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Rocio Sotillo, PhD
International Early Career Scientist / 2012–Present

Scientific Discipline

Cancer Biology, Molecular Biology

Host Institution

European Molecular Biology Laboratory (Monterotondo, Italy)

Current Position

Dr. Sotillo is a staff scientist and European Research Council investigator, Mouse Biology Unit, at the European Molecular Biology Laboratory, Monterotondo, Italy.

Current Research

Chromosome Instability and Cancer

Rocio Sotillo studies how chromosome instability arises in tumors and what consequences it has on tumor initiation and maintenance. She also investigates the mechanisms by which chromosome instability facilitates escape from oncogene addiction, leading to tumor recurrence.

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Biography

When Rocio Sotillo was an undergraduate pharmacy student in Madrid, she witnessed new drugs visibly shrinking tumors in mice during an internship at a pharmaceutical company. “After that, I wanted to understand the mechanisms that lead…

When Rocio Sotillo was an undergraduate pharmacy student in Madrid, she witnessed new drugs visibly shrinking tumors in mice during an internship at a pharmaceutical company. “After that, I wanted to understand the mechanisms that lead to cancer in humans,” she says.

Tumors can form when the regular checks and balances on cell growth fail, and cells are allowed to divide without restraint. But Sotillo, now a staff scientist at the European Molecular Biology Laboratory in Italy, has found that cancer cells can also emerge from messy chromosomal identities created when the mechanics of cell division go awry.

As a postdoctoral fellow at Memorial Sloan-Kettering Cancer Center in New York, Sotillo homed in on a point in the growth cycle just before a cell divides, when chromosomes have doubled and are lined up at the center of the cell. If the paired chromosomes don’t separate properly, daughter cells can end up with too many or too few copies of their genes. That condition, called aneuploidy, is common in cancer cells, but whether it is a cause or a consequence of tumor formation has been unclear.

When she began investigating the relationship between aneuploidy and tumor formation, Sotillo realized that several checkpoint proteins—those that stop cell division if something is wrong—were unusually abundant in tumors. The finding was puzzling, since most scientists reasoned that excess checkpoint proteins should prevent the cell cycle from spinning out of control.

To investigate, Sotillo mimicked the condition in mouse cells by ramping up production of the checkpoint protein Mad2, whose job is to make sure that chromosomes cannot separate until they are tethered to the long, narrow structures called microtubules that will pull them into the forming daughter cells.

Then, using time-lapse microscopy, she watched the cells. Although they temporarily halted their cell cycle, they eventually managed to divide. When they did, they segregated their chromosomes sloppily, creating aneuploid daughter cells. Sotillo hypothesizes that the force of the microtubules tugging in opposite directions either pulls a double chromosome to one side or breaks the chromosomes into odd pieces.

Sotillo found that simply causing these chromosomal breaks by overexpressing Mad2 could lead to tumors in mice. Presumably, she says, the chromosomal breaks, additions, and subtractions caused by the messy chromosomal separation generate cells that either lack the tumor suppressor genes that normally stave off cancer or have too many oncogenes, which can drive tumor formation.

When she introduced extra Mad2 into an existing mouse model for human lung cancer, aggressive tumors showed up and killed the mice more quickly, demonstrating that chromosomal instability can exacerbate other cancer-promoting mutations. “When you pair chromosomal instability with another cancer mutation, you get strong cooperation and more aggressive cancer,” Sotillo explains.

When it came time to leave Sloan-Kettering, Sotillo and her partner, Martin Jechlinger, also a cancer researcher, sought positions in Europe. Rather than relocate to Spain or his home country of Austria, they chose Italy—“neutral ground,” Sotillo says, on which to raise their two children.

In 2010, Sotillo started her own lab at the European Molecular Biology Lab outside of Rome. Her group focuses on the relationship between chromosomal instability and cancer-promoting genes, called oncogenes. Many cancer therapies target specific oncogene mutations, on which tumor cells can become dependent for survival. Blocking an oncogene’s cancer-promoting effects often halts tumor growth, but many patients eventually relapse. Sotillo suspects that chromosomal instability helps some tumor cells thrive even once the oncogene’s effects have been eliminated.

The mice she developed in New York, which carried mutations in the oncogene Kras and were prone to chromosomal instability due to excess Mad2, were perfect to test that idea. In the laboratory, mice with lung tumors driven by Kras mutations respond well to treatments that inhibit the excessive activity of the Kras protein, but inhibiting this pathway in human tumors is not successful. When Sotillo turned both mutations off in her mouse model, the tumors regressed but eventually came back—just like in human patients. In other words, if the original tumors had aneuploid cells, then these cells allowed the tumors to come roaring back, even without the Kras mutation.

It’s still unclear, Sotillo says, how chromosomal instability gives cells the ability to escape from their oncogene addiction. “If we can understand that,” she says, “we could develop better drugs to kill both the cancer cells—depending on the oncogene—and the aneuploid cells to prevent relapsing.”

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Education

  • BS, pharmacy, University San Pablo-CEU, Spain
  • PhD, molecular biology, Autonomous University of Madrid and Spanish National Cancer Center, Spain

Awards

  • Memorial Sloan Kettering Cancer Center Research Fellow Award
  • Charles H. Revson Foundation Award
  • Thomas G. Labrecque Foundation Award, Uniting Against Lung Cancer Program
  • European Research Council Investigator
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