Evolution of Cancer Cell Chromosomes Visualized using Organoids

This is free art suggesting “mutation”.

Tumor cell populations are full of mutations, mutations that provide genetic diversity that can allow some to survive chemotherapeutic agents. A series of single nucleotide changes may lead to tumor growth but most dramatic changes in genome composition, and increases in genetic variation, occur after tumor cells begin replicating without regard for their chromosome number and composition. This chromosomal instability creates variation in tumors, allowing for the most aggressive subpopulations to proliferate and generating a diverse pool of genotypes—all of which need to be wiped out if the cancer is to be eradicated. While it has been possible to identify the effects of chromosomal instability (wide-spread aneuploidy) for a long time, studying the mechanisms directly has been difficult given the limited amount of genome sampling and karyotyping (chromosome imaging) that was possible compared to the amount of change in tumors.

A recent paper by Bolhaqueiro et al. describes a technological advance for studying chromosome instability that involves genetically engineering cancer cells to express fluorescent proteins that label chromosomes and culturing those cells into organoids, 3D clusters that more accurately mimic how cell grow in vivo than cells in a flat culture. This approach allows rapid single cell karyotyping and imaging of chromosome behavior during cell division. Paired with single cell sequencing, the direct study of the chromosome instability in organoids may have broad applicability. Cancer cells all start with a fairly similar toolkit and undergo a finite number of replications, so with sufficient study more of their vulnerabilities become apparent and possible to target.

Below is the introduction and link to a longer summary of the Bolhaqueiro article; the original article is interesting but longer, geared towards an expert audience, and behind a paywall.

Watching cancer cells evolve through chromosomal instability

Chromosomal abnormalities are a hallmark of many types of human cancer, but it has been difficult to observe such changes in living cells and to study how they arise. Progress is now being made on this front.

Sarah C. Johnson & Sarah E. McClelland (2019) Nature

The genomes of cancer cells are littered with mutations (errors in individual nucleotides), some of which might contribute to growth of the cancer by activating tumour-promoting genes called oncogenes, or by switching off genes belonging to a class known as tumour suppressors, which fight cancer. Yet, arguably even more important are the genomic abnormalities that occur in tumour cells on a much larger scale. For example, such a cell might contain anomalous numbers of entire chromosomes (a situation termed aneuploidy). As the tumour evolves, chromosomal abnormalities can vary between neighbouring cancer cells. This suggests that chromosomal changes can occur by repeated chromosomal ‘shuffling’ during each cell division, resulting in a high rate of genomic change, termed chromosomal instability.

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Introduction to organioids

What you need to know about organoids

By Chloe Reichel

Paola Arlotta, chair of and professor in the stem cell and regenerative biology department at Harvard University, is growing brain tissue in her lab. In recent years, scientists have developed new techniques that add another level to the two-dimensional tissue culture of yore (e.g., growing cells in a single layer in a petri dish). These cells grow and divide in three dimensions, ultimately giving rise to samples of tissue that resemble the organ itself. They’re called organoids, but many news headlines have described them as if they are real, live organs.

Take these headlines for example: “Scientists grow human brains in a dish” and “Scientists brew up the creepiest batches of brain balls yet.” While science is in its infancy, the headlines don’t reflect that, taking liberties in describing what organoids are and overstating their form and function.

“You imagine a mini brain in a dish — that’s not what these things are,” Arlotta stresses. That bears repeating: They’re not mini brains; they’re not brains in a dish. They’re brain organoids, simplified replicas with some of the features of the organ they model.

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