New potential to stop pancreatic cancer

20 August 2019

Interview with 

Paul Timpson, Garvan Institute

CANCER-HEADLINE

Headline about cancer

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Pancreatic cancer has a notoriously dismal prognosis; fewer than one in ten of those diagnosed survive for more than 5 years. Now scientists in Australia have uncovered part of the reason why this disease is so aggressive: the tumour secretes chemicals that subvert healthy cells nearby and turns them into a protective shield that nourishes the cancer and promotes its spread. But now that Paul Timpson, at Sydney’s Garvan Institute, has identified the signals that make this happen, it should be possible to block them, and improve the outlook for patients.

Paul - Fundamentally pancreatic cancer is a major killer. The disease is typically surrounded by tissue that typically protects it from chemotherapy. That surrounding tissue also acts as a super-highway to allow the cancer to spread. We wanted to understand two things: how does that work, and how could we target that. So we've done a very simple experiment: we've taken two types of mice that have pancreatic cancer; one that typically spreads all the time, and another mouse that grows the tumour at the same rate but does not metastasise.

Chris - Are these mice that naturally develop pancreatic cancers or are these the mouse equivalent of a human pancreatic cancer?

Paul - Yeah that's a great question.These mice have been genetically engineered to have the typical mutations that a human does. This mouse has pancreatic cancer that mimics the human disease. And so what we did was we asked a simple question: why does one spread and why does the other not. And so we took the cells, which are called fibroblasts, that surround the tumour and protect that tumour and we mixed them. We took the cells from their metastatic spreading tumour and mixed them with a non-spreading tumour, and suddenly that tumour could spread.

Chris - And when you say you took these fibroblasts, these are not cancerous cells, these are just in the normal tissue that's around the milieu of the cancer?

Paul - Yeah. They're called cancer-associated fibroblasts. A cancer can educate its surroundings to manipulate a cell that normally has a function of wound healing for example, and it tells that cell “I want you to produce X amount of molecules to help me grow, to help me protect myself against the chemo and to help me spread”. And so that's why we took these cells, mixed them with the tumour that could not spread, and suddenly that tumour could now spread. Clearly these cells that surrounded that tumour could educate that tumour to now be able to spread. They’re passing on some sort of information to a tumour that cannot spread, and that was something we were really interested in because obviously if it doesn't spread it's more likely to have surgery and you can actually take the primary tumour out before it spreads.

Chris - And do you have any leads yet to what the nature of that conversation may be? So the tumour is secreting something and that something is doing something else to all these surrounding cells and completely re-educating and changing their behaviour as you put it. Have you any insights into how?

Paul - Yeah. So that's a perfect question. We take the surrounding cells, these fibroblasts, and we ask what are they secreting back to the cancer cell to allow it to spread. What we found was that they secrete a molecule called perlecan and perlecan stood out to us because very recently someone had looked at prostate cancer and this was linked to this spread of prostate cancer. We attacked that molecule and assessed whether this was actually one of the key drivers. Interestingly, the cancer cell itself secretes a molecule to actually tell the surrounding cells to produce this molecule, so almost changing its architecture to say “now protect me from chemotherapy and allow me to spread”.

Chris - It's interesting though that this is almost like a switch being thrown whereby the cancer tells these cells to start doing this they start doing it and then they feed back on the tumour, it’s almost like a positive feedback loop.

Paul - So that's a fantastic point. So we call this the vicious circle because as soon as the cancer cell tells the surrounding tissue what to do and produce this molecule, that surrounding cell talks back to the cancer cells and says “yes, I’m producing more”. And it's a vicious circle and therefore a tumour becomes more and more aggressive more and more invasive and obviously more and more deadly.

Chris - Is it also possible then that you could because you make the area more propitious and fertile for cancer cells by doing this that the initial pioneering cells from the cancer that make this change then actually lay a road down which other less invasive cells can more easily flow? So actually you accelerate the progression of the cancer because it's not just these hardy pioneering cancer cells that then can leave and start to spread and cause further disease.

Paul - Yeah. So that's a fabulous point. It's like a domino effect. And this is exactly what we wanted to address. And for any given tumour, many times you will have a non-invasive cell and beside it an invasive cell that has this mutation and that can cause small amounts of the tumour to actually metastasise and spread. All the other cells then follow. It’s almost like the invasive cells create a burrow and therefore all these non-invasive cells spread as well. It's almost like the cancer cell is already looking for its next home. It's priming the next environment for its next home. And it keeps on going and going and eventually that's why it takes over the body.

Chris - On this basis then Paul, do you think that using this strategy can translate into a clinical difference for patients or is this just very early interesting observations that we've got to build a lot more on?

Paul - What we do believe is that this could be a treatment. The reason we believe this is because we allowed the tumours to fully grow, fully develop and allowed them to almost have some early stages of metastasis. We then inhibited perlecan and we could see a significant difference. So we actually used a fully blown disease to test this. And it does work. So we think that this could translate to the clinic. Yes.

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