Mechanobiological approach and understanding the 3D architecture of cancer

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Published: 7 Aug 2014
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Prof G V Shivashankar – National University of Singapore, Singapore

Prof Shivashankar discusses the importance of mechanobiology in understanding cancer. He stresses the value in looking at cancer at the single cell level to see how precise changes to genes come about. He hopes that by understanding the mechanical architecture or genomes we may be able to establish cancer phenotypes.

My laboratory works on how genomes are organised within living cells and how cell mechanics constraints alter 3D architecture chromosomes and how such alterations in chromosomes bring about changes in transcriptional programmes. My background is I did my undergraduate in physics and a Masters in engineering and a PhD in biology and biophysics. So we are taking an approach of a modular approach in thinking about how cells function. In particular the way we are thinking about understanding genome organisation and function is about understanding the physical basis of how DNA can be packed within the cell nucleus - what are the physical constraints, what are the mechanical constraints, what are the chemical constraints that go into this? And how such packing introduces modular rules, modular principles, that underpin how genes are regulated. In that, what I mean is we know very little about the physical chemical principles that underlie it so at the moment we’re not looking at specific genes, we’re looking at modular principles that are central to organising the genomes in living cells which we know very little about.

Understanding that has important implications for the following reason, that when cells perceive mechanical signals from the local microenvironment those signals alter the cytoskeletal structures thereby altering the nuclear organisation, the morphology, the shape, the size and so on and so forth during cell differentiation and reprogramming. In all of that, what we know very little is how does a 3D architecture of genomic templates that are organised perceive these signals? What my lab is now trying to think about is to build physical chemical rules of defining how cell mechanics and genome architecture are coupled.

Could you give us an example?

Let’s take this room as an example. If we change the size of this room different parts of the room come close or far away. In the same manner with the cell nucleus changes in the size of the nucleus, the shape of the nucleus, because the genome is a very large DNA thread that’s packed inside the nucleus, changes in such physical aspects change how different genes come closer, different genes go far apart. The appreciation in the last few years is that the organisation of the DNA within the nucleus, particularly the spacial and temporal organisation of the DNA, is central to understanding how genes are regulated. So, in that manner, changes in shapes of the nucleus have profound influences on how you bring together two or three or multiple parts of the DNA together or close by or far away. When you sequester things close by what we find now is that being together you’re actually regulating things together, either for transcription or the genomic programmes. So how do cells alter these gross properties such as the nuclear morphology but yet bring in such precise encoding of genetic information is rather poorly understood at this time. So my laboratory is trying to construct what are the rules that underpin such changes in spatio-temporal organisation that cells have to do, whether during differentiation or during developmental programmes or when cells acquire disease phenotypes, including cancer which is a good example. In most of these processes cells alter nuclear architecture mechanically but have a very precise biochemical output. So my lab is trying to see how, on one scale, it is a physical architecture, on the other side it’s an information content that you have stored. So changes in such physical architecture introducing changes in information content. There appear to be specific designs in how signals transact with the DNA that we are beginning to uncover at this stage.

How is this related to cancer?

Cancer is an interesting biological question and a problem. Very often cancer is a process of cellular reprogramming and one of the first things that one begins to see is that changes in nuclear architecture is a central phenotype that one finds in cancer cells. Our ideas are that perhaps changes in the spatial organisation of the chromatin or chromosomes that underlie either introducing mutations, damage sites, on DNA or transcriptional mis-regulation might be precursors for the onset of cancer cells. And the more recent years have seen that cancer perhaps is a disease at the single cell level. A single cell in a tissue, perhaps due to a number of stochastic constraints alters its phenotype, thereby DNA damage and so on and so forth, into acquiring mutations. So our hypothesis is that perhaps a single cell perception of microenvironment is a mechanical element and changes in the cell mechanics perhaps changes nuclear organisation, perhaps changes how DNA is packed and perhaps changes how very precise genetic outputs come about during the onset of cancer. That’s the link we are trying to make between how, perhaps, cellular architecture, mechanical architecture, of genomes might be critical in setting up cancer phenotypes.