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Solving Puzzles with Cigall Kadoch

  • From Paths of Progress Spring/Summer 2015

    by Richard Saltus

    For researcher Cigall Kadoch, PhD, the Rubik's cube represents a love of puzzles, as well as the structure of the protein complexes she studies.

    Growing up in the San Francisco area, Cigall Kadoch, PhD, had a passion for puzzles. The daughter of a Moroccan-born father and mother from Michigan who together developed an interior design business, Kadoch excelled in school and pretty much everything else. Above all, she loved to solve brain-teasers.

    In high school, however, Kadoch came up against a problem that defied solution. Breast cancer took the life of a beloved family caretaker who had nurtured her interests in science and nature.

    "I was deeply saddened and very angry at my lack of understanding of what had happened," recalls Kadoch, now a cancer researcher at Harvard Medical School (HMS) and Dana-Farber/Boston Children's Cancer and Blood Disorders Center.

    At the time, she knew little about cancer except that it took lives far too early. "I thought to myself, cancer is a puzzle that isn't solved, let alone even well-defined, and I want to try. As naïve a statement as that was, it was a defining moment – one which I never could have predicted would actually shape my life's efforts."

    Her sense of mission intensified after a summer at Harvard, where her uncle was a radiation oncologist. She spent time in his clinic, observing that some patients were cured and others worsened, and she wondered why. She found textbooks on biochemistry, oncology, and other fields fascinating. Then she was off to the races.

    Kadoch blazed through college, taking pre-med courses, but she chose cancer biology for graduate study at Stanford University. "I couldn't drop this quest to solve puzzles and a chance to contribute new knowledge to the book of medicine," she explains. Dana-Farber Chief of Staff Stephen Sallan, MD, describes Kadoch as "addicted to discovery."

    Working in the lab of prominent Stanford biologist Gerald Crabtree, MD, she authored two cancer research papers. The first, in the high-profile journal Cell, reported her discovery of how a gene mutation in a "chromatin-remodeling complex" leads to a rare, hard to treat cancer called synovial sarcoma. Its fundamental cause had been unknown. Remarkably, she and Crabtree were the only authors of the paper: an impressive achievement for someone so junior.

    The second publication, in Nature Genetics, reported for the first time that at least 20 percent of all human cancers are driven, at least in part, by defects in one of the components of these chromatin complexes, called BAF complexes that disrupt cells' orderly growth. With these insights, Kadoch broke new ground in the hot research area of cancer epigenetics — processes that change how genes operate without altering the genes themselves.

    Hitting the Ground Running

    In 2013, after earning her PhD in less than three years, Kadoch vaulted into a position in Dana-Farber/Boston Children's department of Pediatric Oncology, and is an assistant professor at HMS. At age 27, she was one of the youngest scientists ever appointed to the HMS faculty. She is also a member of the Broad Institute of Harvard and MIT.

    George Demetri, MD, Dana-Farber's senior vice president for experimental therapeutics, played a major role in recruiting her. "Cigall came to Boston and gave a talk at the Broad Institute about her research. One of our investigators — James Bradner, MD — came back and said, 'We've got to get her here.'"

    Stuart Orkin, MD, chair of Pediatric Oncology, noted that while some would find her youth and short track record as risks, "We were convinced she had the drive and the training and the smarts" to succeed.

    In early 2014, she opened her Dana-Farber lab, stocking an empty laboratory space with equipment, mailing box after box of reagents from Stanford. As a new laboratory director, she is younger than several of the trainees she has brought on board.

    George Demetri quote   Applying for "everything under the sun," she has funded her lab thus far through awards and grants, along with philanthropic gifts from donors who have heard her explain her research and its potential for fighting cancer in new ways.

    In 2014, she received a $2.5 million innovator award from the National Institutes of Health and a $1 million American Cancer Society Research Scholar Award. Around the same time, she was named to Forbes magazine's list of "30 under 30" – the top people under age 30 who are making an impact on the world.

    "She hit the ground running," observes Demetri. "She's focused like a laser and is just on fire with her work. The research is gaining wide recognition."

    Chromatin and Cancer

    Kadoch comes at the question of what causes cancer from an unusual direction. For decades, researchers focused on mutations and other alterations in the DNA of genes that force cells into uncontrolled, chaotic growth. Kadoch is interested less in how good genes go bad than in how mistakes in regulation of DNA structure cause normal genes to be activated at the wrong time, in the wrong place, or not activated when needed. And this process begins in the mechanism that stores our DNA and genes.

    Some savvy travelers can cram several weeks' clothing into a carry-on bag. But for packing efficiency, it's hard to beat biology: Our entire human genome — a thin, 6-foot-long thread of DNA carrying about 20,000 genes — is squeezed into each cell's nucleus, a structure 1,000 times smaller than a pinhead.

    Inside the nucleus, the DNA double helix is wound tightly around many spool-like protein structures – nucleosomes. This DNA-protein entity is called chromatin, which is both an organizational scaffold for DNA and the root of an intricate mechanism for switching genes on or off and regulating the translation of their blueprints into proteins.

    Genes can't be turned on and made into proteins when chromatin is tightly coiled on its spools. So when the cell needs certain proteins to be made, the relevant spools unwind to expose a particular gene or genes to be read. Since these genes may be located at different sites along the chromosomes, the process requires different spools of DNA in various locations to unwind.

    All of this chromatin shuffling must be tightly regulated so the right genes are turned on and off at the right time in the right place. This key task is performed by the chromatin-remodeling complexes. Each large complex is made up of multiple subunits that can assume various combinatorial assemblies, like the small individual blocks of a Rubik's Cube.

    "The surprising thing we learned from recent sequencing studies is that these chromatin complexes play a significant role in cancer," Kadoch says.

    Cigall Kadoch, PhD (left), heads a team of about 15 investigators at Dana-Farber.

    Her team's research focuses on how malfunctions of a particular chromatin-regulatory complex called BAF can lead to the misregulation of genes that cause cancer. Normally, BAF complexes help protect the cell against cancer. However, structural mistakes in the subunits making up the chromatin regulatory complexes interfere with their ability to control gene expression, leading in certain situations to cancer. These structural flaws are caused by mutations in the genes that code for the subunit proteins.

    Crabtree, her mentor at Stanford, had done elegant studies on how the BAF complex turns genes on and off to coordinate development of the vertebrate nervous system. But Kadoch was the first to show how abnormalities in the complex's structure could turn cells cancerous.

    "We estimate that these mutations in chromatin complex subunits occur in more than 20 percent of human cancers," says Kadoch.

    That doesn't mean that these mutations are the single driving force in all those cancers. But the research leading to her initial Cell paper was a tour de force that uncovered the mechanism behind the known lone culprit mutation and hallmark feature in synovial sarcoma.

    "If we can understand how the flawed architecture of the chromatin complex can cause cancer, we can hopefully design specific therapeutic strategies," Kadoch explains. She and her team are using biochemical tools to reverse-engineer the structural makeup of the complexes.

    "At this point we don't know how the puzzle pieces fit together in the complexes. We're asking how they are assembled in the first place. How do mutations affecting the complexes change which genes they go to and activate across the genome?"

    Many targeted drugs block the activity of cancer-causing oncogenes. But it is notoriously difficult to treat cancer by restoring broken tumor suppressor proteins – like the BAF chromatin-regulatory complex that malfunctions to trigger synovial sarcoma and other cancers.

    Kadoch remains undaunted. Even if this particular strategy does not apply to other cancers caused by broken chromatin complexes, she believes that understanding how the faulty complexes trigger rare cancers will pay off in discovering the causes of more common cancers.

    And that's a puzzle Kadoch is determined to solve.

    Paths of Progress Spring/Summer 2015 Table of Contents 

Posted on April 29, 2015

  • Cigall Kadoch, PhD
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