A New Idea about How Cancer Begins


A New Idea about How Cancer Begins

It appears to happen more readily than we once believed

A New Idea about How Cancer Begins
Dividing cancer cells.

Cells, the units of life that compose our bodies, are able to make copies of themselves to help us grow, fight disease and recover from injuries. Cells have built-in mechanisms that maintain the fidelity of transmission of genetic information from one generation to the next, and to control cell division in a timely manner, allowing our bodies to build or rebuild various tissues.

But as cells divide to generate new cells, errors known as mutations can arise. And if a cell accumulates enough mutations in the genes that control cell growth and maintain the fidelity of the genome from one generation to the next, known as tumor suppressors and oncogenes, it loses its stability and starts dividing faster than normal, which leads to cancer. Some of these genes can mutate to accelerate the speed at which mutations arise (a phenomenon known as genetic instability).

Genetic instability genes may be relics of a time when single-celled organisms needed to adapt to rapidly changing environments; it is possible that these genes evolved secondary functions that are important for multicellular organismal development, and are therefore essential, despite their role in instability.

In the early 1950s, scientists proposed that it took a double hit of mutations to trigger cancer—because we have two copies of each gene, one from our mothers and one from our fathers. Destruction of the tumor suppressors, or mutation of the oncogenes genes that directly cause cancer, is therefore unlikely; both copies would have to be damaged for cancer to arise. But that idea was contradicted by the high rates of cancer incidence we actually see.

Now, however we have discovered that cancer might arise more easily than previously thought. By doing experiments on both yeast cells and on human cells in culture, my colleagues and I have been able to show that just a single mutated gene suffices to accelerate cancer. The experiments mimic an early event during cancer development—the acquisition of genetic instability—which is characterized by a faster accumulation of mutations, and by genomic changes which can themselves disrupt cancer tumor suppressor genes or activate oncogenes.

So far it has been difficult to identify when and where genetic instability arises, either because tumor samples represent a late stage of cancer development and thus carry many different mutations, or because studies with model organisms are focused on inactivation of specific genes. This new work started from a provocative question posed to me by my mentor, Andrew Murray: “If we let cells choose, how do stable cells evolve into cancer cells?” Catching the initial transition from genetic stability to instability was the crucial goal, and this was done by selecting cells that are able to survive different drugs, each survival step requiring the inactivation of a “tumor suppressor” gene.

Mimicking two important aspects of cancer development, the inactivation of cancer suppressors and the acquisition of drug-resistance, we allowed the cells to choose how to evolve accelerated mutation rates. Surprisingly, instead of the predicted two-hits, a single heterozygous mutation (a mutation in one of the two copies of a gene) was the favorite route to evolve instability. This means that, similar to the famous anime show One-Punch Man, where the hero defeats his enemies with a single hit, cancer might start with a single mutation.

This contradicts the prevailing thinking in the field, which, as I noted, states that two inactivating mutations are required for cancer onset. And since a heterozygous mutation in a single gene suffices to trigger genetic instability, and we predict that human cells have 300 such genes, it is very probable that cells turn on the ability to mutate faster. As a result, the chance of hitting tumor suppressors and oncogenes, and genes that favor metastasis or drug resistance, becomes much higher, accelerating cancer development.

Hence, this work suggests that a single heterozygous mutation, in one of a large number of genes, is an easy way for cells to acquire a “super-mutator” power that allows cancer to progress faster. From the basic scientific standpoint: similar to what was shown in bacteria, which dial up their mutation rates in adverse environments, for instance to survive antibiotics, eukaryotic cells also have pedals (genes) that accelerate the speed of evolution, allowing them to escape growth control.

In collaboration with a research group lead by Ricardo M. Pinto at the Center for Genomic Medicine at Massachusetts General Hospital, we were able to test if the homologs of instability genes we found in yeast worked similarly in human cells. They did: five out of six of the genes tested gave rise to genetic instability when they inactivated. We found a total of 57 human instability genes, 47 of which have not been previously implicated in cancer and require further studies. Moreover, many of these genes do not have a known direct function in genome maintenance, which reveals that other cellular pathways, such as metabolism and protein quality control, can be compromised to cause instability.

Another idea, which I will explore in the future, is that different types of cancer require different instability types (and genes) during different stages of development. Since not all tissues express the same genes, I hypothesize that different targets act locally to initially start cancer, and later during metastasis and treatment resistance.

To test this hypothesis, I will develop experimental evolution systems in organoids (cellular arrays that recreate tissues and organs) and animal models, where I can test the role of instability in different cancers, elucidating for which stages instability is more relevant and how it interferes with different cancer treatments.

Genetic instability also has implications on cellular aging: it is known that as a cell divides, the speed at which its genetic material mutates, as well as chromosomes shorten and structural rearrangements occur, increases. However, the causality of these events is not well established: is it that instability is a consequence of cellular aging and the cellular inability to repair itself, or is instability triggering aging? During my doctoral work I discovered that unicellular organisms are able to replicate without exhibiting aging, and it might be that further studying how these cells maintain genetic stability is key.

Therefore, I plan to establish my own research group using experimental evolution systems to explore genetic instability in the context of aging and cancer development, which are two fast-increasing human malignancies with a heavy individual and societal burden. In the long term, findings on what controls the speed of cellular evolution might lead to targeted therapies that delay genetic instability in specific cancer types and prolong human healthy lifespan.

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