How Good Cells Turn Bad


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(l-r) Amir Bar, Dr. Amos Tanay, Netta Mendelson-Cohen, Prof. Varda Rotter, Dr. Zohar Mukamel, Naomi Goldfinger, Gilad Landan and Dr. Alina Molchadsky













How does a cell turn “bad” – from a well-behaved individual that respects boundaries and only divides when necessary, into a cancerous one whose reproduction is out of control? Is this antisocial conduct simply a product of bad genes, or does something else push it into the life of a cancer cell?

Until recently, genes were assumed to play the sole driving role in this scenario. Indeed, for cancer to develop, a number of genetic mutations that accumulate as cells live and divide are necessary. But researchers have realized that mutations are not the whole story: They cannot fully explain how a cell makes the transition from average good citizen to cancer.
One idea that has been gaining ground in recent years is that epigenetic (literally, “above the genes”) changes taking place in parallel with mutations can play an important role in the initiation and development of cancer. Epigenetic modifications affect the genes and can be passed on to further generations of cancer cells. One important epigenetic mechanism is the DNA methylation system, in which biochemical groups are attached to various genes, thereby “disabling” them. In normal cells, this system helps prevent genes from being expressed in the wrong time or place.
Methylation has been well studied – mostly focusing on its role in embryogenesis. It is commonly believed that the majority of changes in methylation take place before and during embryonic development, after which cells and their descendents become locked into a pattern. Yet it was also known that cancer cells tend to have different methylation patterns from healthy ones. How do these changes come about? Dr. Amos Tanay of the Computer Science and Applied Mathematics, and Biological Regulation Departments, and Prof. Varda Rotter of the Molecular Cell Biology Department decided to explore the methylation of genes in healthy cells as they age and divide, to see if they could learn something about changes that might promote cancer.
(l-r) Dr. Amos Tanay and Prof. Varda Rotter
The two scientists and their groups combined methods and techniques from a number of different fields: Tanay is a computational biologist who has been developing computer-based methods of extracting significant information from huge quantities of genetic data, and Rotter is a cancer cell biologist who has developed original lab methods to investigate the genetics of cancer. Gilad Landan, a joint Ph.D. student with Tanay and Rotter, together with Dr. Zohar Mukamel, Netta Mendelson Cohen and Amir Bar from Tanay’s group, Naomi Goldfinger and Dr. Alina Molchadsky from Rotter’s group, and Dr. Einav Nili Gal-Yam, an oncologist in the Talpiot program at the Sheba Medical Center, created cultures of healthy, “immortal” cells that kept dividing past extreme old age – up to 300 rounds of cell division. The team developed new techniques that permitted the follow-up and analysis of methylation in the genomes of the cultured cells as they evolved over that period.

Among other things, their observations challenged the notion that methylation in cells is fixed early on and more or less maintained in a stable state throughout life. Patterns of methylation in the healthy cells accumulated changes almost from the onset of the experiment. The alterations were basically random, so that the methylation sites in cells that started out identical diverged more and more as division continued. In general, however, the number of genes that had methyl groups attached to them increased dramatically over time. By the 300th division, the cells had highly abnormal methylation patterns and many were on the verge of becoming cancerous. These findings appeared recently in Nature Genetics.

Tanay says that an older cell or one that has undergone too many rounds of division may still mostly function because certain genes that are in active, day-to-day use have mechanisms that prevent methylation. But it might find itself unable to react properly to the kinds of DNA damage or mutation that can initiate cancer growth because many other genes – for instance those that are activated only in emergencies – are disabled by random epigenetic markers. In other words, creeping epigenetic changes may aid and abet the cells’ transition to a cancerous lifestyle because they can have a “calcifying” effect on the genome: Like an aging joint, the genome may lose its flexibility as added methyl groups slow it down.

Tanay and Rotter and their teams are currently exploring the implications of these findings in cancer patients. They want to know more about methylation patterns in the tumor cells taken from those patients, to see if the shifts they identified in the lab match up. They also  suspect that the epigenetic changes may also help the cells keep up their bad behavior on their way down the cancerous path. Among other things, the researchers are now asking how the different methylation patterns might affect tumor cells’ response to chemotherapy.
Prof. Varda Rotter's research is supported by the Adelis Foundation; the Leir Charitable Foundations; and the Women's Health Research Center, which she heads. Prof. Rotter is the incumbent of the Norman and Helen Asher Professorial Chair of Cancer Research.

Dr. Amos Tanay's research is supported by Pascal and Ilana Mantoux, Israel/France; the Wolfson Family Charitable Trust; the Rachel and Shaul Peles Fund for Hormone Research; and the estate of Evelyn Wellner. Dr. Tanay is the incumbent of the Robert Edward and Roselyn Rich Manson Career Development Chair in Perpetuity.