The complex relationship between prostate cancer and obesity

CHRIS HATZIS
Eavesdrop on Experts, a podcast about stories of inspiration and insights. It’s where expert types obsess, confess and profess. I’m Chris Hatzis, let’s eavesdrop on experts changing the world - one lecture, one experiment, one interview at a time.

It’s not a stretch to say that men of a certain age need to look after themselves, especially in ways that they can actually control such as diet and physical activity. I’m putting my hand up right now. But poor fat metabolism isn’t just linked to type 2 diabetes and cardiovascular disease.

Professor Matthew Watt is a prostate cancer and lipid metabolism researcher, and the Head of the Department of Physiology, School of Biomedical Sciences at the University of Melbourne. His research has found that there is a strong link between obesity, diet and poor outcomes in men who develop prostate cancer. In particular, men who consume more saturated fatty acids seem to have more aggressive cancer.

Professor Matthew Watt took some time out to sit and chat about his work with our reporter Dr Andi Horvath.

ANDI HORVATH

Now, you're known for fat metabolism, but you've done a little work in the prostate cancer area. Give us a little insight into what you've revealed about prostate cells.

MATTHEW WATT
Yes, this is some very recent work that's been conducted with our laboratory, in collaboration with researchers at Monash University. Essentially what we've found is that, unlike other cancer types, which rely heavily on glucose to fuel both their growth and their proliferation, prostate cancer cells are very highly reliant on fatty acids. This is important, because what we've shown in our own research is that when we block the capacity of these prostate cells to take up fatty acids, we've been able to slow their growth dramatically. We think this has very important implications in understanding both the progression of the disease, but also ways in which we might be able to therapeutically target prostate cancer in the future.

ANDI HORVATH

So, these cancer cells eat fat and you've blocked the transport molecule that takes the fat to the cells?

MATTHEW WATT
Yeah, that's correct. So, that was one of the key findings from our paper. So, we've known for many years that there's a certain protein that exists and it's called CD36 and that transports fats into other tissues. What we've specifically shown in this research is that CD36 exists in prostate cancer cells. It's actually up-regulated, or its activity is increased and this is very important in bringing fat into the tissue to help the prostate cancer grow.

ANDI HORVATH

So, how have you reduced the cancer growth in your trials? Is it a drug, is it an injection, what is it?

MATTHEW WATT
Yeah. So, we've done this through two different methods. So, we're able to firstly genetically delete CD36, or this protein, from prostate cancer cells. By doing that we are able to show, at least in mouse models, that we can reduce prostate cancer growth by about 50 per cent.

We've also done other studies where we've used pharmacological inhibitors of CD36 to slow down the uptake of fatty acids into cells. Again, we've shown remarkable improvements in slowing down cancer growth.

What was really important in those studies, those cells were derived from human patients who had undergone radical prostatectomy, or had their prostate tissue removed. We were able to get those cancer cells and use those to provide really important clinical evidence, if you like, that this process may work.

ANDI HORVATH

Wow. When does it go to market?

MATTHEW WATT
Well, that's a really good question and it's a tough question. So, typically, when we think about drug discovery, it usually takes about 10 years from initial discovery into the clinic. There's a lot of limitations for that process. We need to be able to convince pharmaceutical companies that it's an interesting target. Then of course, you need to undergo clinical trials, both phase 1, right through to phase 3, to show that your drug firstly works, but also is safe to use in humans.

ANDI HORVATH
Now, I know your main research area is fat metabolism in cells and we're going to talk later about obesity and these types of mechanisms in the body, but what got you into this prostate cancer direction?

MATTHEW WATT
Yeah, it's a really interesting question, Andi and I think it really relates to my age and my understanding that prostate cancer is a very important issue to men as they're growing older. I'm now in my mid 40s and I've got a lot of friends, obviously, in the same age group and a bit older. It's becoming a big issue for all of us and we talk about this regularly. What was very interesting is that a number of years ago another group, another research group moved into a lab next door to mine and they worked on prostate cancer. I worked on lipid metabolism and obesity. I said to this research group, isn't it really interesting that men that are obese are more inclined to get prostate cancer. So, from that point, we've conducted a whole series of studies trying to understand how prostate cancer develops at faster rates in men with obesity and of course, our answer is at the moment, that it's due to an increase in fat metabolism.

ANDI HORVATH

Now, I believe also that men are getting prostate cancer earlier and that's related to obesity, as well.

MATTHEW WATT

Yeah, there's some evidence that there are increased rates of prostate cancer in younger men, which has typically been seen as a disease for older men in the past. Indeed, you're right in saying that it's probably due to an increase incidence of obesity.

But I think specifically you need to understand that there are a number of changes that happen in the body when you are obese, or in obese individuals, that could lead to the progression of cancer. So, one of those may be changes in fat metabolism, but of course, there's other changes related to endocrine function that may also be important. I know that groups both in Melbourne and internationally are studying these relationships at the moment.

ANDI HORVATH

If I was to follow you after our studio interview into your lab, what would we find you doing? I know you work on fat metabolism and obesity. Tell us about your work there.

MATTHEW WATT
For many years my laboratory's really been focused on obesity-related disorders. When we talk about that, we talk about a cluster of diseases that are very closely associated with obesity and they include type 2 diabetes, non-alcoholic fatty liver disease and cardio-vascular disease. Our lab doesn't specifically work on cardio-vascular disease, but rather has a very strong focus on understanding how defects, or changes in fat metabolism, can pre-dispose people, or promote pre-diabetes in individuals. Then more recently we've been very interested also in understanding how defective fat metabolism leads to non-alcoholic fatty liver disease.

Now, the reason why this research is really important, at least in my eyes, is that about 70 per cent of individuals with fatty liver disease have type 2 diabetes. We know that fatty liver disease rates increase by up to 90 per cent in individuals with obesity.

We also know that the majority of people with type 2 diabetes are also obese. So, this cluster of diseases tend to go hand in hand. I guess, it's our responsibility now to better understand how these diseases develop and think about smart ways in which we can prevent them from progressing.

ANDI HORVATH

So, you're looking at how the cell uses fat for energy, its relationship with insulin at the hormonal level and its relationship with these diseases.

MATTHEW WATT
Yeah, that's correct. I mean, it's a big body of work that we do and it's hard to think about that in its entirety. But if we break it down, we can think about fat when it enters the bloodstream as a bad thing if it enters at high rates. So, the reason I say this is that a natural response in your body is to release fatty acids from your adipose tissue. We're talking about the fat that sits around your stomach and around your organs. We need that as a fuel source normally.

What often happens, in states like obesity, is that the rate of fat released is increased into the bloodstream and that fat isn't burnt at sufficient rates. What then happens is that those fats accumulate in tissues like the muscle, the liver, the heart, the pancreas, and it's the accumulation of these fats that's linked to disease states.

ANDI HORVATH

So, there's going to be a different transport system than, say, in the prostate cancer research? You're looking at the molecules that are shuffling these fatty things around, but also what triggers the shuffling of fats around the body?

MATTHEW WATT

That's correct. So, we're particularly interested in understanding, firstly, how fats are released from our fat stores. Secondarily, how they're taken up into other tissues like the liver and the muscle. Now, I guess the really important thing is, when a fat enters a tissue, let's say we use the liver as an example, it has a number of different fates. It can be burnt as energy, or it can be stored as a number of different lipid types. Depending on where it's stored, might dictate disease status, all right. This is a very important question, particularly in the field of fatty liver disease, but also type 2 diabetes. It's something we've worked on for the last 10 years, or so.

ANDI HORVATH

Oh, back to the lab for you then [laughs].

MATTHEW WATT
Yes [laughs].

ANDI HORVATH

You've got your work cut out for you [laughs].

MATTHEW WATT
Sometimes in the lab, yep.

ANDI HORVATH

Matt, since you've been working in the area of physiology, what's changed? What sort of changes have you seen that are worth reflecting on?

MATTHEW WATT

That’s a really good question. I think one of the major changes that's happened in the field of physiology particularly is the use of specific tools to assess molecular biology, in combination with the physiology. What I mean by that is that about 20 or 30 years ago it was very difficult to perform experiments where we could understand the precise molecular detail that happens within a cell. So, we're talking at the level of the nucleus and we're talking about the cellular components.

Now we have the tools to be able to do our physiology experiments, so to be able to assess whole body function, but also, at the same time, to be able to take samples and very small samples. Like you'd be thinking a piece of tissue that might be the size of the end of an eraser on a pencil, for example and from that we can get a full molecular profile.

So, we can get all the genes in that cell. We can get all the proteins in that cell, that one single sample. So, we can very easily now marry up the molecular biology, or those intricate events in cells, with our whole-body responses. I think that's been a major revolution in the field.

ANDI HORVATH
I'm keen to explore misconceptions. Have you encountered misconceptions about your area of research, or from the public, when it comes to fat metabolism and obesity?

MATTHEW WATT
I think one of the major issues we have in the field of understanding obesity is that the perception from some people in the public that it's the obese person's fault that they're obese. Some people may wonder why we're actually funding research into this, when it's their problem and they should eat less and exercise more, would be the pervasive attitude. We don't share that view. We know that there are very distinct changes that happen in the body, not just with obesity, but as you're developing towards obesity.

These changes happen at the level of the brain, but also in your peripheral tissues, like your muscle and your liver and some of your other endocrine organs that secrete hormones, that regulate both food intake, but also energy expenditure.

So, what we know is that over time that your body becomes resistant to some normal signals that indicate that you may have eaten enough, or other signals that suggest that you should be burning more energy. They're very hard to reverse those signals.

So, it's our job, as researchers for example, to understand what those signals are and how we may be able to reverse those. Of course, it's hard to relay that message to the general public, because they're very complex messages. One of our biggest challenges is to be able to deliver that message in a readily understandable way so that people appreciate that.

Of course, there's the perception from others in the field that suggest that we should be investing more into public health research. So, this would be the type of research that would be understanding why people have certain behaviours that may be linked to obesity and disease development.

Of course, the government have invested a lot of money into that field for many years and I think that's still a wise investment. But I think, from my perspective, there needs to be greater funding into areas of basic science, so we have a greater appreciation of the basic biological processes that lead to obesity and its co-morbidities, which include diabetes and non-alcoholic fatty liver disease. But also, to encourage this early work, which can lead to therapeutic development, which is a very difficult field to enter.

ANDI HORVATH
There's a lot of confusion out there about what to eat, whether we go down the ketogenic, high-fat, medium protein, almost no carbohydrate, or the low-carbohydrate diet, or the eat-clean-and-green vegan-ish. There's so much confusion.

MATTHEW WATT

Andi, you're setting me up for failure here. This a very hard question to answer. So, first, a lot of the confusion's born about the mixed messaging from researchers and how we promote our findings and that's for sure. The second one is that there's obviously key bodies that are very interested in promoting different diets, that's also important.

My commentary around this would relate to our understanding that one diet won't be effective in all people and that some individuals will respond better to a high-carbohydrate diet, low-fat diet. Other individuals will respond better to a high-fat, low-carbohydrate diet. Of course, there's also different composition of different fatty acids which people are interested in.

What I think people need to understand is that there is a genetic basis to these responses and depending on what your genetic make-up is may dictate how you respond well, or not, to a certain diet. So, this one-size-fits-all type thought process, really isn't an accurate reflection of how we should be thinking about diets.

I think some really simple advice would be that if we're eating foods that are as close to the source as possible, that would be a great start. The other advice would be, if you're thinking you're eating too much, you probably are and try to pull back just a little bit on your food intake, which can often be quite difficult.

ANDI HORVATH
I've got to pull back on the sausage rolls.

MATTHEW WATT

Sausage rolls for breakfast, yeah, probably not a good option.

ANDI HORVATH

Matt, I want to explore the curious scientist here. What got you into this area? What captured your imagination about fat cells, about hormones, about the body, obesity ?

MATTHEW WATT

Sure. I think what you're after here is some sort of eureka moment, but it wasn't that simple. So, by way of background, my training was in exercise physiology. So, understanding how we can exercise better as individuals. A lot of my work had direct application to endurance-based athletes, et cetera. I guess, the one moment that caused the shift in my career, was when I was flying across to the United States for a conference and I was sitting next to a lady who would have been in her probably mid to late 60s. We were just discussing science in general and she told me about her diabetes. At the time I wasn't working in the field at all and I wasn't aware of the complications, et cetera, that are associated with type 2 diabetes.

It was at that moment I really reflected on the importance of my work and really, do I want to spend the rest of my life researching high-end exercise performance which may impact 0.001 of the population, or be doing some work that really goes to understanding a really important disease state? So, I went down that angle and I certainly don't regret it.

ANDI HORVATH
What's one of the things that surprised you most about your journey in research in fat metabolism, so far?

MATTHEW WATT
So, one of the things that surprises me most about the field is that we keep learning. Much of the textbook material regarding fat metabolism was written 50, 100 years ago and we're still coming up with these eureka moments. An example of that might be that our understanding of how fat cells break down fat. The detail of that was discovered probably about 40 or 50 years ago. The intricate detail of that was discovered about 30 years ago. We thought we had that all under control and we knew everything. In 2006, three groups independently published a brand-new finding, showing that there was another unidentified, or previously unidentified protein, that controlled fat breakdown in your adipose cells. This was a eureka moment for the whole field.

Since that time there's been many groups that have been trying to understand how this protein works and also how to therapeutically target that protein to activate it, to increase fat breakdown in people. I think that's just a really great example that after 50 to 100 years of understanding a process, that we now have new insights into that and new ways in which we may be able to treat diseases that are associated with defective fat breakdown.

ANDI HORVATH

If we were able to time travel into the future, what would you like to see have happened?

MATTHEW WATT
I mean we've touched on a lot of topics here today and I think if we talk about fatty liver disease, that would be a really important one. We know at the moment that there are no cures for fatty liver disease, in fact no therapeutic has been approved on the market. This is completely perplexing and this is a really serious disease, because it leads to more serious liver disease, which results in your death.

What I would hope to see in the future and I'm hoping in even the next five to 10 years that there are new strategies that we develop to be able to treat fatty liver disease, which is a disease that impacts 20 to 40 per cent of the population, so it's a huge problem. That's what I'm really hoping for.

ANDI HORVATH

In your lab, with your lab associates, do you have like a hit-list of molecules, your kind of like wanted posters on the wall, going, is it this one, or is it this one that is making life hard for those who are obese?

MATTHEW WATT

Have you been in my office recently?

ANDI HORVATH

Oh, is that what they were?

MATTHEW WATT

[Laughs] So, we do. So, a lot of our work is really around discovery, looking at new molecules, or new proteins, that may be important in the pathogenesis, or the development of certain diseases. Specifically, we've been looking at recently understanding how the liver, for example, releases subsets of proteins into the bloodstream in disease states.

We now have a list of about 300 different proteins which we need to try to understand their potential involvement in disease pathogenesis. So, that's a real challenge in trying to understand which protein do we prioritise, what are the criteria for prioritising a certain protein, that we would then go on and potentially do 10 to 15 years of work on understanding how it works. So, it's a list that we're working through and it's list that we're hoping to get to the bottom of, one day.

ANDI HORVATH

Good luck, I hope you find the culprits, even if it's - it's probably a few of them, isn't it? It's probably not just one.

MATTHEW WATT
Yeah, I think it's my suspicion there's quite a few different proteins that are involved in the aetiology of the diseases we're talking about, but I think it's also about being smart and understanding which ones do we select. I think one of the challenges we face is convincing people with money, so the pharmaceutical industry, investing into our discoveries.

So, if you think about this as a basic scientist, the way the process works is that we make these discoveries, often with the help of public-funded money, so money from research grants from the government. So, we're essentially working for you, as an example. What happens is, once we make that initial discovery is, we need to transition that into a therapeutic. The issue we have there is that costs a lot of money. So, for example, to do a clinical trial in diabetes, it might be in the order of $300 million. Clearly, we don't have the budget.

If you even think about the National Health and Medical Research Council this year, their Ideas Grant budget, and this is for the whole country, was only $250 million. So, you can see where we're coming from, when we say we need money. So, one of our jobs is to convince pharmaceutical industry that our targets are good, they're worthwhile investing in. I think that's one of the big gaps we're trying to bridge at the moment.

ANDI HORVATH
Matt, you've got a lot of students in the lab. Your lab is full of PhD students, there's activity all round every lab corner. What advice do you give your students?

MATTHEW WATT

So, sometimes I might be accused of giving too much advice, but I think, one of the best messages that I can give to my students and others, is to think about the process and enjoy the journey. I think sometimes people are focused too much on the outcomes.

So, for a scientist, an outcome is a publication in a high-impact journal, or getting your next grant. I think sometimes we just need to step back and enjoy the discovery process, enjoy that eureka moment when you discover something new in the lab and try to understand what it means and pursue that line of enquiry. So, that would be probably my biggest advice.

ANDI HORVATH

Okay, Matt, next time I shove a greasy french fry into my gob, what should I be thinking about?

MATTHEW WATT

As an obesity researcher, I'd be saying, think about the motivation that led you to want to have that greasy french fry and whether you really needed it. Then think about all the research that goes in to understanding why that might be the case and thinking about how we might be thinking of ways in which we can stop that from happening in the future.

ANDI HORVATH

Is it my hormones talking, is it my cells talking, or is my brain talking?

MATTHEW WATT

They're all talking to each other, in fact. I think that's a really key point in understanding that there is a very complex interaction between all these systems that happen. I think one of the beauties of being a physiologist, which I am, is that we have an appreciation that there is this network talking to each other that dictate our behavioural responses.

ANDI HORVATH

Good luck in identifying amongst those 300 suspects that may actually hold the key to a better future of human health. 
Professor Matt Watt, thank you.

MATTHEW WATT

Thank you, Andi, very much.

CHRIS HATZIS
Thank you to Professor Matthew Watt, Head of the Department of Physiology, School of Biomedical Sciences, University of Melbourne. And thanks to our reporter Dr Andi Horvath.

Eavesdrop on Experts - stories of inspiration and insights - was made possible by the University of Melbourne. This episode was recorded on May 6, 2019. You’ll find a full transcript on the Pursuit website. Audio engineering by me, Chris Hatzis. Co-production - Silvi Vann-Wall and Dr Andi Horvath. Eavesdrop on Experts is licensed under Creative Commons, Copyright 2019, The University of Melbourne. If you enjoyed this episode, drop us a review on iTunes and check out the rest of the Eavesdrop episodes in our archive. I’m Chris Hatzis, producer and editor. Join us again next time for another Eavesdrop on Experts.