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Tumor-Associated Immune Cells Hinder Frontline Chemotherapy Drug in Pancreatic Cancer

posted Mar 27, 2019, 6:20 AM by Lyssiotis Lab

Researchers have shown how tumor-associated macrophages release compounds that block gemcitabine in the most common type of pancreatic cancer

Costas Lyssiotis, Ph.D., and Christopher Halbrook, Ph.D.

A frontline chemotherapy drug given to patients with pancreatic cancer is made less effective because similar compounds released by tumor-associated immune cells block the drug’s action, research led by the University of Michigan Rogel Cancer Center found.

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The chemotherapy drug gemcitabine is an anti-metabolite. It’s similar to normal metabolites taken up by the cell, but once inside it kills the cell by disrupting its functions — like a Trojan horse. In pancreatic cancer, tumor immune cells release metabolites that are nearly identical to gemcitabine, and these block the activity of the drug in malignant cells, the researchers found.

"Why does gemcitabine work pretty well in some cancers but not in pancreatic cancer, that’s the big question my lab was trying to answer,"
Costas Lyssiotis, Ph.D.

These insights could be used to predict which patients will respond to gemcitabine therapy, as well as shed new light on other types of cancer where immune cells may be playing an important role in resistance to chemotherapy, according to findings published recently in Cell Metabolism.

“Why does gemcitabine work pretty well in some cancers but not in pancreatic cancer, that’s the big question my lab was trying to answer,” says study senior author Costas Lyssiotis, Ph.D., assistant professor of Molecular and Integrative Physiology at the U-M Medical School.

Pancreatic cancer is one of the most lethal types of cancer. It’s typically aggressive and doesn’t respond well to traditional chemotherapy and radiation treatments. And although progress has been made in recent years, five-year survival rates are still in the single digits.

“Malignant cells often only make up about 10 percent of a tumor,” says study first author Christopher J. Halbrook, Ph.D., a postdoctoral researcher in the Lyssiotis lab. “The remaining 90 percent are other types of cells that support the growth of that tumor — like structural cells, vasculature, and immune cells. Our work has been focused on the interaction between malignant cells and immune cells.”
Tumor-associated immune cells release a compound that hinders chemotherapy. (Habrook et al./Cell Metabolism).

Large contingents of immune cells known as macrophages are often found in pancreatic ductal adenocarcinoma, the most prevalent type of pancreatic cancer. And while macrophages were known to prevent the activity of gemcitabine chemotherapy, exactly how the immune cells did this had been unclear.

Lyssiotis and his collaborators at U-M and in Scotland investigated the interaction between malignant cells and tumor-associated macrophages, finding the immune cells released a host of compounds known as pyrimidines, which are metabolized by the malignant cells.

One of these compounds, deoxycytidine, has a chemical structure that’s very similar to gemcitabine and directly blocks the activity of the chemotherapy drug in the malignant cells.

“Deoxycytidine basically outcompetes gemcitabine,” Lyssiotis says, adding that the physiological reason underlying the immune cells’ release of the pyrimidines is still unclear.

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After genetically and pharmacologically depleting the number of tumor-associated macrophages in mouse models, the team showed that the tumors were less resistant to gemcitabine — offering a clue toward potentially making patients’ tumors more responsive to chemotherapy.

The researchers also looked at data from patients with pancreatic cancer and found that patients whose tumors had fewer macrophages had responded better to treatment.

“When we think of personalized medicine, we often think about what’s going inside of the malignant cells, what specific genetic mutations a patient’s tumor may have,” Lyssiotis says. “In our case, we’re thinking about, ‘What does this tumor look like as a whole? What does its ecosystem of cells look like?’ And hopefully we can use an understanding of the interaction between different types of cells to develop new approaches to treatment.”

Powering Off Cancer

posted Jun 10, 2017, 6:14 PM by Lyssiotis Lab   [ updated Jun 10, 2017, 6:17 PM ]

Cancer cells survive and grow according to their own schedule, while managing to survive in inhospitable environments under immune cell attack. The associated survival and growth processes are metabolically demanding. Renewed interest in this concept has led to important discoveries about the ways that cancer cells are powered. On-going studies now hope to leverage these insights to turn the power off on cancer.

In principle, this idea is not new. In fact, its origin is nearly 100 years old and is based on the observation that, relative to normal cells, cancer cells avidly consume glucose and metabolize it without using oxygen. Today we know this phenomenon as the Warburg Effect. However, even in Warburg’s time, this observation presented a bit of a conundrum. Productive glucose metabolism was thought to require oxygen metabolism in mitochondria, the cell's power source. This led Warburg to believe that cancer was somehow a disease of damaged mitochondria.

A century later, we now know that mitochondria are so vital that cancer cells cannot grow without them. The role of mitochondria in cancer extends well beyond their classical role of making the bioenergetic currency ATP. Mitochondria are also the primary source of the basic building blocks from which lipids, nucleotides, and proteins are derived.1 Recent insights reveal that mitochondria can regulate cell signaling and gene expression by tuning the rates of metabolic reactions.2

Building from this logic, if we were able to shut down the mitochondria, could we not power down cancer cells? This, of course, is the mechanism by which cyanide and other poisons act. Which brings us to the biggest challenge: can we power down cancer cells without killing healthy cells? Indeed, emerging data from numerous preclinical studies illustrate that targeting mitochondria may be a new and powerful approach to treat cancer.

Like all cellular functions in cancer, utilization and dependence on mitochondrial processes varies by cell/tissue of origin, genetic background, and ‘stemness’. Several recent studies have revealed contexts in which targeting the mitochondria is uniquely efficacious. This research highlights themes that are now being elaborated upon to determine the most effective means to harness mitochondrial-targeted therapies in cancer. These ideas and therapies are just now being tested in patients and hopes are high.

For example, metformin, one of the most widely prescribed drugs in the United States, is a mitochondrial inhibitor. Metformin is used by millions of Americans to manage blood glucose levels in type 2 diabetes. Intriguingly, recent retrospective epidemiological studies have suggested that people on metformin have a reduced incidence of many different types of cancer.3 For this reason, and our evolving understanding of the role of mitochondria in cancer, there is significant interest in the repurposing of metformin for cancer therapy. Preclinical and clinical studies testing the utility of metformin, however, have been mixed and difficult to interpret. This almost certainly owes to its pharmacological properties. Outside of the liver, where it acts to regulate blood glucose, metformin is not widely tissue penetrant. Exceptions include renal (e.g. kidney, bladder) and gastrointestinal (e.g. intestine, colon) cell types, which express the machinery to import metformin. The more promising results with metformin have been in the diseases of these organs. Importantly, this has helped to focus where metformin may ultimately have clinical utility.

Given the constraints imposed by tissue penetrance, metformin analogs with greater availability are now also being explored in cancer. For example, in BRAF mutant melanoma models, treatment with the tissue-penetrant metformin analog phenformin synergized with BRAF pathway inhibitors to regress established tumors. The synergistic activity owed in part to the targeting of slow cycling cells by phenformin. These exciting studies have prompted clinical trials with phenformin (Clinical Trial ID: NCT03026517).

In cell culture-based studies, where metformin can be delivered at a concentration that penetrates cells, metformin exhibits selective toxicity to cells with ‘stem cell’ properties. These cells tend to be more metabolically quiescent and rely on mitochondrial oxidation for bioenergetics. These observations are consistent with the mechanism of metformin and its analogs, which inhibit complex I of the electron transport chain, the machinery that makes ATP.

The antibiotic doxycycline has also been found to target cancer cells that are more dependent on the mitochondria. The utility of doxycycline as an antibiotic is derived from its ability to inhibit bacterial protein biosynthesis. Mitochondria are believed to have evolved from bacteria that were engulfed by and adapted to live symbiotically within a host cell. Accordingly, mitochondria have their own protein biosynthesis machinery. These share homology with bacterial ribosomes, including the ability to be inhibited by antibiotics like doxycycline, albeit at higher doses. In fact, doxycycline is one of the safest and most effective antimicrobials, and efforts are now on-going to develop more potent drugs designed around doxycycline for cancer therapy.5

Beyond repurposing efforts with well-known drugs, more recent work is now being done to develop and implement new mitochondrial inhibitors for cancer therapy. For example, a study in pancreatic cancer revealed that cells sensitive to treatment with chemotherapy use a non-mitochondrial metabolic pathway, glycolysis, to generate energy.6 In contrast, the chemotherapy-resistant cells are uniquely dependent on mitochondrial energy production, and, accordingly, highly susceptible to death by mitochondrial inhibition. Furthermore, it was found that the cells which remained after tumor debulking exhibited tumor initiating capacity and were responsible for disease relapse. In mouse models of pancreatic cancer, tumor debulking led to initial shrinking, which was later accompanied by disease relapse. In contrast, while treatment with an inhibitor of mitochondrial energy production alone had no discernible effect, the combination eliminated tumors and prevented relapse in the majority of animals.

The mitochondrial inhibitor oligomycin was used in these studies. It is much more potent than metformin and doxycycline, and for the same reason, it is not safe for use in humans. Based on these studies, a new, potent and safe inhibitor of mitochondrial bioenergetics, IACS-010759, was developed. Initial studies with this drug showed it to be highly effective and easier to dose in preclinical blood cancer models.7 IACS-010579 is now being tested in phase I clinical trials (Clinical Trial ID: NCT02882321). Promising results in these trials would open the door to testing mitochondrial inhibitors against residual disease, like the pancreatic cancer stem cells described above.

Insights into mitochondrial metabolism in cancer have revealed safe drugs that are being repurposed for cancer. Such insights have also provided new drug targets and the impetus to design cancer metabolism-based targeted therapeutics. It will be exciting to see if these methods to block mitochondrial metabolism can safely and effectively power down cancer.

Selected References

Vander Heiden MG, DeBerardinis RJ, Cell 168 657 (2017); PubMed [PubMed Abstract]
Chandel NS, Cell Metab 22 204 (2015); PubMed [PubMed Abstract]
Klil-Drori AJ, et al., Nat Rev Clin Oncol 14 85 (2017); PubMed [PubMed Abstract]
Eniu A, et al.,  ESMO Open 1 e000030 (2016); PubMed [PubMed Abstract]
Peiris-Pagès M, et al., Oncoscience. 2015 Aug 24;2 696 (2015); PubMed [PubMed Abstract]
Viale A, et al., Nature 514 628 (2014) PubMed [PubMed Abstract]
Molina JR, et al., Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics (2015);

Should Cancer Patients Take Antioxidant Supplements?

posted Nov 10, 2016, 7:46 AM by Steven Kasperek   [ updated Nov 22, 2016, 6:18 PM by Costas Lyssiotis ]

Graphic of antioxidant supplements

While the jury is still out on antioxidant supplements in general, for people with cancer, they cause more harm than good.

Antioxidants give foods like blueberries, dark chocolate and pecans their status as superfoods. These powerful chemicals can help reverse damage that occurs in the body’s cells, potentially lowering the risk of some diseases and slowing the effects of aging.

SEE ALSO: Connecting Dietary Sugar and Cancer: Does One Feed the Other?

But while we should include these foods in our diets, what about antioxidant supplements?

“In general, there’s no data to say either way whether antioxidant supplements are helpful. But if you have cancer, antioxidant supplements are not a good idea, and studies do show that,” says Costas Lyssiotis, Ph.D., a researcher at the University of Michigan Comprehensive Cancer Center who studies how cancer cells use the body’s metabolism.

As cancer cells begin to take hold in the body, antioxidants actually fan the fire. Part of the normal process of our bodies aging involves oxidative stress, a process that causes cell damage, which can lead to disease or make us look old. Antioxidants counter that by fighting off the oxidative damage.

But cancer cells turn on antioxidants as a tricky way of trying to survive. So antioxidant supplements provide support not only for the body, but also for the cancer.

“Antioxidants can help prevent cancer in healthy people, but antioxidants in supraphysiological doses, like those in supplements, have the opposite effect in people who already have cancer,” Lyssiotis says.

The best source of antioxidants is food. Several types of berries, nuts and beans rank highest in antioxidants. And Lyssiotis does not advise that anyone — with or without cancer — forgo blueberries or other healthy foods.

But he says if you have cancer, avoid antioxidant supplements. Even if not, with no clear evidence that these supplements help in healthy people, Lyssiotis suggests everyone opt for fruits and vegetables instead.

Connecting Sugar and Cancer: Does One Feed the Other?

posted Oct 6, 2016, 12:38 PM by Gang Xu   [ updated Nov 22, 2016, 6:17 PM by Costas Lyssiotis ]

A U-M cancer metabolism expert says scientists are making real headway in understanding the link between dietary sugar and cancer development.

What we are learning about sugar may soon have a direct impact on cancer prevention.

SEE ALSO: What Cancer Patients Should Know About Nutrition

Currently, there is no evidence that limiting the intake of sugar (or certain types of sugar) makes any difference if you have cancer, or are trying to prevent cancer through lifestyle choices, according to the National Cancer Institute. But careful controlled studies have not been done. Scientists like those in my lab are excited about current research and the potential for significant discoveries that may relate sugar to cancer development.

Here’s what you need to know now about the relationship.

The skinny on sugar

Dietary sugar can come in several varieties, most of which are composed of the simple sugars glucose and fructose. Both of these are found naturally in many foods.

Glucose is the predominant sugar in breads, grains and potatoes; fructose is found primarily in fruits. While they have the same caloric value, the body recognizes and processes them differently. Glucose travels to tissues and muscles, where it is broken down to provide energy. Fructose heads directly to the liver, where it is converted to fat.

Extra sugar, particularly fructose, is often added during food processing. It is these added sugars that have the greatest potential to pile up in someone’s diet. That is why nutritionists suggest avoiding sugary breakfast foods, pastries and other sweet foods, as well as sugary beverages, particularly soda, fruit drinks and juices.

The link between fructose and cancer

Among the different types of sugar, glucose and fructose are the two we study in relation to cancer. Between these, fructose is the more nefarious because of the way the body processes it.

The fat that fructose creates in the liver is released into the blood stream and later stored in the liver and as fat tissue. If not managed, this fat accumulation contributes to insulin resistance, which means the body cannot process insulin like it should, leading to ever-increasing amounts of insulin circulating in the blood stream.

Many types of cancer — including endometrial, breast, ovarian, colorectal, liver, pancreatic and urinary tract cancers — feed on insulin. So, if you have an overabundance of insulin in your bloodstream, the pre-cancer cells can respond to it and grow, and, ultimately, mature into bona fide cancer cells.

People with type 2 diabetes, or who are obese, are particularly vulnerable, because their condition automatically creates more insulin in the bloodstream. Then, eating sugary foods laden with fructose also leads to more fat in the liver and more insulin in the bloodstream.

Anyone looking for ways to eat healthier should limit the amount of fructose in their diet, but those who are obese or have type 2 diabetes should take special care to learn about fructose and how to avoid it.

Tips to cut sugar from your diet

The best defense against sugar, particularly fructose, is to learn how to read and understand nutrition facts on food labels.

SEE ALSO: To Fight Cancer, Put These Foods on Your Plate

Most processed foods — foods that were canned, boxed or otherwise packaged in a factory — contain sugar, which may be labeled as glucose, fructose, high-fructose corn syrup or a host of other names. Even processed foods deemed healthy — such as fruit juices, yogurt with fruit or soups — can pack a sugary punch.

If you are ready to learn more about what is in the processed foods you eat, plan on spending an extra 15 minutes or so at the grocery store for a few weeks. After reading the labels of your favorite foods, you may wind up putting some of those boxes or jars back on the shelf while you look for new, healthier alternatives.

Although we can’t say there’s a definitive connection between dietary sugar and cancer growth at this time, your body can benefit in all kinds of ways when you eat less sugar. You can get more information on using food as medicine, and recipes and nutrition for cancer patients through the registered dieticians at the U-M Cancer Center.

Cell Hunters: Starving Pancreatic Cancer by Targeting Cell Metabolism

posted Oct 6, 2016, 12:33 PM by Gang Xu   [ updated Nov 22, 2016, 6:23 PM by Costas Lyssiotis ]

Comprehending how pancreatic tumor cells thrive might be the key to new therapies and diagnostic tools.

The biochemical pathways and metabolic requirements that enable tumor survival and growth may be used to design targeted cancer therapies.

Costas Lyssiotis, Ph.D., studies this idea in his lab at the University of Michigan Comprehensive Cancer Center.

“I would argue that the most important feature about a cancer cell is its metabolism,” says Lyssiotis, an assistant professor of physiology and medicine. “Normal cells can only become cancer cells by rewiring the way that they acquire and utilize nutrients, the processes generally referred to as their metabolism.”

The reason that cancer cells do this is that they have two primary goals: to survive and to reproduce.

Lyssiotis explains that if you are a cell within the context of a healthy organism, you listen to the instructions provided by the body to determine when it’s time to eat, when it’s not time to eat, when it’s time to recycle materials that have gone bad or when it’s time to die.

If you’re a cancer cell, on the other hand, you’ve gone rogue. You ignore these signals, and take up nutrients, when and as much as you want.

“But because you’re a rogue cell, the rest of the body is out to get you,” Lyssiotis explains. “So you’re scurrying away, trying to live in other places. You wind up in nonnative environments that can be very stressful and nutrient poor. So these cells divert a lot of energy to fending off this stress. But, since they are nutrient limited, they wind up on the brink of starvation.”

If researchers can understand metabolically what makes cancer cells different from normal cells, they might be able to exploit this knowledge to design better drug targets and therapies.

In other words, these cells can be pushed over the edge and starved to death.

Pancreatic cancer’s unique metabolism

Unlike many tumors, pancreatic tumors are rock hard. When researchers examine what’s inside, the cancer cell content can be as low as about 10 percent.

Much of the rest of the tumor is a type of scar tissue, called stroma. The stroma releases a lot of extra cellular matrix protein, which retains water, creating pressure so that the blood vessels collapse. Without vasculature, the pancreatic cancer cells are left to find nutrients outside the blood stream.

This stresses the cancer cells inside the pancreatic tumor. They can’t get the nutrients and oxygen they need, which leads to oxidative stress. At the same time, the immune system is trying to figure out how to kill the cancer cells, causing additional stress. You would think with all these stressors that the cancer cells would not survive. But they do, and they kill patients.

How? Lyssiotis says pancreatic cancer cells turn into professional scavengers in a variety of ways. They activate recycling pathways within the cell, and they forage for nutrients outside the cell in nontraditional ways.

One of these processes is called macropinocytosis, where cells eat whatever they can find in the bulk extracellular space of the stroma. Researchers suspect that this leaves the remaining 90 percent of the pancreatic tumor as a foraging ground that the cancer can co-opt for nutrients.

This is a major focus of Lyssiotis’s lab. By understanding how these nutrient-scavenging processes are activated and used, Lyssiotis and his colleagues can perhaps identify new selective and safe drug targets.

"Cancer cells use different metabolic pathways than normal cells, and understanding how these pathways work is important for identifying [new] drug targets."
Costas Lyssiotis, Ph.D.

Exploiting pancreatic cancer’s unique characteristics

Metabolomics, a technique that allows for the study of all the metabolic reactions inside the cell at the same time, is a key technology in this research.

“This information gives us a sense of the metabolism pathways that are being used by the cells,” Lyssiotis says. “Cancer cells use different pathways than normal cells, and understanding how these pathways work is important for identifying drug targets that when inhibited with a cancer-targeted drug will not harm the normal, healthy cells.”

One of the enzymes Lyssiotis studies closely is called aspartate transaminase, or GOT1.

“As best we can tell, pancreatic cancer cells are uniquely dependent on the action of this enzyme, and normal cells tolerate inhibition without overt consequence,” says Lyssiotis. “Recently, we have teamed up with a pharmaceutical company to develop drugs that inhibit GOT1. These will be moved to preclinical development in the near future.”

But don’t expect the drugs to work alone. Few targeted drugs will, Lyssiotis says.

“Cancer cells ultimately find a pathway of resistance to a single drug. Logical combinations of drugs are harder for cancer cells to block quickly,” he explains. “That understanding is the foundation for precision medicine.”

Further prospects in cancer research

Lyssiotis says new imaging techniques based on cell metabolism are also on the horizon. These could help detect disease earlier, potentially finding pancreatic tumors when surgery is still an option.

The technique could have implications for other types of cancer as well. It’s all about tailoring cancer diagnosis and treatment to each individual.

“Precision medicine is coming into its own,” says Lyssiotis. “There’s an electricity, a cumulative appreciation that this is the way to go, that we need a better, a deeper understanding of each individual’s tumor if we are going to treat patients effectively. I believe cell metabolism is going to play a big role in that.”

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