Opening New Research Avenues in Epigenetics

Manel Esteller (Credit: Manel Esteller)

Spanish cancer researcher Manel Esteller, 42, has the temperament of an explorer. "There are some people [who] like to stay in their niche, but I'm not made this way," he says. "I like to start many things, to make one of the first discoveries, and then switch gears." The young, expanding field of epigenetics has proved to be an ideal platform for his style of science.

"When I see a cancer cell, I see [it] as something that's very bizarre, that has genetic lesions, that has DNA methylation alterations, that has histone modifications, that has noncoding RNA aberrant expression." -- Manel Esteller

Trained as both a medical doctor and a research scientist, Esteller was attracted to epigenetics after stumbling upon a research question that genetics alone could not answer. Since embracing epigenetics research, he has gone on to explore several of its aspects in the context of cancer, helping to identify biomarkers for the disease and response to treatment and to pave the way for the development of epigenetic cancer drugs. "What fascinates me is that there's so much unknown in this area," says Esteller, now the director of the Cancer Epigenetics and Biology Program at the Bellvitge Institute of Biomedical Research (IDIBELL) in Barcelona. "There is so much to do."

Biomedical research

Inspired by popular images of doctors and a low-resolution microscope he owned as a child, Esteller entered medical school at the University of Barcelona in 1986 already intending to become a biomedical researcher. Rather than treat patients face to face, "I wanted to study medicine to have a view of the disease" and then apply this knowledge in the lab to develop new treatments, he says. He spent his free afternoons in the school of medicine's Department of Biochemistry and Molecular Biology, studying how thyroid hormones regulate gene expression.

The 29 October issue of Science contains a special section on epigenetics. It includes a series of Reviews and Perspectives that look at what defines an epigenetic system and how epigenetic processes influence biology, a Perspective about the possibility of using stem cells to study epigenetic perturbations, and a News Focus story on drugs that reverse the abnormal epigenetic patterns in tumors.

After obtaining his medical degree, in 1992, Esteller went straight into a Ph.D. program in human molecular genetics at the Vall d'Hebron University Hospital in Barcelona. He chose to study endometrial cancer, a little-studied hormone-related cancer that affects the lining of the uterus. "There was almost no information about how many mutations were there, how many deletions, translocations, et cetera," he says.

So for his Ph.D. research, Esteller studied tissue samples and found several major genetic mutations in endometrial carcinomas. He demonstrated that endometrial tumors from patients with good prognoses and patients with bad prognoses have strikingly different mutation patterns.

His mixed background gave him a definite advantage. Esteller had already mastered basic molecular biology techniques when he started his Ph.D., and he was able to convince oncologists and pathologists of the relevance of his research so that they would give him the tumor tissues he needed. If he had not spoken the same language and known the clinical aspects of the tumors, such research would have been impossible, Esteller says.

Toward the end of his Ph.D., he noticed that some tumor-suppressor genes were neither active nor mutated. At about that time, researchers elsewhere were starting to report that some antitumor genes were inactivated in cancer cells because of chemical changes to DNA that affect the expression of genes but not the DNA sequence, now known as epigenetic modifications. Seeing this as a possible explanation for his own observations, Esteller decided to do a postdoc with two pioneers in the field, Stephen Baylin and James Herman, both of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

On the epigenetics track

The addition of methyl groups onto DNA, an epigenetic process called methylation, is essential for marking which genes cells should express. At Johns Hopkins, using a technique previously developed in his lab, Esteller added many new tumor-suppressor genes to the list of those silenced in cancer cells by hypermethylation -- excessive methylation -- of their regulatory regions. "At that point, epigenetics really became mainstream" in oncology research, Esteller says.

In collaboration with David Sidransky, a physician-investigator at Johns Hopkins, Esteller also detected aberrant methylation in the blood of patients with lung or head and neck cancers and in the urine of prostate patients -- new biomarkers for the diseases. Next, in 2000, he served as the lead author on work showing that the methylation status of a certain gene can predict patient response to chemotherapy, which could allow clinicians to make more personalized treatment decisions.

Manel Esteller (Credit: Michelle Ferrara)

After 3 years as a postdoc and 1 year as a research associate in the United States, Esteller received an offer to become a group leader in cancer epigenetics at the newly established Spanish National Cancer Research Centre (CNIO) in Madrid. "I was offered very excellent conditions to do my research, with people and ... funding," Esteller says. It would have taken several more years to find a comparable position in the United States, he believes.

Esteller joined CNIO in 2001, using the opportunity to pursue a then relatively unknown area of cancer epigenetics: the chemical modification of histones, nuclear proteins that package DNA and regulate gene expression. In 2005, in collaboration with several other labs in Europe and the United States, his group detected aberrant histone modifications in a broad range of cancer cell lines and primary tumors. Until then, only isolated instances of the phenomenon had been reported. The comprehensive study "was critical because people then realized that histones were very important for cancer," Esteller says.

The same year, by studying cell and tissue samples from identical twins, Esteller and collaborators showed that epigenetics could explain how identical genomes can yield different traits. Identical twins "have the same DNA [but] can have different diseases because they have different epigenetics" due to different environmental exposure, he says.

A global approach

Esteller returned to Barcelona in 2008 to begin his current positions as director of the Cancer Epigenetics and Biology Program and leader of the cancer epigenetics group at IDIBELL. Building on some of his previous research, he is working on better understanding the machinery behind epigenetics, including the roles and properties of enzymes responsible for DNA methylation and histone modification, and determining whether those enzymes may themselves be disrupted in cancer patients. He is also working on a comprehensive inventory of DNA methylation marks and histone modifications in different types of cancer cells.

In another line of research, he is comparing the epigenetics of the genes for noncoding RNAs in normal cells and cancer cells. The bulk of our genome is transcribed into RNA molecules that never get translated into proteins, but these noncoding RNAs can have functions such as controlling the expression of other genes. Little is known about the extent to which the genes for noncoding RNAs may be hypermethylated in cancer cells and "if there will be drugs able to revert and to restore the normal phenotype of these cells attacking this particular mark," Esteller says.

"When I see a cancer cell, I see [it] as something that's very bizarre, that has genetic lesions, that has DNA methylation alterations, that has histone modifications, that has noncoding RNA aberrant expression," he says. "I have to be able to understand it globally to be able to cure this disease."

Epigenetics and translation

Although much of Esteller's research focuses on providing a basic understanding of epigenetics, there is a translational element to it. Beyond the search for epigenetic biomarkers, he is now testing in cell lines and mouse models whether certain drugs can restore normal gene expression in cancer cells by targeting enzymes of the epigenetic machinery. The establishment of the DNA hypermethylation of tumor-suppressor genes as an important mechanism in cancer has led to the current use of DNA-demethylating agents in the treatment of leukemias, for example. Pharmaceutical companies are also developing new drugs that target histone modifications.

And more is to come, says Esteller, who believes that epigenetic mechanisms will prove important in all diseases. "If genetics is important for all diseases, and it is," he says, then epigenetics will prove to be important, too. "I feel sometimes that genetics is reaching a limit. ... A lot of work has already been done there. But in epigenetics, still there's a lot of space for many, many scientists."

Elisabeth Pain is contributing editor for South Europe.

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