Pancreatic Cancer Cells Recruit Nerves to Supply Nutrient
Research in cancer cells, in mice and in human tissue samples has shown how pancreatic cancer cells can prevent starvation by secreting a nerve growth factor that triggers nerve cells to grow into the tumor mass and release the amino acid serine, which is needed to support cancer cell survival and growth. Led by teams at NYU Grossman School of Medicine, the department of radiation oncology at NYU Langone Health, and Perlmutter Cancer Center, the studies also showed that pancreatic cancer growth in mice could be slowed by combining treatment using an already FDA-approved drug, with a low serine diet.
“Our study offers more proof that pancreatic cancers are remarkable metabolic scavengers, which contributes to their deadliness,” said corresponding author Alec Kimmelman, MD, PhD, the Anita Steckler and Joseph Steckler chair of the department of radiation oncology at NYU Langone. “The ability of nerves to funnel nutrients from the bloodstream to the more austere pancreatic tumor microenvironment is a fascinating adaptation, and could lead to therapeutic approaches that interfere with this unique flexibility.”
Kimmelman and colleagues reported their findings in Cell, in a paper titled, “Neurons Release Serine to support mRNA Translation in Pancreatic Cancer.”
Pancreatic cancer ductal adenocarcinoma (PDAC) is the deadliest cancer form of pancreatic cancer, with a five-year survival rate of less than 10%. A common symptom among PDAC patients is neuropathic pain, which can lead to the need for invasive procedures, the authors noted. Interestingly, genetic analyses of PDAC have revealed frequent mutations in regulators of nerve axon guidance, which also suggests a role for neuronal support in tumor growth. Studies have shown that surgical denervation, or ablation of nerves, can increase the survival of PDAC-bearing mice, which further supports a pro-oncogenic role for nerves in the disease.
PDAC encourages the growth of dense tissue that presses on blood vessels, reducing the supply of blood-borne nutrients, such as serine. This amino acid is used as a building block for proteins, and is required for cancer cells to multiply. “Serine (Ser) is a conditionally essential amino acid (AA) that can be obtained from the microenvironment or produced via the Ser biosynthesis pathway (SBP) from glucose and is the second most abundant AA found in human proteins,” the authors wrote.
Their studies have now found that pancreatic cancer cells starved of serine take advantage of the process by which mRNA is translated into proteins. mRNA is decoded into amino acids using units of three bases, or codons. Ribosomes read the codons as instructions for which amino acids to link together in the right order. But ribosomes will stall this process if there is a lack of available amino acids.
Surprisingly, the research team found that serine-starved pancreatic cancer cells more significantly slow the rate at which two of the six serine codons—TCC and TCT—but not all six, as assumed, are translated into amino acid chains. Under serine-starved situations, this variability lets cancer cells minimize the production of certain proteins, to preserve energy stores during starvation, but continue to build stress-adaptive proteins, such as nerve growth factor (NGF), which happens to be encoded by few TCC and TCT codons. “Surprisingly, Ser deprivation specifically decreased the mRNA translation efficiency of two out of six Ser codons, TCC and TCT, and allowed the selective translation and secretion of nerve growth factor (NGF),” the authors wrote.
Nerve growth factor and other factors are known to encourage nerves to grow into pancreatic tumors, and to increase tumor growth. The current study found that pancreatic cancer cells secrete nerve growth factor, which sends signals to nerve cell axons to grow deeply into tumors, where they secrete serine, which then rescues the pancreatic cancer cells from starvation, and restores their growth.
The work is claimed to be the first to show that axons provide metabolic support to cancer cells by secreting serine in nutrient-deprived areas. The new publication is one of a number in recent years by Perlmutter researchers, which have described the ways in which pancreatic cancer cells find energy. A 2016 study revealed that such cells send signals to nearby stellate cells, causing them to break down their own cell parts into building blocks that can be used by tumors. A study towards the end of 2019 found that pancreatic cancer cells also hijack a process called macropinocytosis, which normal cells use to pull nutrients in through their outer membranes. Interestingly, the latest work found that stellate cells and macropinocytosis cannot supply enough serine for the cancer cells to grow, and that axonal delivery is required.
With a glimpse of potential future applications for the study, the researchers also showed that PDAC tumor-bearing mice that were fed serine-free diets exhibited 50% slower tumor growth. To see if it was possible to hold back tumor growth even further than by dietary serine restriction alone, the team also inhibited the recruitment of axons into PDAC tumors, using an FDA-approved drug called LOXO-101. The drug blocks the activation of a receptor protein on the surface of neurons that interacts with nerve growth factor (also called TRK-A), and so inhibits the ability of neurons to send their axons into tumors.
While the mouse experiments found that drug treatment alone didn’t slow PDAC tumor growth, it did slow tumor growth by an additional 50% when combined with a serine-free diet, compared with dietary restriction alone. This further supported the suggestion that nerves were necessary to support PDAC cell growth in serine-deprived tumor regions.
“Our results identify a previously undescribed role for neurons, via their peripheral axons, to metabolically support PDAC cell growth under nutrient limiting conditions,” the authors wrote. They said that their study results suggest that targeting nerves and Trk signaling in PDAC patients could potentially reduce tumor recurrence by limiting both the supply of neurotrophic factors and nutrients to tumors … “Our findings highlight the importance of Ser availability, axon-cancer metabolic crosstalk, and selective mRNA translation in PDAC cells and offers potential therapeutic options in the treatment of this disease,” they wrote.
Lead study author Robert Banh, PhD, a post-doctoral scholar in Kimmelman’s lab, further noted, “As TRK inhibitors are approved in the treatment of some cancers, they might have value in combination with a low serine diet following surgery in the perhaps 40% of patients with PDAC tumors that can’t make serine … Whether this approach could decrease tumor recurrence by limiting the nutrient supply would need to be confirmed in clinical trials.”