ASHANI WEERARATNA: The microenvironment has always fascinated me. I was not even in
grad school yet, and I heard Mina Bissell give a talk where
she showed a cell that she had taken from the prostate and put
in a mammary microenvironment. And that cell actually started
producing milk, which I thought was the most fascinating
experiment I'd ever seen.
VOICEOVER: Professor Ashani Weeraratna has been studying the cellular
microenvironment in her lab for the past 17 years. Cells don't
live in isolation. The other cells, molecules and blood
vessels in their surroundings can have a powerful effect on
their behaviour. And this is especially important when it comes to cancer.
ASHANI: So the tumour microenvironment is really the
neighbourhood in which the cells sit. They sit in a network of
matrix and mesh, and they have other cells that are around
them, and the impact and the crosstalk of those cells with
the tumour cells can have a huge impact on the behaviour of the
tumour cells outside of genetics. My lab and others are
looking at the impact of ageing of normal cells in the tumour
microenvironment and how those impact cancer development and
progression. It's such an obvious thing that cancer and
ageing go hand in hand. And yet despite that, until we really
started digging around, I don't think even I realised how
important it would be to understand what those changes
are and how we can target them.
VOICEOVER: Cancer is often defined as a disease of ageing, and the vast majority of cases occur in
people over the age of 50. As global populations live longer,
cancer is set to become a major public health burden. So how
does an ageing micro environment around a tumour affect cancer progression?
ASHANI: What we're finding is that the cells that are ageing normally
as they're supposed to do around the tumour cells are sending
signals to those tumour cells that make them more metastatic
and more invasive and more resistant to therapy. For
example, if you look at the skin, we see collagen that is
nice and firm and very dense in younger skin, but that we lose
that density and that firmness in aged skin. And that provides
ways for tumour cells to move differentially through that
collagen. Also immune cells, the immune system changes
dramatically as we age. And what we're finding is that there are
changes that are both beneficial, as well as
detrimental in the aged tumour microenvironment. So for
example, in melanoma, patients are often treated with therapies
that boost the immune system, so immunotherapies, and we find
that older patients actually respond much better to
immunotherapy such as anti PD-1 than younger patients, because
they don't have the same level of regulatory checkpoints that
younger patients tend to have.
So one of the things we've been most excited about recently is
the fact that we have found changes that occur in tumour
cells that we put into ages microenvironments, rather than
young microenvironments, and we can actually target those
changes. We see those changes in patients and when we target them
in mice, we can overcome therapy resistance and reduce
metastasis. And so that is fascinating, and we're hoping to
push that into clinical trials over the next few years. So are
researchers currently paying enough attention to the effects
of the ageing tumour microenvironment? As a
community, we're not really taking the ageing
microenvironment into account. We are designing preclinical
studies that are all based in six to eight week old mice, we
don't really tailor our therapies from young to older
patients. Our work has revealed that older patients respond very
differently even to targeted therapy. So that has been a
really fascinating finding for us. Because one of the early
experiments that we did was to take
genetically identical tumours that bore a mutation that we
could target. And yet when we put the same tumours in either a
young mouse or an aged mouse, what we saw was that the tumours
in the aged mice, despite the fact that you had one gene and
one drug to target that gene, behaved completely differently.
I think one of the most important milestones we're going
to see over the next five to 10 years is the movement of some of
this work into the clinic. So for example, the target that I
was speaking of earlier, is a target that we can make a drug
for, which we are doing, and then get
to patients in the clinic. I also hope that people will start
thinking about designing preclinical studies in young and
aged mice. We're beginning to show that there are differences
in older females and older males. So I think that's going
to be an area of great importance as well. And finally,
really what I'd like to see is the way we treat patients, how
important it is to treat them according to their age.