Breaking Up Is Hard To Do

 

Thus Neil Sedaka, the American pop songster back in the 60s. He was crooning about hearts of course but since then we’ve discovered that for our genetic hearts — our DNA — breaking up is not that tough and indeed it’s quite common.

A moving picture worth a thousand words

When I’m trying to explain cancer to non-scientists I often begin by showing a short movie of a cell in the final stages of dividing to form two identical daughter cells. This is the process called mitosis and the end-game is the exciting bit because the cell’s genetic material, its DNA, has been duplicated and the two identical sets of chromosomes are lined up in the middle of the cell. There ensues a mighty tug-of-war as cables (strands of proteins) are attached to the chromosomes to rip them apart, providing a separate genome for each new cell when, shortly after, the parent cell splits into two. When viewed as a speeded-up movie it’s incredibly dramatic and violent — which is why I show it because it’s easy to see how things could go wrong to create broken chromosomes or an unequal division of chromosomes (aneuploidy). It’s the flip side if you like to the single base changes (mutations) — the smallest damage DNA can suffer — that are a common feature of cancers.

In Heir of the Dog we showed pictures of normal and cancerous chromosomes that had been tagged with coloured markers to illustrate the quite staggering extent of “chromosome shuffling” that can occur.

Nothing new there

We’ve known about aneuploidy for a long time. Over 20 years ago Bert Vogelstein and his colleagues showed that the cells in most bowel cancers have different numbers of chromosomes and we know now that chromosomal instability is present in most solid tumours (90%).

Knowing it happens is one thing: being able to track it in real time to see how it happens is another. This difficulty has recently been overcome by Ana C. F. Bolhaqueiro and her colleagues from the Universities of Utrecht and Groningen who took human colorectal tumour cells and grew them in a cell culture system in the laboratory that permits 3D growth — giving rise to clumps of cells called organoids.

Scheme representing how cells grown as a 3D clump (organoid) can be sampled to follow chromosomal changes. Cells were taken from human colon tumours and from adjacent normal tissue and grown in dishes. The cells were labelled with a fluorescent tag to enable individual chromosomes to been seen by microscopy as the cells divided. At time intervals single cells were selected and sequenced to track changes in DNA. From Johnson and McClelland 2019.

Genetic evolution in real time

As the above scheme shows, the idea of organoids is that their cells grow and divide so that at any time you can select a sample and look at what’s happening to its DNA. Furthermore the DNA can be sequenced to pinpoint precisely the genetic changes that have occurred.

It turned out that cancer cells often make mistakes in apportioning DNA between daughter cells whereas such errors are rare in normal, healthy cells.

It should be said that whilst these errors are common in human colon cancers, a subset of these tumours do not show chromosomal instability but rather have a high frequency of small mutations (called microsatellite instability). Another example of how in cancer there’s usually more than one way of getting to the same end.

Building bridges …

The most common type of gross chromosomal abnormality occurs when chromosomes fuse via their sticky ends to give what are called chromatin bridges (chromatin just means DNA complete with all the proteins normally attached to it). Other errors can give rise to a chromosome that’s become isolated — called a lagging chromosome, it’s a bit like a sheep that has wandered off from the rest of the flock. As the cell finally divides and the daughter cells move apart, DNA bridges undergo random fragmentation.

… but where to …

Little is known about how cells deal with aneuploidy and the extent to which it drives tumour development. This study showed that variation in chromosome number depends on the rate at which chromosomal instability develops and the capacity of a cell to survive in the face of changes in chromosome number. More generally for the future, it shows that the organoid approach offers an intriguing opening for exploring this facet of cancer.

Reference

Bolhaqueiro, A.C.F. et al. (2019). Ongoing chromosomal instability and karyotype evolution in human colorectal cancer organoids. Nature Genetics 51, 824–834.

Lengauer, C. et al., (1997). Genetic instability in colorectal cancers. Nature 386, 623-627.

Johnson, S.C. and McClelland, S.E. (2019). Watching cancer cells evolve. Nature 570, 166-167.

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