Cancer Metabolism: Sugar, Fructose, Lipids & Fasting | Gary Patti | 215

Short Summary: How dietary sugar (fructose) affects the growth rate of cancer.

About the guest: Gary Patti, PhD is a professor at Washington University in St. Louis, holding appointments in chemistry, medicine, and genetics

Note: Podcast episodes are fully available to paid subscribers on the M&M Substack and everyone on YouTube. Partial versions are available elsewhere. Full transcript and other information on Substack.

Episode Summary: Nick Jikomes talks to Dr. Gary Patti, exploring how cancer cells metabolize sugars like glucose and fructose, focusing on a recent study showing fructose indirectly boosts tumor growth in mice via liver-produced lipids called lysophosphatidylcholines (LPCs). The discussion covers cancer biology basics, the Warburg effect, tumor microenvironments, and the systemic metabolic impacts of cancer, while also touching on dietary implications, fasting, and the complexities of nutrient utilization in cancer progression.

Key Takeaways:

* Cancer cells often rely heavily on glucose, excreting it as lactate even when oxygen is available (Warburg effect), but take up more than their mitochondria can handle.

* In a study, high fructose diets accelerated tumor growth in mice by 4x, not because cancer cells use fructose directly, but because the liver converts it to LPCs, which tumors use to build membranes.

* Tumors are not just cancer cells; they recruit healthy cells in their microenvironment, and their metabolic effects ripple across the entire body, altering distant tissues.

* Excessive fructose consumption (e.g., from soda, not fruit) may worsen tumor growth, but cutting it poses little risk and could benefit cancer patients, pending human studies.

* Fasting may reduce cancer initiation risk in animals, but its effect on existing tumors is less clear and could worsen wasting (cachexia) in late stages.

* The body tightly regulates blood glucose via the liver, so simply cutting dietary glucose won’t starve tumors, highlighting cancer’s metabolic adaptability.

Related episode:

* M&M #200: Dietary Fats & Seed Oils in Inflammation, Colon Cancer & Chronic Disease | Tim Yeatman & Ganesh Halade

*Not medical advice.

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* Episode transcript below.

Episode Chapters:

00:00:00 Intro00:05:35 Cancer Biology Basics00:11:26 Tumor Initiation and Immune Evasion00:17:13 Studying Early Cancer with Zebrafish00:23:19 Metabolic Changes in Tumors00:29:16 Tumor Microenvironment and Healthy Cells00:34:28 Glucose vs. Fructose Metabolism00:40:17 Fructose and Cancer Cell Growth00:46:04 Fructose Processing in the Body00:52:49 High Fructose Diets in Mice00:59:22 Liver’s Role in Tumor Growth01:06:06 Identifying LPCs as Key Nutrient01:12:03 LPCs and Dietary Fat Connections01:17:19 Fructose Intake Implications01:23:40 Endogenous Fructose and Drugs01:27:57 Ketogenic Diets and Cancer01:34:09 Fasting and Cancer Risk01:39:59 Cancer Phases and Diet Strategies

Full AI-generated transcript below. Beware of typos & mistranslations!

Gary Patti 1:31

yeah. Name is Gary patti. I'm a professor at Washington University in St Louis. Actually wear a few different hats. I'm in a couple different departments, chemistry, medicine and genetics, and I run a relatively large lab. We study cancer and metabolism. I also serve as director of some cores at the university, the clinical research core, as well as some metabolomics and proteomics cores. And then lastly, I'll just mention that I'm also a CSO of a company that does contract research services for for different omics, multi omics technologies.

Nick Jikomes 2:12

Yeah, so, so you've got quite an interdisciplinary lab. You do a lot of stuff that's related to metabolism and metabolomics. You do a lot of stuff related to cancer biology, which will probably be our focus here. Today, we want to get to a paper that I thought was very interesting and very relevant to a lot of people, you know, out in the real world, which has to do with the relationship between sugar metabolism, particular, and and tumor growth. Before we get there, I want to cover off on some basics on cancer biology and and sugar and fructose metabolism. So, you know, I'm somewhat familiar with cancer biology. I'm a biology guy by training, but I was never a cancer biology person. And sort of the cartoon that I've always had in my head, or I had when I was, like a student in college and stuff, is that, you know, cancer is a cell. You know, cancer cells are cells that are have escaped the normal cell cycle regulation, and they're growing uncontrollably, and that that is largely often a genetic thing. So, you know, I learned about oncogenes and tumor suppressor genes, and so the idea was, cancer is typically a series of mutations in specific genes that allow the cell to break free of the cell cycle. Can you just give us a general sense of, are most cancers, or is the average cancer? Whatever that means, is it largely a matter of mutations in genes, or can cancer arise through non mutation mechanisms?

Gary Patti 3:36

Really great question, and a good summary of the historical there's a little bit of history and how the our understanding of cancer has evolved over the last 100 years or so. And I won't impose an age upon you, but I think depending on when you got trained and when you learned about some of the stuff, different items and different aspects of cancer biology were emphasized, actually, the very some of the very some of the earliest discoveries associated with cancer were not based on genetics, but actually were metabolism. The if you go back about 100 years ago or so, there was a German scientist named Otto Warburg who was really the first person to think about cancer from a metabolic perspective, and he noticed that cancer, sugar metabolism, specifically, which we'll get into more here in the next few minutes, was altered in in cancer. And so his definition of cancer, actually, you know, a century ago, was that cancer cells have altered metabolism. And he actually asserted that a certain piece of cancer, the power an organelle inside cells called mitochondria that is sometimes known as the powerhouse of cells. It's where. It's not the only place where metabolism occurs, but at least we teach the undergraduates that that's where a lot of the important metabolism, certainly where most of the energy in a cell is made. He actually argued that what causes. Answer is not oncogenes as you as you described, but actually failed mitochondria, and that it was that alteration in metabolism that was the cause of cancer. Now we know that's usually not the case cancer. Most cancers have completely functional mitochondria, and in fact, they need mitochondria. That's something that our, our perception has evolved over the years about cancer, but, but as genomics evolved there, there is in many fields, cancer fell victim to, sort of being, getting obsessed with molecular biology and genetics, and we

Nick Jikomes 5:35

as a consequence of what the tools were that emerged,

Gary Patti 5:39

exactly, yeah. I mean, I think the Human Genome Project, you know, played a big role in that and the excitement of being able to do sequencing, yeah, and rightly so. I mean, it was an exciting time. In 30 years, we'll look back on today and say, Oh God, they were so, you know, they were obsessed with whatever we're doing today. So I think that that's just how science evolves. But, but, but there was a, you know, we learned that genes, you know, mutations and certain genes, were sufficient to cause cells to behave abnormally, and specifically, not just abnormally in some way, but they lose their ability to to to regulate proliferation, so they proliferate uncontrollably. And that's really the one of the main driving characteristics of cancer cells, is that most normal cells know when to stop growing and stop turning into new cells. But cancers cells don't do that. They they proliferate uncontrollably. And so genes are at the basis of that, and they cause that. But exactly how they cause that, I think, is the really interesting question. So I think what you say is totally correct, but it's only a piece of the equation. You know. How does an oncogene allow a cell to proliferate uncontrollably where a non transformed cell that doesn't have that oncogene doesn't do that? You know

Nick Jikomes 6:58

how? And I guess if you just think about it in sort of common sense terms, it would almost have to be true that in some way, whatever these genes are that might drive certain cancers, they would have to affect metabolism, because, almost by definition, cancer is going to have an altered metabolism because it's it is uncontrolled growth. Yeah,

Gary Patti 7:16

it's actually amazing how, how long that that? I totally agree with you, but there are several decades where metabolism was back burnered As part of cancer. I mean, I think it's fair to say that cancer is a metabolic disease. There are certain hallmarks that classify cancer and altered, deregulated metabolism is one of the hallmarks of cancer. So it's not specific to pancreatic cancer, lung cancer or brain cancer. Altered metabolism is something that most cancers across the board share. Yeah,

Nick Jikomes 7:47

I want to ask a somewhat vague question, but, but it's an important question, and anyone who's not a cancer biologist, like I'm not might wonder this. So obviously, there are different forms of cancer, in the sense that the cancer can arise in different tissues, pancreatic cancer, brain cancer, whatever. But how much, how much diversity is there in terms of the fundamental type of cancer? It is, from a cell biological standpoint, do most cancers? Is it sort of the same basic phenomenon, or is there a lot of variation where two different cancers can behave cell biologically, very different from one another, apart from the fact that both are unregulated cell growth?

Gary Patti 8:29

Yeah, amazing question, and one that I think that we're still trying to figure out, certainly the tissue of origin is what you described. So some cells, some cancer cells, might be derived from pancreatic cells, or, you know what, hepatocytes, or whatever the whatever cell type they originate from, plays a role, because those cells are already programmed to operate in one way. And so certainly you see diversity if you look at tumors and different tissues. But what's really interesting is that there's also quite a bit of diversity in those same tumors. So it's not just diversity between brain cancer and liver cancer, it's actually there are lots of diversity in brain cancer, right? And so I think the certainly, the tissue of origin, plays a big role in how the provides, really a starting point for where how the cell is going to thrive. But the other thing that plays a major role in this is a good segue into some of the other topics we're going to discuss is the environment, because cells to proliferate. So, you know, just to really provide context what we're talking about here, one cell has to turn into two cells. So a cell has to replicate its contents, and to do that, it requires a lot of synthesis. You know, you have to rebuild all of the protein machinery, you have to rebuild all the lipid membranes, you have to rebuild all the genetic material, and that takes a lot of biomass, and you have to build. All that stuff from something, and it takes a lot of energy. And so the question is, what nutrients is a cell going to use to support that anabolic process? And what's remarkable about cancer, I think that's totally fascinating, is the versatility that they have and the plasticity that they have in the nutrients that they can use. It's it's rare that they are limited to one nutrient. You know, we're going to talk about sugar today, and they love sugar. Most cancers are addicted to sugar. And you might think, Well, if we remove sugar, and we've tried this experiment, star of cancer cells of sugar, then does that prevent them from doing that in most case cases, the answer is no. They just move to a different nutrient. So there is a lot of flexibility. They don't always operate. Yes, they start as the tissue of origin. They seem to start in that way. The other thing that happens is that tumors can metastasize. So you can imagine that a tumor starts in, you know, the lung or the breast, and then it metastasizes to the liver. So now you have cells that originated as breast cells, but now they're in the liver in a totally different environment. And so it gets kind of interesting. Do they start behaving more like tumors that would primary tumors that recur in the liver, or do they retain their program that originated in the breast but conduct that in the liver. So you get those kind of interesting questions too, because cancer is mobile.

Nick Jikomes 11:26

So my understanding is cancer, we're basically all getting cancer at some baseline rate, but most cancer cells that emerge get taken care of by the immune system. They're detected. The body notices that they're abnormal and we don't want them, and then we get rid of them. But obviously, in some, some percentage of cases that those checkpoints, those those mechanisms, can't get rid of the cancer, and then, then we get full blown cancer. When we think about cancer generally, is, are there sort of certain phases or or parts of the life cycle that we can talk about where so, so obviously cancer can be initiated. But if a cell becomes cancerous, that doesn't mean we're going to get cancer, because the immune system might might get rid of it, and it often does. What is, what is that transition like? Where you go from a cancer cell start, you know, you get that first cancer cell, and it gets past the normal mechanisms the body has to detect it and become, say, a full blown tumor?

Gary Patti 12:27

Yeah, yeah. So from a metabolic perspective, I think it's a really fascinating question, and it's proven to be somewhat difficult to study, because usually what we're talking about there are small numbers of cells. And if you think about the ways that we generally study cancer, yeah, most of those things are subclinical, like you can't see, yeah, you don't see that. First one, there's no symptoms. Exactly, there's no symptoms, and you can't detect it on a you know, we often use something like a PET scan. I think most people are probably familiar with PET scan. So essentially, what you do is you give patients a radioactive chemical, and then they then you put them in a scanner, and you can detect the uptake of that chemical and and unfortunately, if you have a small number of cells, one cell or a handful of cells, they don't show up on those kinds of on those kinds of tests. So it's proven to be very difficult to study these processes, and the way in which we typically do it is is fairly artificial. So we can study them in things like culture, you know, and cell culture, yeah, we put them in a dish, and you could do things like irradiate them or cause initiation by giving them chemicals and and see but, but how it translates to the body. I think that's an exciting area where we keep pushing Now, the other thing you bring up, which is incredibly important, is the immune system, and that's an area where I think we've seen enormous development and progress over the last 10 years, where it's not just because you're right, the immune system plays a major role in trying to keep things contained and controlled, but it doesn't always work. I mean, a lot of people get cancer, and so, you know, I think one of the really exciting things that's been happening is, is, can you tune the immune system in such a way to make it more aggressive, more active, to go after some of these tumors, and that's when you start getting into the immunotherapies, using the immune system to try to sort of put the immune system on steroids, to go after this stuff. And, you know, it's been pretty, pretty effective, and a lot of difference. It's not, obviously not perfect, but a lot of progress in that space. So

Nick Jikomes 14:29

it sounds like basic the sort of basic problem here is, you can study the origins of cancer. You can look at the birth of that first cancer cell, the early phases of, you know, going from one cell to two cells to a small tumor, it's you can you can study that in a dish, in a artificial setting, which is amenable to experimental interrogation, but obviously that's removed from the natural context of the whole animal that we ultimately want to understand it in actually understanding those early phases of cancer in a whole animal in vivo situation is tough. Be just for the very reason that it's hard to spot it. When it happens, it's small and difficult to detect. And we don't really see these things in animals, for humans, until they're in a much more mature phase. Yeah,

Gary Patti 15:11

yeah. I can give you one sort of, I think what you said is generally true. There are, you know, ways, innovative ways that people are coming up with to try to study this. And I can just give you a little bit of a technical example, if it'd be of interest to and that is a way that we've been trying to tackle this question, using a model organism called zebra fish. And zebra fish are interesting model systems for people that aren't familiar with them. They're about the size of goldfish, and they are aquatic, and they present some advantages there. They're they're translucent, so they're easy to study. And what we what we do, if you put a oncogene in fish, you can put a certain genes, like we use, BRAF, b6, 100 D, which is a mutation that commonly occurs in various forms of skin cancer. And if the fish have that, just like some humans that have genes like you might be familiar with, say, the bracket genes, you have a higher incidence of developing cancer. The fish, too, because they have this gene, will have a higher incidence of developing cancer. And so what we do is we genetically engineer the animals to have this gene, BRAF, e6, 100 E, and then when the gene gets expressed, we use that expression to drive the expression of GFP green fluorescent protein. And what that does, particularly in this unique system of sea bird fish, which, like I said, is translucent, we can put them under a microscope, and when the cell turns cancerous, you see a single cell level it turns green, yeah. So we can do things like ask, start asking questions. You know that we've we've figured out a way to make it more visual so that we could study it more quantitatively at higher detection limits. And we can do things like ask, How does sugar influence initiation, or, How does sugar influence the development those early stages of development before you get a clinical sized tumor? Does diet play a role there? I think those are really interesting questions that, like I said, we're just starting to really develop some tools that are allow us to dig into some of that stuff. So

Nick Jikomes 17:13

again, high level, I would imagine that when a cancer so there's the birth of a cancer cell, most of them aren't going to live long past their birth, because the immune system will take care of them, but when they do get past that, does that involve some there must be some kind of evasion technique that the cancer cells use. Are they able to camouflage themselves or just avoid how do they avoid detection by the immune system to really get going as tumors?

Gary Patti 17:39

Yeah. Well, there's a couple of things that are involved. There's also repair, intracellular repair mechanisms that that can the immune system isn't the only ways. And you know, the things that need to be evaded. There's other DNA repair type systems that can come into play as well. So, you know, fortunately, we have a couple of mechanisms to try to catch these things, but, but the other thing that starts to be really interesting is signaling. So cancer cells at a certain level start to do, start to really when you, when you get enough cancer cells, you start to develop a tumor. And when you have a tumor, at some point, it starts to integrate into the physiological system of the host. So if you think about your body, you have a bunch of different tissues, bunch of different organs. You have liver, kidney, lungs, and when you have a small number of cancer cells, they just operate kind of independently in their own world. But when they get to be a certain size. What starts happening is they start integrating into the physiological system of the host. So they start communicating and signaling with other tissues. So

Nick Jikomes 18:48

they start releasing detecting molecules coming from healthy tissues to literally, sort of integrate physically with with healthy tissue. Yeah, they start

Gary Patti 18:57

engaging and basically biochemical exchange. So they release molecules, they go to other tissues, and that changes, reprograms the tissues that other tissue might, send molecules back, so they have these, this inter cellular communications and exchanges, and that gives them a certain robustness, that that makes them much more difficult to to to try to combat the other thing that tends to happen at certain limits is like we think of vascularization. So you get sprouting, where you actually get more blood vessels that come in and start to feed, because as the as you get more and more cells, you need more and more nutrients. And the blood supply, the nutrients are primarily derived from the blood, and you need blood to do that, so you'll start to actually vascularize the tumor. So they start telling, you know, they start basically manipulating our native responses and using those in pathological ways. And I think, in my opinion, that's one of the most interesting aspects of cancer right now, is that we're, you. We're starting to appreciate that, and some of these things we've known for a while, but it's becoming, I think, even surprising on the context of some of the more historical stuff. And that is, is that they're, they're really able to hijack a lot of the systems that are already in place and use them to their advantage. Yeah?

Nick Jikomes 20:19

So, I mean, I mean, naturally, you think so if, by definition, these cells are growing too fast, so they need to fuel that growth somehow. They're going to need to instigate a remodeling of, say, the vasculature so they can get that extra blood flow they need to support that. They're going to need to sort of suck up extra nutrients compared to what a normal cell would, and that would somehow have to involve, I mean, not only sort of building just the physical capacity to do that, like the blood vessels that will inject all those nutrients, but they, they probably have to signal to other cells to, sort of, I would imagine that, like our cells are normally set up with, with with mechanisms to say, like, you know, the nutrients Have to be apportioned according to the needs of all the cells. And I would imagine there's natural mechanisms that prevent one cell from getting out of control, and some of the cancer cells have to circumvent those things so they can take more than their fair share. Basically, yeah,

Gary Patti 21:12

exactly. I mean, I think that's exactly right. I mean, if you think about just nutrition as a whole, you know, you put new you put food in your body, and that food has to be allocated among all of the trillions of cells in your body. And how does that actually happen? Like, who decides who gets to eat what? And it's actually remarkably complex and symbiotic. You know that one cell the way, it's just totally amazing. I mean, metabolism is just so freaking cool. Because what happens is that some cells say, Okay, well, I'm not going to use these nutrients because we need that nutrient for, say, the brain. The brain is highly specialized, and it's going to, it needs nutrient act, so we're not going to touch that. And then these other tissues over here, we're they're not going to use this nutrient because this so everybody gets sort of a sign certain ways in which they should biochemically behave, so that everything operates correctly in a holistic fashion. Yeah. And what happens with cancer is that they just sort of disobey all those rules. They come in and shake everything up. And not only do they themselves use nutrients in a way that is flies in the face of the whole physiology, but they reprogram other tissues to use nutrients inappropriately, so it just really throws the whole thing out of whack.

Nick Jikomes 22:27

Yeah, yeah. And okay, so you know where we're going to go with this particular fructose paper we're going to end up talking about, but before we get there. But with that in mind when we think about certain types of cancer, tumors. You know, I'll let you decide which ones are the best to talk about. But the tumor microenvironment that gets created to support this unchecked growth that is cancer. What are some of the hallmark metabolic changes? Or is that even a good question, that support that growth? And I guess what I'm really asking there is, is this typically a process that's going to rely on heavily on glucose metabolism? Is it going to be a mitochondria thing? Is it going to involve, you know, using glycolysis more or less? How does a cancer cell oftentimes switch its metabolism relative to a healthy cell in terms of the bioenergetics?

Gary Patti 23:19

Yeah, yeah, there's a ton there. I'll start to tackle some of that, and you can steer me along, as I probably spend the next hour talking trying to answer that one question. So how does a cancer cell so one of the things you said is, how does a cancer cell itself reprogram its metabolism in the face of this anabolic burden that has to replicate? And that alone is an incredibly interesting question, and one that's actually puzzled cancer biologists for over a century. It seems like it should be pretty easy, you know, you say, Okay, well, they the cell needs to replicate, so it should just turn up, dial up all the pathways, you know, everything should be up. It should take up more sugar, it should take up more, more of every nutrient, and just ramp up every minute of all pepper. And that's actually, superficially not what seems to happen. So if you think about I'm going to try to break metabolism down extremely simply here, because I know a lot of people probably aren't into the weeds. Aren't as excited about this topic as I am, but when glucose comes into a cell, it can be really metabolized in two ways. Yep, it can be metabolized without oxygen, which converts it into a molecule called lactate. And when you do that, you only get two ATP, which is the currency of energy in a cell. But alternatively, the glucose can be oxygen can be metabolized oxidatively in mitochondria, totally break it down into CO two. And when you do that, you get something like 30 to 38 ATP. So it would seem that the cancer cell needing a lot of energy, yeah, the second one. Ron, yeah, the second one. But that's actually not what happens. Most of the glucose that enters the cancer cell gets excreted as lactate. So. So you don't get a lot of energy, and most, most of the carbon is wasted because it it's lactate is a byproduct. Okay,

Nick Jikomes 25:06

so, so a glucose molecule can come into a cell, it can go down. You can metabolize it in the cytoplasm without oxygen and get a couple of ATP molecules. Or you can funnel it through a mitochondria, and it's going to do the oxidative phosphorylation, thing, you're going to use oxygen and that you can get a lot more ATP, a lot more bang for your buck that way. You would think naturally, cancer cells got to grow a lot. It's going to probably crank up and use the more efficient way to make ATP. But you're saying that often does not happen.

Gary Patti 25:34

It does not Yeah, that's right. So it's like I said, this has been the paradox. This is something that's almost synonymous with cancer metabolism, called the work. Metabolism, called the Warburg effect, that was observed by this German scientist, Otto Warburg 100 years ago. And we've been trying to figure out why that doesn't happen. As anybody, if we asked 100 people, 100 people would probably say, That's what should happen, why that doesn't happen. And, you know, I think we finally start to understand why. You know, I think we now have a good explanation. For that, but. But the key thing to emphasize here for for the listeners that might be saying, well, you just said that, that tumors outgrow their blood supply, so the reason they metabolize glucose in this way without oxygen is because there's not enough oxygen. So they're doing this because they're hypoxic, is the word, but, and that's a great point, but cancer cells do this in the presence of oxygen. That's really the key thing. Yeah, even though they have oxygen, they still do this.

Nick Jikomes 26:31

So in a sense, they don't need to do it this way, but they choose to. They choose to,

Gary Patti 26:35

and it does seem and so I think we've made a lot of progress. I'm trying to answer this in the last five years or so. And actually what seems to happen is, if I could, if I could, kind of jump to the punch line. What seems to happen is that the cancer cells take up too much glucose. So the reason that most of the glucose gets excreted as lactate is not as was once positive that that it's because the cancer cells don't want to metabolize it oxidatively. But as it turns out, the amount of glucose that they take up is far greater than the amount of maximum glucose they can oxidize. So they do oxidize a lot of glucose in mitochondria, it just turns out that they take up so much more glucose. Okay, mitochondria can support that. It gets excreted. So

Nick Jikomes 27:18

the mitochondria, they're, using the mitochondria. It's just that. It's just that the mitochondria have some there's a rate limiting thing here. They can only process it so quickly, and all the excess stuff will naturally just go to glycolysis. And because they have so much glucose, that's going to be a natural side effect, that seems to bring us to the point of, okay, so they are, they are somehow sucking up a hell of a lot of glucose,

Gary Patti 27:41

exactly, and that's, and that's, you know, really, since the 90s, that's something that we've exploited clinically. So if anybody's wondering, you know, what is metabolism done? Who cares about metabolism? Why does it matter? The best testament as to why metabolism is important is because this is the main way in which we diagnose stage and test tumors how they're responding to therapy. So I alluded to this earlier, but now that we've provided a little more context, I can give a little more detail. So what you'll do is you give patients a radioactive form of glucose, and because tumors take up glucose faster than any other cells, you've probably seen these images, they're PET scans, yeah, and the tumors are really bright because they take up all of the radioactive glucose and most of the other healthy tissues don't. And that's a main way in which we how we diagnose and tumors, you know that they're there, or try to stage how big they are, or how well a person's responding to therapy, as we do this test. Now the other point, if I could go back to your original question, which was really contained a lot of information is that when we think about tumors, an important point is that tumors are not just cancer cells. So cancer cells, I would say, Are these cells that are like you said, have oncogenes. They're malignant. We say they're transformed, but if you look at a tumor, yes, it has these malignant cells, but a large portion of the cells are not malignant. Tumors actually recruit healthy cells to their micro environments, and they abuse them. They're extensively healthy, but they're, they're reprogrammed in a way to support the tumor.

Nick Jikomes 29:16

Wow. It's like someone who's unwittingly recruited into like, like an organized crime scheme, and they're just, they're just the shop operator, but, but they need them to run the operation. Yeah, no,

Gary Patti 29:26

I like that analogy. I mean, the analogy I often use is it's kind of like outsourcing. You know, we said that cancer cells need a lot of materials to build, you know, to build stuff. And just like if you were building a house, you may not want to do everything from scratch. You can go to Home Depot and buy pre made buy pre made toilets or pre made whatever. And that's sort of what cancer cells do. They they can rely on some of these other cells to to outsource some of the production. And so these other cells then can produce things and ship them off to the cancer cells. And then the cancer cells don't have to start from scratch. They can build from these in. Puts a lot of that energy demand and that anabolic burden on other cells. So you had asked maybe for an example, and I could just give you one example that I think is a really easy among the those that are not, maybe one of the easier ones to conceive, and that is breast cancer. So in breast cancer, you have cancer, malignant cells that are juxtaposed next to fat cells, adipocytes. In those adipocytes, an adipocyte is a cell that stores a lot of lipid, and lipid is people probably can appreciate, is a really rich source of energy that you can burn for fuel. And what we know happens actually, not just maybe we can get into this later, not just breast cancer, but but tumors. A lot of tumors have a disposition to want to make themselves adjacent to fat. And what we know happens is that these fat cells channel, funnel the lipids that they have inside to the to the cancer cells, to the malignant cells, so that the malignant cells can use it as a type of fuel or to build things, to build membranes and so forth. So it is literally using the lipid component of these adipocytes to feed malignant cells. Yeah,

Nick Jikomes 31:14

and there's a whole, there's a whole world of stuff here, you know, I've had people on recently, you know, we were talking about things like polyunsaturated fatty acids and the potential role in supporting tumors that originate in colon cancer. And maybe if we have enough time at the end, we'll loop back to metabolic flexibility and lipid stuff, but keeping on the subject of sugar. So hey, I just want to repeat a couple of things for people. So I don't even know if I fully appreciated this, one of the simple, basic things that you said was tumors are not just clumps of cancer cells. It's a whole environment that includes cancer cells and healthy cells that have been sort of recruited into this mass. And so there's normal tissue and cancer tissue in a tumor, the cancer cells themselves, the cells in the tumor, are really good at sucking up a lot of energy, and it sort of alluded at least that they can suck up energy. They'll get energy some way, somehow, no matter what. But they often are using glucose, because that's what's around, and that's what's going to be easiest, in some sense, for them to support this unchecked growth. We've we've mentioned glucose already, before we get into the cancer stuff. More, I just want to give people a bit of a picture on glucose versus fructose metabolism under normal conditions. So glucose and fructose, two forms of simple sugar. What are the key differences there in terms of how cells use these forms of sugar for energy? Yeah,

Gary Patti 32:42

great question. So fructose and glucose are structural isomers. So what that means is that if you look at their components, they're exactly the same. They have the exact same collection of atoms. The only difference is that the atoms are are positioned in slightly different ways, which is why fructose is different than glucose. As you point out, glucose is is we know is key to our physiology. You know, if you think about something like diabetes, hyperglycemia, hypoglycemia, when you go to the doctor, they don't measure fructose. Measure glucose levels. We regulate glucose levels with extreme amount of you know, it's, it's exquisitely controlled. You know, we keep glucose levels in in certain ranges. And if you don't do that, your body is it's bad, you know, you end up with all kinds of different diseases. It's damaging. Glucose comes from the food. Fructose can also come from the food, in fact, increasingly so. And that whole history there is interesting, because one of the questions that I think is really important, and maybe I'll let you decide if you want to go down that path. But why this? Actually, this trend is happening, but we've started to consume more and more fructose, really, over the last 40 years, it's, it's gone up quite a bit, and it's been used in many ways as a replacement of glucose. One of the reasons for that is because fructose, it's actually cheaper. It's, it's cheaper to make, and per molecule of fructose, you get more sweetness out of it, wow. So if you, if you had the exact same amount of fructose and glucose, and I gave both to you, yeah, you would perceive fructose to be sweet. Oh,

Nick Jikomes 34:28

wow. So I, I've, I've known that the fructose glucose ratio, um, has a big effect on palatability and and how sweet we perceive things. So I always assumed that the reason that all of these big companies have converged on these very particular fructose glucose ratios of like 5545 is that they're optimizing for the sweetness that comes from having a little bit higher fructose than you would say, get with sucrose, and that's driving increased palatability and therefore increased consumption, which is going to support their business. Models, what you're saying is actually there's actually, like a dual there's a there's a dual thing here, which is, not only is it modulating palatability by boosting fructose, it actually is more economic for the companies because the fructose is cheaper. Yeah,

Gary Patti 35:13

that's right. And actually you can track some of the stuff back to the the embargo that with with Cuba, back in the Cuban Missile Crisis, when there was a demand to generate, you know, we, we the United States needed to be more self sufficient. And that's when a lot of the production of fructose started occurring. And if you look back historically, that's kind of when there was a flat line, and then all sudden, things started to go up and around that era. Now there have been some flattening of that curve as of recent, because I think people are becoming a little more, thankfully, a little more conscientious about what it is they put in their bodies. I think that's the message for everyone. We should think about what it is we're eating, but, so I think, but, but it's still used massively. I mean, if you walk around and look at the things you're eating, unless you're actively trying to avoid fructose, it's likely that you're consuming quite a bit of it. And so back to your question, though, about how is it metabolized differently? Yeah. So when you look at how glucose gets metabolized in the cell, it actually gets metabolized to fructose. You go through. You go through. If you look at glycolysis, fructose is, is an intermediate of glycolysis, not directly, but it's structuring, okay,

Nick Jikomes 36:37

so it's intermediate of glycolysis. So the thing that gets us to ATPs per glucose molecule in the cytoplasm that's necessarily going to create a fructose molecule in the process of generating that energy? Exactly,

Gary Patti 36:48

yeah, and so, so, and when glucose comes in, it's highly regulated. Utilization of glucose is highly regulated. And the the kind of off on the control switch there, the control valve is really high up. When glucose enters the cell, there's an enzyme, couple enzymes, that controls whether or not how much you want to metabolize it. Now, when fructose enters it's actually possible that it can enter directly. It can bypass that essentially control valve, and enter directly downstream, directly into the fructose intermediate. I see, so essentially, what you're doing is fructose has some capacity to bypass some of the regulatory steps that, historically, that our cells have evolved to basically utilize.

Nick Jikomes 37:36

So I see, so on one hand, this, this. So two things are coming to mind here. For me, it makes sense intuitively that would happen. I mean, if it's an intermediate, you're just you're just skipping the first step because you already have the second step there. But what you're saying is the first part that would normally take you from glucose to fructose is very highly regulated, which would imply that the cell can control and turn things up and down in a very precise manner. If you have excess fructose and you're bypassing that step, you the cells tune ability, its ability to regulate how much of what is happening is going to be less

Gary Patti 38:09

Exactly. Yeah, that's exactly, right. And so, so, you know, the there's a correlation with the consumption of fructose and the obesity epidemic. You know, we've in around the world, but in the United States in particular, there's an increasing amount of obesity. And some have argued that that you know that fructose, the increasing usage of fructose, is associated with that. And it kind of makes sense, just from a very high level perspective, that if you're putting a lot of nutrient in your body, and you can't regulate its utilization, that's going to drive and we know that when you, when you, when you consume more fructose, that you make more fat. That's definitely happening. It promotes de novo lipogenesis. Exactly promotes the Nova lipogenesis. So, so we know that's happening. And so, so, you know, it all kind of makes sense. So the but you're back to your question about fructose. So we know, we've known for 100 years that cancer cells take up glucose, and the question that's emerged in the last couple decades is, well, what happens with fructose? The discovery about glucose was was made 100 years ago, but but fructose wasn't in high utilization back then. So what happens now that that fructose is being utilized to cancer cells. You know, should we be using fructose as an imaging agent? And you can imagine that a fructose could be utilized with greater efficiency and without regulation. These are all the things that seem like they would benefit a cancer cell. We talked about cancer cell wants to proliferate without regulation. That's the definition. So it seems like fructose might be a really great nutrient to support that cause. And there has been some evidence, you know, we're going to get to the paper that you're referring to, where we show that at least in the cancer cells that we studied, that's not the case. But there have been a pro there have been a couple prior studies that it indicates. That in some other cancers, that is the case, that cancer cells can utilize fructose, and that putting fructose into the body gives the gives the cancer cells access to the fructose, and that that escalates, you know, amplifies growth. So

Nick Jikomes 40:17

apart, so fructose is an intermediate in glycolysis. It can be turned glucose. Can be turned into fructose on the way to creating ATP in the cytoplasm. You can also bypass that by just having the fructose directly, sort of plug into that second part there. What about, what about the mitochondria, and what about the the So, so when we, when we think about dietary fructose, so exogenous fructose that we are consuming, is there, I guess the basic question I have is, is, Can fructose be used to create ATP to the same extent as glucose? Are they as efficient at creating energy as one another?

Gary Patti 40:51

Yeah, yeah, yeah. They are. They can both be oxidized in mitochondria. You both. They're both six carbon substrates. They both produce two pyruvates which which go into the mitochondria and get oxidized. So for all practical purpose. Now, there is one caveat, and this could come into play. It's, I think it's potentially interesting. You do make a phosphorylated fructose intermediate, and some have argued, so there's fo what that means is you're adding phosphate to fructose. And some have argued that because you take fructose up with such high avidity and that you can't metabolize it fast enough that you end up putting a lot of phosphate on fructose, and that actually sequesters your phosphate. Now we've been talking a lot about ATP, which is the currency of a cell, right? ATP is got three phosphates on it, right? So

Nick Jikomes 41:42

if you sequester all your phosphates now, you're gonna be energy limited. Yeah. So

Gary Patti 41:45

there is some question as to whether or not fructose might might be playing a role in some kind of ATP limitation in that sense. And there have been, there's this example that people often talk about where they tried to treat diabetics with fructose, because they thought, well, if they can't use glucose, let's try fructose. And that ended badly because of, at least, supposedly, because of the sequestration of the phosphate and some limitations that that had on the regulation of ATP.

Nick Jikomes 42:17

Okay, so now, okay, so glucose, fructose, we've got cancer cells form. They are good at sucking up energy. Are they using? Is there anything notable or weird about cancer cells, generally speaking, in terms of glucose, fructose, do they do they? Are they deviating from normal cells? Use of those things in any notable way.

Gary Patti 42:41

Yeah, it's a, it's a that's a really important question, and one that seems like it should have an easy, obvious answer. And that was really the origin of our study. Is that we, we wanted to take cold cancer cells in the dish, in culture, and give them fructose and and we, we expect it that, and there was literature out there to support it. We expected that the cancer cells would take up fructose and use it like, you know, like crazy, much like glucose. And so we started the this whole paper that you're referring to start it with us taking cancer cells and giving them fructose and making the observation that they actually don't utilize it. And we, we looked at a pretty large number of cancer cells. Obviously, nobody can look at every cancer cell, but we looked at, you know, I don't know, maybe 3040, cancer cell lines. And in no cases did we find now, some were a little better at it than others, but it was not able. Fructose alone was not able to support the growth of the proliferation of cancer cells. In other words, if you took out all the nutrients and you only gave them fructose, they really could not proliferate effectively, but they could with glucose, presumably, but they could all yes and not presumably, we actually tested in every case, they could proliferate with glucose, but they could not proliferate with fructose, yep.

Nick Jikomes 44:02

Which is, which is a little weird, as you said, you would have expected them to be good at using either source. You tested a bunch of different cell types in a petri dish, not in a live animal, but you looked at a bunch of different cancers, and none of them were particularly good at using fructose, even though they could all get by with glucose. Exactly,

Gary Patti 44:16

that's exactly, right. And so we started to try to figure out why that was and the answer proved to be actually quite simple. When you feed fructose into glycolysis, it doesn't just go in directly. You have to modify it a little. You have to add phosphates. And as it turns out, the cancer cells don't have that ability to add the phosphate they lack that they don't have the right enzymatic machinery

Nick Jikomes 44:43

to do it. So part of the changes that make them a cancer cell have have prevented them from having that ability.

Gary Patti 44:50

So that that was, that was kind of where we went next. Because, you know, like I said, we when you think about it, generally speaking, cells have this capacity. Capacity. But then we started asking, Well, is it true that cells in general should have that enzyme? We certainly know that some cells have that enzyme. And in this context, I think it's important to consider how fructose is actually metabolized when you eat it. Because what generally happens is, it turns out, even though we, eve