Starving cancer away | Sophia Lunt | TEDxMSU

I love sweets, does anyone else like sweets? Many of you also like

cancer

cells. Cancer cells love sugar, as many of you know that

cancer

is still the second leading cause of death in the United States, which means we still need better therapies for our cancer patients today. I would like to tell you about an exciting new approach to cancer therapy based on sugar metabolism. In fact, we have known for a long time that cancer cells love sugar almost a hundred years ago, in 1924, a famous German scientist and Nobel Prize winner named Otto Warburg. observed that cancer cells eat much more sugar than normal cells, so this observation that cancer cells love sugar is known as the Warburg effect and the Warburg effect tells us that normal cells can stop after just one piece of candy, but cancer cells cannot stop. eating sweets and we take advantage of the Warburg effect for the diagnosis of cancer through PET images.

Here is a PET scan of a patient with pancreatic cancer. The patient was given radioactively labeled glucose that lights up when concentrated in an organ that the pancreas normally does not. It doesn't light up because normally it doesn't like to eat so much sugar, but in this case the patient has cancer cells in the pancreas, it is eating all the sugar, concentrating it and causing it to light up on the PET scan and we can diagnose the patient as well. It is good that we take advantage of sugar metabolism and the Warburg effect for cancer diagnosis, but I want to go one step further and use it well as therapy, in addition to eating much more sugar, cancer cells also metabolize it. sugar differently there are two main ways to metabolize sugar one way is to use the oxygen we inhale and convert it to carbon dioxide which we exhale if we don't have enough access if we don't have access to enough oxygen we can also convert sugar into lactate aka as lactic acid, and we have all experienced this during exercise, when we cannot supply enough oxygen to our muscles, we become breathless and start to build up lactic acid and feel like our muscles are burning.

From an energy point of view, it is much better to metabolize sugar using oxygen because you can generate up to 36 energy molecules called ATP. If you convert sugar to lactate, you only create up to... well, normal cells take in sugar, use oxygen, and convert the sugar into carbon dioxide. many energy molecules, but cancer cells eat much more sugar and convert most of it to lactate even when they have a lot of oxygen available and don't generate much energy, so why would cancer cells make good use of such an efficient metabolism to respond? In this question we have to think about what a cancer cell needs.

A cancer cell needs to grow, divide, and make more cancer cells. You cannot produce more cancer cells simply with energy, just as you cannot build a new house simply with electricity. So yes, we can produce energy from sugar, but we can produce other things like DNA and RNA, which serve as genetic blueprints for the cell, just as you will need a blueprint to build a house, you can also make carbohydrates, proteins and fats, just as you will. We need building blocks, concrete insulation and other elements to build a house and we believe that the Warburg effect supports all of these biosynthetic pathways that generate cellular building blocks and if we want to take advantage of the Warburg effect we have to understand it in more detail so that our shape favorite sugar is called glucose and glucose is primarily metabolized through a pathway called glycolysis which has many steps that eventually generates a metabolite called pyruvate without oxygen lactate can be generated from pyruvate with oxygen carbon dioxide can be generated now the The enzyme that generates pyruvate is called pyruvate kinase and is altered in all cancer cells.

There are actually two main forms or isoforms of pyruvate kinase M 1 and M 2 and one is found in many normal adult cells, which means that these cells no longer grow. M 2 is found in all cancer cells. study to date, but to complicate matters further, it is also found in some normal growing cells, so what I did in the lab was remove pyruvate kinase M 2 from both normal and cancerous growing cells and see what happened. and this is what I found in normal cells. they grow well as you can see in the yellow line with pyruvate kinase M 2 and when I remove it they stop growing completely as you can see in the red line when I do this with the cancer cells, they can grow with or without them.

So how are they doing this? Has your metabolism changed? Are they rewiring their metabolism to be able to do this? We have to be able to look at their metabolites and we can't just put them under a microscope and look at the metabolites. It's too small, so I need very expensive and sensitive experiments. I'm told this looks like a Slurpee machine, but it's actually a very expensive instrument called a mass spectrometer and it can detect thousands of metabolites based on the mass of a molecule. These are instruments that Otto Warburg did not make. we have, but we have access to them and we can study cancer metabolism in great detail and I want to show you my data using this instrument, but first I don't want you to look at the words, I want you to look at the colors.

Is it black or do you see many colors? If it is black, that means there are no changes in the metabolites. If you see a lot of colors, the metabolites are changing, so let's take a look, as you can see that these cancer cells are completely changing their metabolism. We are increasing their metabolites in yellow and decreasing their metabolites in blue so they can still grow without them; so it's like that if cancer cells are invading what this Wharton Center at Michigan State University and we found out that they're coming in through Wilson. Road, so what do we do right?

We block Wilson Road, we remove that road so they can't get in, and what do they do? They find a new way, they rewire their route even though it has more traffic and is more indirect, they still find their way without em - normal cells stop growing and cancer cells continue to grow by rewiring their metabolism, so what What I'm doing now in the lab is blocking multiple pathways at once, multiple genes so that cancer cells stop growing while normal cells continue to grow, so we just talked about glycolysis and pyruvate kinase, but the metabolism is a lot. more complicated than this and I want to give you an idea of ​​that, so I'm going to reduce glycolysis and move it to the top left corner of the screen and now I'm going to fill in the rest of the metabolism, so take a deep breath and let it out, because you can see that metabolism is very complicated and this is still just a simplified map of metabolism.

Remember that normal cells come from cancer cells, so some pathways are shared. and some pathways are different, which means we have to understand complicated normal metabolism as well as complicated cancer metabolism, but this is a very interesting pathway for therapy because these are just some of the enzymes that are mutated, deleted or are altered in some way in cancer cells, so these are all potential targets for therapy, so here's our research strategy first. I want to identify all the key metabolic pathways that help cancer. Then I want to do deeper mechanistic studies that tell us exactly how each pathway helps cancer cells.

Does it help your survival? To your growth? its invasion or something else, then I want to take all this information and use it to design a personalized therapy because, as you know, all individuals are different with their own genetics, diets and environments, so we have only just begun to understand the different metabolisms and cancers and take advantage of them. for therapy there are many different types of cancers with all types of mutations but they all have one thing in common they all have to eat cancer cells they have altered sugar metabolism and I want to starve the cancer