Due to the uncontrolled proliferation of cancer cells, tumor microenvironment gets rapidly deprived of oxygen and nutrients. Therefore, cancer cells need to adapt to survive and grow in such nutrient-deprived conditions. For instance, in human pancreatic cancer microenvironment, serine concentrations are about 60% lower than in benign adjacent tissues. Serine in an essential amino acid, the second most abundant amino acid in human proteins; cells can obtain it from the microenvironment or synthesize it starting from glucose. Being involved in multiple cell pathways, serine may become a limiting factor for growth and survival of cancer cells.
In a large majority of pancreatic cancer patients, tumors show extensive innervation; this is associated with bad outcome. In mice, removal of pancreatic cancer innervation increases survival, suggesting the involvement of neurons in supporting tumorigenesis.
Main finding. In a paper recently published in Cell, the authors demonstrate that neurons –via their axons– play a key role in pancreatic cancer growth in nutrient-poor conditions: in particular, they show that some human pancreatic cancer cell lines are unable to produce serine, being thus dependent on exogenous serine to grow. Serine deprivation decreases protein synthesis. The release of serine from neurons innervating pancreatic tumors can support pancreatic cell growth in such conditions.
Experimental details. Authors observed that about 40% of human pancreatic cancer cell lines lacked the necessary enzyme to convert glucose into serine, being thus completely dependent on exogenous serine.
Why serine deprivation prevents pancreatic cancer cell growth? What is the role of serine in pancreatic cancer cells? Serine deprivation results into ribosome (macromolecular complex synthesizing proteins) stalling at specific regions (codons) on the messenger RNA, resulting into a decreased protein synthesis in exogenous serine-dependent pancreatic cancer cells (while serine-independent cells did not show any effect). Synthesis of proteins involved in several pathways were affected by serine deprivation. However, NGF (nerve growth factor) synthesis and secretion were not influenced: exogenous serine-dependent pancreatic cancer cells secrete high levels of NGF. As protein synthesis normally requires a lot of ATP (molecule providing energy for cellular processes), the reduced protein synthesis due to serine limitation reduces ATP demand, in turn resulting in a decreased mitochondrial activity. Interestingly, these changes in protein synthesis efficiency have been observed not only in pancreatic cancer cell lines, but also in breast cancer and melanoma cells, suggesting the possibility of a broader, non-cancer type specific effect.
Impaired growth of pancreatic cancer cells dependent on exogenous serine in serine-poor conditions is rescued when pancreatic cancer cells are co-cultured with neurons. Authors proved that, in a nutrient-poor environment, axons can release amino acids, such as serine. Though axons do not produce enough serine to support pancreatic cancer cell growth in total absence of serine, they are able to replenish serine that is consumed by proliferating pancreatic cancer cells, thus supporting tumor cell growth in poor serine conditions –but not in serine-free conditions.
What about in vivo? Exogenous serine-dependent pancreatic cancer cells were injected in the pancreas of mice kept either on a serine-free diet or on a normal diet. In serine-free fed mice, tumors were smaller than in control standard diet fed mice, indicating that serine affects tumor growth.
Moreover, in serine-free fed mice, tumors were more innervated compared to the control animals. As axons secrete serine and pancreatic cancer cells can secrete NGF in poor serine availability, it is likely that pancreatic cancer cells recruit nerves to get their metabolic support for growth when serine levels are low. Pharmacologically inhibiting (by inhibitors of TRK, the receptor of NGF) the recruitment of neuronal axons by pancreatic cancer cells occurring in serine-poor conditions further impairs cancer cell growth. Moreover, in patients, pancreatic cancer denervation correlates with better overall survival.
Conclusions. Neurons innervating pancreatic cancer can provide cancer cells in low nutrient environment with the amino acid they need to survive and grow. It may be thus hypothesized that serine limitation through dietary restriction may slow down pancreatic cancer growth in patients. Interestingly, the authors have shown that in mice TRK inhibitors reduce pancreatic cancer innervation, resulting into impaired tumor growth, suggesting that this approach in patients may reduce tumor recurrence. Notably TRK inhibitors are approved drugs for cancer treatment. Would the combined TRK inhibition/dietary serine restriction represent a viable therapeutic option for cancer patients?
Reference. Neurons Release Serine to Support mRNA Translation in Pancreatic Cancer. Banh, Biancur, Yamamoto, Sohn, Walters, Kuljanin, Gikandi, Wang, Mancias, Schneider, Pacold, Kimmelman. Cell 2020.