Floris Foijer (educator)
In my lab we study the relationship between aneuploidy, ageing and cancer.
Location Groningen
Activity
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I would imagine so. I do not know of any studies that have tested this (not trivial to test, as you would need to assess this at the single cell level, I think, and you need the right controls). But a very interesting hypothesis.
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I think all chromosomes have rRNA genes on them, so probably chr. 21 as well, so this could be indeed one of the reasons.
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Indeed, and this is very much what we see when we assess this in model systems for CIN.
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Indeed: in Down syndrome, and other aneuploidy/CIN imposed ageing syndromes, ageing results from the CIN phenotype. Vice, versa, we think that aneuploidy (or related processes) also increase with ageing, exemplified in this study https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053425/
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Good point: in the lecture I meant to say that lower CIN rates as compared to the CIN rates that cause embryonic lethality. Aneuploidy typically leads to a growth delay in cells, can lead to senescence and premature ageing phenotypes. The more severe the CIN rate, to more toxic it gets and beyond senescence, cells would die because of CIN.
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This is a very interesting point that the field has not fully addressed yet. When we measure the transcriptome of aneuploidy cancer cells (i.e. how many RNA molecules are being made from each gene), we find that the RNA molecules increase mostly proportionally with the increase of gene copy numbers that are caused by the aneuploidy. In other words, the cells...
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Indeed, and this reduced viability is what we call the aneuploidy paradox. Somehow cancer cells adjust to the disadvantages, either by selecting for favourable karyotypes and/or by activating mechanisms that overcome the disadvantages of aneuploidy. This is why we think that aneuploidy is a powerful accelerator of cancer, or an enabling hallmark of cancer: it...
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Good reasoning. However, when you predispose mice with a cancer mutation, induced aneuploidy does further accelerate cancer, indicating that it is not just a consequence of cancer, but it also has a role in accelerating cancer.
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Very true and we are only beginning to understand the 3D makeup of a nucleus. IN the next years, we hope to be able to tell you more how this makeup has changes because of an aneuploid DNA content (plus the consequences).
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What causes aneuploidy in human cancer is still somewhat of a mystery: many processes that lead to aneuploidy have been described and modeled in tissue culture systems and mouse models, but we cannot be sure which were the triggers of aneuploidy in human cancer until we can identify the premalignant cancers in a human setting. But to name a few potential...
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In the aneuploidy mouse models tumorigenesis is probably late because the premalignant cells first need to encounter predisposing mutations that then together with aneuploidy lead to cancerous growth. So the aneuploidy is facilitating the tumorigenesis. Having said that: aneuploid tumors that occur in the same tissues quite often show the same karyotype,...
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Indeed, this is what we see in the skin and liver for instance.
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Mouse models have shown that aneuploidy can speed up ageing in model organisms, but our more rencent findings are that there are few aneuploid cells in naturally aged human tissues.So the contribution of aneuploidy to ageing remains unclear. However, telomere shortening will ultimately cause aneuploid cells to arise, which will then stop cell division leading...
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Indeed, this is what we think is happening
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However, mice only live for 2 years: it could still be that an aneuploidy-provoking mutation in human cells would be sufficient to case a cancer over the course of many years. However, this is very difficult to test until we can very reliably sample large numbers of cells from individuals for aneuploidy (which so far is very expensive).
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This is very well possible for some cancers: some mutations that help cancer cells grow are known to cause aneuploidy on the side. However, we think that the resulting aneuploidy then accelerates the evolution of the tumor. This is why we think you need a cancer predisposing mutation first and then aneuploidy to accelerate the tumor growth.
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Indeed: we think that aneuploidy reshuffles the genome into a 'new' combination of gene numbers that are beneficial. However, since chromosomes each carry many genes, aneuploidy also comes with adverse effects for the cells (e.g. genes on a gained chromosome that inhibit growth). We think that aneuploid cancer cells have found ways to cope with the...
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Tumors that are not aneuploid are typically caused by mutations in genes that protect our DNA from point mutations (for instance the mismatch repair system). These tumors exhibit high numbers of post mutations and therefore have less of a need to reshuffle their genome through aneuploidy to become cancerous.
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That is exactly what we try to understand as well: to what extent aneuploidy contributes to natural ageing. We think aneuploidy contributes, but how, we need to better understand,
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Down syndrome is aneuploidy syndrome with clear effects on mental development. It has also been suggested that 1:3 of the neurons in our brain are aneuploid, is this were true, aneuploidy would likely contribute to mental health. However, so far we have been unable to confirm the latter observations: we used a different, much more sensitive technique and found...
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This is indeed a difficult question that we as of yet have been unable to answer. It is clear that aneuploidy provokes a premature ageing phenotype, both in mouse models and human congenital aneuploidy disease, so in a predisposed setting it CAN be a cause of premature ageing. However, to what extent it contributes to 'natural' ageing, still needs to be...
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Thanks!
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This is probably true, although we have not yet been able to measure the exact frequency of mitotic errors in various tissues in the context of a living organism, this is one of our current challenges.
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This is what we actually see in the skin of the mouse. Stem cells in the skin are very sensitive to aneuploidy, whereas the epidermal cells (that form the barrier to the outside world) can cope much better. This makes sense in a way, since the latter cell type needs to protect us from damaging events (UV light for instance) from the outside world.
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When we refer to 2 out of 3 cancers, we refer to 2 out to 3 tumours. In some tumour types aneuploidy is more prevalent (e.g. glioblastoma >95% of the cases) and in some aneuploidy is less frequent (leukaemia (~50% of the cases). Some hereditary intestinal cancers are non-aneuploid: these cancers are driven by mutations in a DNA repair system (mismatch repair)....
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We hope so!
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Indeed: we use conditional knockouts that allow us to provoke aneuploidy in tissues of choice at time points of choice.
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Our current experiments are suggesting that we have only very few aneuploid cells in our bodies, at least much fewer than I originally anticipated. This might be good news as aneuploidy targeting therapy would have very few side effects.
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We think that if aneuploidy comes first a cell either stops dividing or even dies (depending on the cell type). Maybe the arrested aneuploid cells behave as aged cells, this is something that we are currently investigating. If the cells then acquire another mutation that help them cope with the disadvantages of the aneuploidy, then the cell is well on its way...
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Constant stress is certainly not healthy. I am not sure whether it will directly lead to cancer, but I think that there is evidence that prolonged stress affects the immune system. There are also indications that the immune system is important to clear (pre)cancerous cells, so indirectly prolonged stress could contribute to the proces of tumorigenesis. ...
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With high and low grade I mean the degree of aneuploidy in a cell: this is a bit arbitrary, but low grade aneuploidy would be one extra chromosome per cell, whereas high grade aneuploidy would mean 5-6 extra copies per cell. Indeed, homozygous loss of e.g. mad2 results in high grade aneuploidy and heterozygous loss results typically in low grade aneuploidy.
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This is indeed complex. We know that aneuploidy can arise early in cancer, but for that one also needs to define when a cell on its way to become cancerous really has become a cancer cell. From the mouse models we have learned that one mutation is enough to convert an aneuploid cell into an aneuploid cancer cell: so technically you could argue that aneuploidy...
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Very true. The difference is that when this happens in meiosis, that all cells in the organism will be affected as the aneuploidy arose before the first cell division took place. This is the type of aneuploidy that we see with Down Syndrome, where each cell in the body has an extra copy of chromosome 21.
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Part of the answer to that (whether particular chromosome combinations are favoured) is in the next lecture. Briefly, we find that if cancers arise in an aneuploid setting, that the cancer cells then select for a particular combination of chromosomes. We think that cells still 'throw the dice' every cell division with respect to which chromosomes are lost or...
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When cells are not yet (very) cancerous, they typically go into a G1/G0 arrest when they encounter aneuploidy. Some mutations (such as the very common mutation of p53 in cancer) result in an override of this G0/G1 arrest: cells that became aneuploid now no longer arrest and keep dividing. The response to aneuploidy thus depends on the genetic context of the...
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Indeed. Microtubule poisons are commonly used to treat cancer (e.g. Paclitaxel, Vincristine). These compounds disrupt mitosis and result in such high grade aneuploidy that the cancer cells typically die. The problem lies with the fact that also healthy dividing cells die as a result. Furthermore, if cancer cells (or healthy cells) survive the treatment, they...
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I am not sure. It seems that the regenerating liver cells are not the result of stem cell expansion, but rather more differentiated cells proliferating: possibly these more differentiated cells can cope better with aneuploidy leading to a more aneuploid tissue.
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A third copy of p53 would make the cells very sensitive to DNA damage and possibly also block aneuploid cells. We actually very rarely see amplification of the chromosome that carries p53, maybe because of that.
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And actually, we are still working on this question: it has been tremendously difficult to isolate the stem cells while they become aneuploid, we still think that they are more sensitive, also because others have shown that stem cells are more sensitive to other sources of genomic instability (e.g. irradiation). Also we have some evidence in other tissues that...
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Very true: even though in a model aneuploidy accelerates ageing, we have not yet properly quantified to what extent aneuploidy leads to ageing in man. New technology will clarify this issue in the next few years.
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We think that aneuploidy facilitates cancer as it helps the cells reshuffle its genomic information into a new combination that helps cells divide. One could compare it with shuffling a deck of cards and at the same time adding extra cards. These extra cards, or chromosomes, can result in a higher activity of the genes on those chromosomes and as such help the...
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I agree: correlation does not mean causation, however it is very likely that when aneuploidy presents itself in cancer in the vast majority of the cases that is has some role in the development of the cancer. We think that p53 can indeed make aneuploid cells cancerous, but others have shown that other cancer predispositions (e.g. RasV12, Her2) can also...
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All of these 4 explanations can very well contribute to the low cancer incidence. Some other factors might be the low rates of aneuploidy provoked by the heterozygous models (even though aneuploidy rates were reasonably high in these mice). Another explanation could be that mice do not live long enough to develop cancer: however this also implies that...
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To complicate matters: there is new evidence (Knouse et al, PNAS 2014) that suggest that the aneuploidy reported in brain is much lower than previously reported. These newer publications make use of next generation sequencing, which is a more reliable technique than the techniques used in the papers that reported high rates of aneuploidy in the brain: maybe we...
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Thanks for your questions
1) We see mostly 'random' aneuploidies: individual cells have different chromosome combinations. We do see more chromosome gains than losses, suggesting that the cells that have chromosome losses die because of the aneuploidy.2) The genes for the hair follicle stem cells are on various chromosomes, we did not observe any skewing...
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4) We believe that the aneuploid cells are metabolically deranged because on average they have extra chromosomes. These extra chromosomes need to be copied each cell division and also result in extra RNA and protein. In other words, extra DNA means that the cells need to 'work harder' resulting in an unregulated metabolism.
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c) Sometimes cells fail to divide all together and end up with a double DNA content. If cells continue to divide from that state, they are likely to become aneuploid.
d) sometimes chromosomes end up being bound by both division poles at the same time. The 'double bound chromosome' (merotelic attached) will be pulled in both directions and end up in the... -
Thank you for your questions:
1) We tried to inactivate Mps1 in skin and we found it to be embryonically lethal: mice dies before they were born. Mice developed normally until just before birth and when we examined the skin from the embryos it seemed to be thinner than normal mouse skin at that stage. We did not come up with a full explanation yet, but we... -
True! This is exactly what we think is happening: the majority of aneuploidies will result in a growth disadvantage and therefore not be 'selected' by the cancer. Some aneuploidies will confer a growth advantage and be selected for. What we do not completely understand is what causes the initial chromosome segregation errors. Furthermore, we need to better...
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This is probably true and most likely both are true: one the one hand a deregulated cell cycle will cause aneuploidy, which through more mitotic errors will result in even more aggressive cells.
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It indeed seems that only part of a chromosome is lost in the movie. It is actually hard to say from the movie whether this was a small chromosome or a chromosome fragment. The most common definition of aneuploidy is loss or gains of whole chromosomes, in other words any combination of chromosomes that is different from the normal state, as rightly summarised...
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We don't really know this yet. It will probably depend on the tissue, and it might even differ between individuals. In other words, maybe my skin accumulates aneuploid cells after than yours (or vice versa) only because of the differences between our genetics. To measure this, one needs to analyse this at the single cell level for all chromosomes at the same...
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Can you imagine that our bodies on average encounter 10 to the 16th cell divisions throughout our lifetime? It is simply amazing how well our cells can faithfully divide.
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Very much. There was a very recent publication that exactly showed that: http://www.ncbi.nlm.nih.gov/pubmed/25477213. In this case they measures the frequency of chromosome Y loss (which is the easiest to measure as it is unique) in smokers.
As chromosome Y loss is the smallest chromosome and a cell can easily live without it, the frequency of Y-loss...
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This is still a debate in the field. Our observations were done in mice, and mice only live for 2-3 years of which focussed on tumors within the first year. Human cancer can take 20-30 years to arise (from an initiating event like smoking, asbestos, etc.). It could very well be that subtle errors in cell division over a very long time (20 years or more) can...
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If the paradox would have been easy to solve, others would have solved it before us :). So we hope to be able to contribute to solving this paradox. What we try to understand is how cells (both cancer cells and 'normal' cells) respond to aneuploidy. It could very well be that aneuploid cancer cells divide less than non-aneuploid cancer cells, but even that we...
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This is indeed very true. In our models we find chromosome gains more frequently than chromosome losses (apparently losing a chromosome is not well tolerated at all). Importantly, we also find recurrent copy number changes within the same tumor type: for instance always gain of chromosomes 14 and 15 in aneuploid mouse lymphoma. Interestingly, we see different...
