deprivation owing to ribosome stalling. “This selective translation specifically limited the production of TCC and TCT-high coded proteins, and allowed the synthesis of TCC and TCT-low coded proteins, such as nerve growth factor (NGF),” says Banh.
In an in vivo mouse model, exogenous serine-dependent PDAC tumours deprived of serine and glycine were significantly smaller than those in mice fed a complete amino acid diet and had increased sympathetic and sensory nerve innervation. To assess whether nerves metabolically support tumour growth during serine deprivation, the researchers treated mice orthotopically injected with PDAC cells and on serine and glycine-free or control diets with LOXO-101, an inhibitor of the receptor for NGF, thereby reducing tumour innervation. The mice treated with LOXO-101 and on a serine and glycine-free diet had a decreased tumour burden. Finally, PDAC tumours from patients with high or low levels of PHGDH were analysed. Patients with PDAC with high expression of PHGDH had a significantly reduced overall survival, less innervation and reduced expression of NGF. These findings supported the in vitro and mouse observations.
“peripheral axons metabolically adapt to support PDAC growth during serine deprivation”
Taken together, these observations suggest that peripheral axons metabolically adapt to support PDAC growth during serine deprivation, but there are still unanswered questions. “We will be working to understand the mechanisms that allow neurons to metabolically support PDAC cells, to elucidate the regulation of differential translation efficiency of codons, and to assess whether perturbation of these pathways significantly limits PDAC tumorigenesis,” says Banh. “A better understanding of the underlying mechanisms that allow PDAC cells to adapt to nutrient-poor environments may lead to the identification of novel therapeutic targets and improve outcomes for patients with PDAC.”
Banh, R. S. et al. Neurons release serine to support mRNA translation in pancreatic cancer. Cell https://doi.org/10.1016/j.cell.2020.10.016 (2020)
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Hindson, J. Neuronal innervation supports PDAC growth via release of serine. Nat Rev Gastroenterol Hepatol 18, 5 (2021). https://doi.org/10.1038/s41575-020-00394-1