Some cancer cells may not be as immortal as we thought
14 December – Scientists at the Institute of Molecular Biology (IMB) and Mainz University in Germany may have discovered new insights into how cancer cells regulate the ends of their chromosomes, called telomeres. Certain cancers use a specific type of telomere regulation called ALT, which was thought to allow them to become immortal. Prof. Brian Luke and his group found that ALT cells may actually undergo senescence, which could mean that they are vulnerable to drugs designed to kill senescent cells. This finding could open the way for new therapies to slow or stop ALT cancer cells from growing.
Cancer remains one of the biggest killers and is among the hardest diseases to treat. The root cause of all cancers is the uncontrolled growth of cancer cells, which multiply rapidly until they form large tumours that spread throughout the body, causing sickness and even death. The reason why cancer cells grow so quickly is in part due to their ability to lengthen the ends of their DNA, which are called telomeres.
When normal, healthy cells divide, the ends of their chromosomes get shorter with each division. Eventually, they get so short that the cell detects a problem and stops dividing. This halt in cell division is called replicative senescence and is an important safety mechanism that prevents cells from becoming cancerous.
Cancer cells, however, manage to find ways to circumvent this by lengthening their telomeres, preventing them from shortening. This allows them to keep dividing and proliferate beyond the normal limit, effectively becoming immortal. Most cancers do this by activating a factor called telomerase, which adds more telomeric DNA to the ends of chromosomes, while about 15% of cancers activate an alternative mechanism called ALT (Alternative Lengthening of Telomeres), where the cell uses its own existing telomeres as a template to make more copies of telomeric DNA.
Previously, scientists thought that ALT allowed cancer cells to become immortal – i.e. that they could grow and divide forever. However, Prof. Luke’s lab at the University of Mainz now find in their most recent study, which was published in Nucleic Acids Research, that this is not the case. His lab uses baker’s yeast to study how ALT works. “Under certain conditions, yeast cells can lengthen their telomeres in a manner nearly identical to ALT cancer cells; we call them ALT yeast,” he explains. Stefano Misino, a former PhD student in Prof. Luke’s lab, says “We discovered that ALT yeast only appear immortal if we grow them as a mixed population of cells with different telomere lengths. However, when we isolated and grew ALT yeast cells individually, we could clearly see that they started to grow slower and slower after multiple cell divisions”. They saw that the telomeres in these individual ALT yeast cells also became shorter over time.
This indicates that cells that maintain their telomeres with ALT still undergo replicative senescence, and they may in fact not be immortal. This is an exciting finding because if ALT cancer cells do undergo senescence, they could be treated using new drugs that specifically kill senescent cells.
In addition, Prof. Luke and his team found that an RNA molecule called TERRA, which is made at telomeres, can control the rate of senescence in ALT yeast cells and appears to affect how quickly telomeres shorten. He is hopeful that these new findings will pave the way for new strategies to treat cancer. “If we can figure out a way to manipulate the RNA, we could increase the rates of senescence in these ALT cells to slow down or even stop their growth.”
The image above shows trees (which represent telomeres) on rolling hills (representing the senescence curves). At the bottom of the first curve, the cells hit a low point of proliferative potential, however they recover and form ALT survivors. Thanks to the findings in this paper, we now know that these cells also start going down the hill again, losing telomere length and replicative potential. Illustration generated with the AI software DALL-E and Photoshop.
Further information can be found at https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkac1125/6885047
Brian Luke is a Professor at the University of Mainz and an Adjunct Scientific Director at the Institute of Molecular Biology. Further information about research in the Luke lab can be found at: https://www.imb.de/research/luke/research
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The Institute of Molecular Biology gGmbH (IMB) is a centre of excellence in the life sciences that was established in 2011 on the campus of Johannes Gutenberg University Mainz (JGU). Research at IMB focuses on three cutting-edge areas: epigenetics, developmental biology, and genome stability. The institute is a prime example of successful collaboration between a private foundation and government: The Boehringer Ingelheim Foundation has committed 154 million euros to be disbursed from 2009 until 2027 to cover the operating costs of research at IMB. The State of Rhineland-Palatinate has provided approximately 50 million euros for the construction of a state-of-the-art building and is giving a further 52 million in core funding from 2020 until 2027. For more information about IMB, please visit: www.imb.de
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The Boehringer Ingelheim Foundation is an independent, non-profit organization that is committed to the promotion of the medical, biological, chemical, and pharmaceutical sciences. It was established in 1977 by Hubertus Liebrecht (1931–1991), a member of the shareholder family of the Boehringer Ingelheim company. Through its Perspectives Programme Plus 3 and its Exploration Grants, the Foundation supports independent junior group leaders. It also endows the international Heinrich Wieland Prize, as well as awards for up-and-coming scientists in Germany. In addition, the Foundation funds institutional projects in Germany, such as the Institute of Molecular Biology (IMB), the department of life sciences at the University of Mainz, and the European Molecular Biology Laboratory (EMBL) in Heidelberg. www.bistiftung.de
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