A new study has shown that nutrients provided by neighboring cells drive metabolism in the mitochondria of pancreatic ductal adenocarcinoma cells. Indeed, it has been shown that pancreatic cancer cells grow by instructing neighboring cells to provide them with nutrients. (1) (Source) The title of the Nature study is : “Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion”. (See footnote 1)
The researchers found that when grown together in culture, cancer cells prompted cells from the tumor microenvironment (2) to degrade their own proteins and supply the cancer cells with the resulting amino acids. This external nutrient supply led to increased metabolism and growth in the pancreatic cancer cells. (3) In separate experiments in mice, blocking the supply of nutrients from cells in the tumor microenvironment slowed pancreatic tumor growth.
According to the study’s lead investigator, Alec Kimmelman, M.D., Ph.D., of NYU Langone Medical Center, and his colleagues, the study is one of the first detailed reports of what they called “metabolic crosstalk” between pancreatic cancer cells and cells in the tumor microenvironment.
The Pancreatic Tumor Microenvironment
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer. A distinct characteristic of PDAC is the presence of a dense web of proteins and noncancerous cells surrounding the cancer cells, collectively called the stroma. In holistic oncology, we call this the “bio-terrain”.
Interactions with stromal cells can be both beneficial and harmful for pancreatic cancer cells. The thick stroma protects pancreatic cancer cells by limiting their exposure to chemotherapy drugs, but it also blocks their access to blood vessels that supply nutrients such as glucose. As a result, pancreatic cancer cells are forced to scavenge for other nutrients to support their metabolism and growth.
Pancreatic stellate cells (PSCs), star-shaped cells that secrete structural proteins, are abundant in the stroma. Previous studies suggested that PDAC cells encourage PSC growth, and that PSCs, in turn, can promote PDAC growth by helping out with the cancer cells need to obtain an abundance of nutrients. .
To test their idea, the researchers treated either human PDAC cells or healthy pancreatic cells with culture medium (an aqueous solution that contains molecules secreted by the cultured cells) from a PSC cell line. They found that the treated PDAC cells, but not the healthy pancreatic cells, showed signs of increased metabolism specifically in the mitochondria, the compartment in cells that generates energy.
The researchers then analyzed the PSC culture medium to try to identify what was driving the increased PDAC metabolism. Of the nearly 200 candidate metabolites they analyzed, (4) they found that two amino acids secreted by PSCs, alanine and aspartate, were absorbed by PDAC cells. But, they showed, only alanine stimulated mitochondrial metabolism in PDAC cells. Alanine has not typically been studied as a major fuel source for tumor cells; it is mostly viewed as a building block for proteins. But with this case, we can see that alanine has a critical role in tumor metabolism.
The researchers believe that using alanine as a main energy source allows “the cancer cells to utilize more traditional fuel sources (like glucose) for other invasiveness requirements, like making building blocks of DNA and RNA.
Alanine from Autophagy
The team then delved further into this “crosstalk” between PDAC cells and PSCs. They hypothesized that PSCs may produce extra alanine through autophagy, an essential function in cells that degrades superfluous, damaged, and toxic molecules into basic units (such as amino acids).
The researchers discovered that when they co-cultured PDAC and PSC cells together, autophagy increased in the PSCs. Furthermore, they found that PSCs required essential autophagy genes to secrete alanine and enhance PDAC metabolism.
The team also observed that PSC culture medium enhanced PDAC cell growth in low-nutrient conditions (similar to the actual tumor microenvironment) and that this effect was dependent on autophagy in PSCs. They found that in mice, tumors from PDAC cells implanted along with PSCs that lacked autophagy-related genes grew slower and were less lethal than tumors from PDAC cells implanted with normal PSCs. (5)
These findings demonstrate the importance of studying cancer metabolism holistically, as biological phenomenon that occurs within an altered bio terrain. Too often, in maintream oncology, cancer cells are studied in vitro and in in isolation. And this metabolic crosstalk between stromal and cancer cells is not the only mechanism that we need to better examine. We also should also better examine the role of mammalian microbiota, as the trillions of living critters that are in our gut have over two million genes, all of which communicate with not only our human genes, but with cancer genes. Unfortunealy, this study did not delve into this question or many other pathways that Holistic Oncology considers relevant. And while the role of autophagy in cancer cells has been studied for many years, the tumor inhibition of autophage and even senescence cells have been under-estimated. (6)
Christian Joubert (ACRI director)
The Study under consideration
“Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by an intense fibrotic stromal response and deregulated metabolism. The role of the stroma in PDAC biology is complex and it has been shown to play critical roles that differ depending on the biological context. The stromal reaction also impairs the vasculature, leading to a highly hypoxic, nutrient-poor environment. As such, these tumours must alter how they capture and use nutrients to support their metabolic needs. Here we show that stroma-associated pancreatic stellate cells (PSCs) are critical for PDAC metabolism through the secretion of non-essential amino acids (NEAA). Specifically, we uncover a previously undescribed role for alanine, which outcompetes glucose and glutamine-derived carbon in PDAC to fuel the tricarboxylic acid (TCA) cycle, and thus NEAA and lipid biosynthesis. This shift in fuel source decreases the tumour’s dependence on glucose and serum-derived nutrients, which are limited in the pancreatic tumour microenvironment. Moreover, we demonstrate that alanine secretion by PSCs is dependent on PSC autophagy, a process that is stimulated by cancer cells. Thus, our results demonstrate a novel metabolic interaction between PSCs and cancer cells, in which PSC-derived alanine acts as an alternative carbon source. This finding highlights a previously unappreciated metabolic network within pancreatic tumours in which diverse fuel sources are used to promote growth in an austere tumour microenvironment” (Source)
(2). The microenvironment is made up of normal cells, molecules, and blood vessels that surround and feed a tumor cell. A tumor can change its microenvironment, and the microenvironment can affect how a tumor grows and spreads.
(3). Metabolism is the chemical changes that take place in a cell or an organism. These changes make energy and the materials cells and organisms need to grow, reproduce, and stay healthy. Metabolism also helps get rid of toxic substances
(4). A metabolite is a substance made or used when the body breaks down food, drugs or chemicals, or its own tissue (for example, fat or muscle tissue). This process, called metabolism, makes energy and the materials needed for growth, reproduction, and maintaining health. It also helps get rid of toxic substances.
(5) Several completed and ongoing clinical trials have tested autophagy inhibitors, with mixed results.
(6). The scientists are now working to uncover the molecular signal PDAC cells use to rev up autophagy in PSCs. There have only been a handful of secreted molecules reported to increase autophagy. While there can be a tumor-promoting effect of autophagy in noncancerous cells, when the patient nurtures a holistic lifestyle, autophage like senescence tend to favor healthy life spans rather than the catabolic breakdown of the body. When metabolic pathways that breaks down molecules into smaller units that are either oxidized to release energy, or used in other anabolic reactions, there is always a chance that a cell’s genes can go haywire cancer-wise. But with Evolution’s billions of years of fine-tuning of the human engine, we have multiple defense systems, including DNA repair mechanisms to favor a healthy long life span over chronic diseased breakdowns.