Stefan M. Schieke, MD, is out to prove a point. In terms of cancer, cellular metabolism is not just a passive player. It's more than "something" happening in cells to make sure the needs of cellular functions are covered. "It is quite the opposite," said Schieke, a board-certified dermatologist with a specific interest in lymphomas of the skin.
"Metabolism can actually be a very significant driver of cellular functions, growth, migration, and spread in cancer. And that reality opens up the door to a completely new way of thinking about metabolism. It is not just the passive follower, but instead an active driver of cancer cell behavior."
That understanding, said Schieke, may open the door to therapeutic targets found in metabolic steps. "I think that is something which is essential and critical for everybody to understand. And it helps the clinical oncologist to grasp the potential power of this approach."
Schieke, an active researcher with his own lab at the University of Wisconsin-Madison, also heads the university's Cutaneous Lymphoma Clinic and is Assistant Professor of Dermatology. Married and father of a 9-year-old son, he speaks polished English with a hint of a native German accent. Born in Frankfurt and raised in Dusseldorf, he completed medical school in Germany then came to the U.S. to do postdoctoral research work in mTOR signaling and mitochondria in aging and stem cells. Though he intended to return to Germany after his postdoc studies, love intervened. He met his wife, now a radiologist, and decided to do a dermatology residency and undertake U.S medical exams so that he could practice here and, in time, accept a faculty position.
Schieke recalled having a scientific bent, even as a child. "From early on, biology was fascinating. I also had a big focus on chemistry and set up my own chemical lab in the basement of my parents' house. There was gun powder down there. I wanted to understand why it explodes. Luckily, I didn't blow anything up," he said with a chuckle.
Science continues to flavor various interests in Schieke's life, even those outside of his laboratory and clinical practice. Consider exercise, for example. "I do a lot of high intensity exercise. I integrate that with my interest in metabolism; I follow a lot of biometric parameters to make sure that I get the maximum benefit out of training. By measuring my glucose and lactate levels, etc., I can exactly gauge the exercise and know that I hit the sweet spot in terms of improving my mitochondrial strength and endurance," said Schieke. "Even with a little bit of metabolic focus, it is still fun and relaxing."
Clinician in the Lab
A physician scientist, Schieke said he tries to understand clinical challenges from a scientific basis, and conversely apply scientific principles to clinical practice. He admitted, "... that's hard, though, and sometimes almost mutually exclusive. On the other hand, taking the clinical questions and clinical observations into the lab and letting the research be guided by what I see with patient experience when I'm in the clinic can be very rewarding."
Asked to detail the main focus of his research, Schieke told Oncology Times, "We are trying to understand metabolic features and metabolic dynamics. For a long time, cellular metabolism has been seen as something in place to supply the demands of certain cellular functions." It was thought metabolism performs at the command of cancer cells as well. If the cell needs to grow, then the metabolism gets rewired to make sure that all the metabolic needs are met to allow cell growth or survival.
But this simplistic view of cellular metabolism is not accurate, said Schieke. "In fact, the metabolism is so much more. It's not just passively following cellular function; it can actually act in the reverse. It can not only contribute, but actually dictate and regulate certain cellular functions. We now know that it is possible to prompt metabolic re-wiring-reprogram the cellular metabolism-and change cell behavior. And that really puts the metabolism into the driver's seat."
The parts of the metabolism Schieke's lab is particularly interested in are the mitochondria, which he described as the bioenergetic hub of the cell. "We know they also have a main role in signaling. We're trying to understand how the function of these mitochondria varies, because we know it's not a static state thing for the entire lifespan of every single cell."
In fact, Schieke said, "There are fluctuations, there are oscillations. It is very dynamic. We just don't even know exactly what these different states are. So, our main focus is mitochondrial function in lymphoid cancers."
A Look at the Research
Schieke's lab made an impressive impact on the field with a recently published study (Cell Rep 2019;29(10):3009-3018.e4). In an abstract accompanying a mini review (Mol Cell Oncol 2020;7(2):1718475) of the study, the authors concluded, "Metabolic flexibility represents a potential point of attack for novel cancer treatments. We recently described the signaling mechanism inducing a metabolic shift in response to metformin and phenformin in leukemia and lymphoma cells. Enhanced glucose utilization was critically dependent on mitochondrial stress signaling/hypoxia-inducible factor-1[alpha] representing a therapeutic vulnerability."
Schieke explained, "We used a drug that has started to enjoy a renaissance, metformin, most commonly prescribed drug for patients with type 2 diabetes, and also phenformin, which is not on the market any more due to fatal side effects that it showed in some patients. But still, we can get it in the lab and it's a fantastic tool to study the biology of these drugs, which are also known as biguanides. It's been known for quite some time, based on epidemiological observations, biguanides decrease the risk of cancer in patients with type 2 diabetes. Could these biguanides be used to treat cancer in the future? A lot of basic science labs stormed into that area using biguanides."
Schieke's lab, however, made a startling discovery. "When we used it in our cancer model, it didn't do anything," he said. "The cells slowed down a little bit if we incubated or treated them with metformin and phenformin. But they survived. And if we implanted those cells into mice and administered those drugs to the mice, the tumors grew, completely untouched by those drugs. The reason that this is interesting is because those drugs target the mitochondria. As I said before, the mitochondria are the major metabolic hub in the cells. It is surprising to realize that even when you poison and inhibit this major metabolic hub, the cells do find a way to get around that, and the cancer finds a way to continue to grow and spread in the mice."
Next, Schieke and his lab wanted to understand what sort of metabolic flexibility was behind this observation. "What are the metabolic dynamics that allow these cells to bypass the inhibition of mitochondrial function, to bypass the effect of those biguanides?" asked Schieke rhetorically before adding, "We do have the answer and it is called metabolic flexibility or metabolic plasticity in cells.
"You can block one metabolic pathway, whether a less important pathway or a critically important one, and chances are the cells can still find a way to continue to grow. We can actually show that if we take cancer cells and put them into glucose-free media-though glucose is largely considered to be a very fundamental fuel for cancer cells-they will continue to grow. They also continue to form tumors. Even though conventional wisdom is that glucose is necessary for cancer cells, the data really suggests that, while it may be fundamental for some things, it may not be essential for survival and simple growth. You take it away, and the cells switch over to something else."
Going a step further, Schieke's lab demonstrated that upon poisoning the mitochondria, cells experience "... glucose addiction. And only then, if we take away the glucose, the cells die," he said, stressing this major finding. "But without those drugs-without the biguanides-we can take away glucose all day long and the cells don't die. Think of it as a buffet: You take the chocolate cake away, so everybody then goes for the strawberry cake. But if you take both away, well, then there might be no dessert. And that's basically what our work shows.
"We found we have to target two pathways in order to make the cells die. More specifically, the first intervention, poisoning the mitochondria with the biguanides, creates a very specific and defined metabolic need that we then can attack."
What was uniquely specific about the work was the fact that not only did the researchers take glucose away together with biguanides, but they figured out the mechanism that makes the cells glucose-addicted.
"We identified the intracellular signaling pathway that the cells use to re-program their metabolism from being able to utilize various different fuels to all of a sudden become highly dependent and addicted to glucose," reprised Schieke. "We realized if we target that cellular signaling, transduction pathway, then all of a sudden we could kill cancer cells."
The Human Aspect
Schieke said the next step in the work is to create a metabolic/therapeutic target with the first intervention. And the second intervention can then target that need and result in the death of cancer cells.
"I think the most fascinating aspect of this work is that not only could we show it works in cell culture and in mice, but we could show that it works in isolated cells from patients with chronic lymphocytic leukemia and acute lymphoblastic leukemia. To see that was truly moving," said Schieke, reverently. "The tricky thing with targeting cancer metabolism is it is very easy to take nutrients and fuels away from cells in culture. It is more difficult-but still doable-to do that in mice. But it is very difficult to do that in real patients. I think that most metabolic studies are incomplete without having in vivo proof-the translation of proof-that those pathways are really true and relevant. So when an idea we had in the lab all of a sudden worked in cells isolated from very, very sick patients, some of whom might not be alive anymore, and we saw this might have a therapeutic potential, it was more than exciting. It was humbling."
Schieke and his team took cancer cells from patients with leukemia and compared those leukemic lymphocytes with healthy lymphocytes from healthy donors.
"Interestingly, the response which we saw, that dependence on glucose and that underlying signaling mechanism, was highly specific for the cancer cells. Though glucose dependence is also seen in normal lymphocytes, the metabolic rewiring does not depend on hypoxia-inducible factor-1 alpha (HIF-1a) and so suppressing HIF-1a during metformin/phenformin is selectively lethal for malignant lymphocytes," said Schieke. "So that would allow us to spare the healthy lymphocytes, let them do their job fighting the cancer on their own, while at the same time to target and kill the cancer cells."
Furthermore, Schieke noted that this mechanism has not been found in any other types of cancer. "This really seems to be specific for blood cancer, the lymphomas and the lymphoid leukemias in particular."
Schieke pointed out that the metabolic adaptation and glucose-dependence during exposure to biguanides is mediated by HIF-1a. This is a key signaling pathway in cells, the discovery of which was awarded the Nobel Prize for Physiology and Medicine in 2019.
As for the very concrete next step of the metformin and leukemia study, "We are actually trying to take that to patients," noted Schieke. "We are combining metformin with inhibition of these sort of escape pathway routes, extending the work, using more cells isolated from patients, using patient-derived xenograft models to study before we hopefully roll this over into a clinical trial and really see whether this does have any treatment potential for patients with lymphoid cancers. We are hoping to open a phase I trial in 2021."
Moving Forward
Where does the research go from here? "In the big picture, we're trying to figure out how the metabolic wiring of a cell impacts the behavior of it. How does the metabolic dynamics control or influence the phenotype of the cancer cell? And that is immediately tied in with how the diet affects the cancer in different stages, different behaviors or phenotypes of the cancer cells," explained Schieke.
"Do they have different fuel needs? We're trying to understand what controls the spread of lymphoid cancers in the human body. What controls whether these cells infiltrate the liver, infiltrate the bone marrow, or go to the brain. And it seems-though not surprising to anybody who is interested in metabolism-the metabolism and the mitochondria are very critical regulators for this spreading phenotype of those cancer cells. And in that regard, the diet and dietary targeting of very specific metabolic fuel needs and preferences might actually play a role. That's the bigger picture."
While cancer research usually begins with cell culture, progresses to mice, then with luck translates to humans, Schieke hopes to flip that sequence. "We want to ask questions in patients, get human data, because we know that the metabolic phenotype of cells we're studying in culture looks very different in mice and then could be completely different in humans," he noted. "We are trying to understand and describe certain metabolic types and preferences of those cells in patients, and then derive our lab studies in culture and in mice."
Schieke hopes that others in oncology will grasp two big takeaways from his research efforts. "Number one: Metabolism is not just a passive thing happening in cells; we know it is an active driver of cancer cell behavior. And number two: Metabolic features of cells in cultures are so different from metabolic features that we see in cells in living organisms, in mice, or in humans. That really is the next big frontier in understanding pathways, some of which we have studied in culture for decades.
"We must begin to understand how these pathways look and work in patients. If we implant cancer cells in a mouse and figure out they are depending on glutamine, other amino acids, or certain other fuels, we need to know if these are the same fuel preferences for cancers in patients. That is the big question. If we can find answers combining these two things-the critical driver function of cancer cell metabolism and specifically how cancer cell metabolism looks in patients-we could be on the verge of a very powerful approach to define new treatment targets."
Schieke and team are making strides in an area that is still understudied. "The role of cancer cell metabolism is widely appreciated, but it still has some major hurdles to clear," said Schieke. "It's odd. People have no problem accepting that if we eat fries and chocolate brownies for a month we'll probably gain weight. Right? And if we eat that for many years, we might end up with hypertension, or type 2 diabetes. Nobody has any issue with that. We need to apply that same acceptance to diets at the cellular and molecular level. If we feed certain things to cells, it affects the behavior and cellular function. And that could also mean if we offer cancer cells certain fuels, they may become more or less aggressive. Nutrition is a part of the equation. Period."
Valerie Neff Newitt is a contributing writer.
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