Cigall Kadoch, PhD, Dana-Farber Cancer Institute, was awarded The Mark Foundation Emerging Leader Award in 2019. Less than three years later, in September 2021, she was selected to become a Howard Hughes Medical Institute (HHMI) Investigator, one of the most prestigious honors in science. Reflecting on the catalytic role played by the Emerging Leader award in advancing her research, Kadoch remarks, “What type of work does HHMI look for? Exciting, creative, potentially transformative science that often has been supported by ‘high-risk, high-reward’ funding opportunities, such as those offered by The Mark Foundation.”
Kadoch started her scientific career studying an extremely rare soft-tissue cancer, synovial sarcoma. “I was incredibly intrigued that nearly 100% of these cancers are driven by one problem, one molecular lesion,” she recalls, “a fusion protein that we found integrated and usurped protein complexes that govern the architecture of our genomes.” To ensure proper gene expression, our cells must perfectly coordinate site-specific access along the two meters of DNA that is supercoiled and folded into the tiny nucleus of each cell. BAF complexes, the focus of Kadoch’s lab, are multiprotein assemblies that bind to and open up particular segments of DNA at specific times, in a process termed chromatin remodeling. In synovial sarcoma, the chromosomal translocation hallmark of the disease causes one component of the BAF complex to be expressed as an oncogenic fusion protein. Kadoch discovered that this fusion protein drags the BAF complex to the wrong regions of the genome, activating the wrong genes and fueling cancer cell growth.
For Kadoch, the power of studying a rare cancer in immense detail, particularly at the outset of her studies in this area, was the ability to then apply insights to a broader range of diseases. “Pattern recognition is key,” she emphasizes, “and it behooves us to look for patterns early and often, because nature tends to repurpose mechanisms.” In fact, it’s now known that mutations in chromatin remodeling complexes are incredibly common across cancer types, and that mutations specifically in the BAF complex occur in more than 20% of all cancer cases.
Leveraging her discovery of the mechanism of oncogenic BAF fusion proteins, Kadoch questioned what factors might influence BAF mistargeting in more common cancers. A major driver of many cancers is the dysregulated expression of transcription factors. Kadoch’s team discovered that certain transcription factors can engage BAF complexes to direct them to the wrong sites on DNA at the wrong times. The same theme of aberrant localization – a pattern – leads to more questions to reveal the molecular ‘navigation system’ for these complexes.
Last year, Kadoch’s group published a study in Science in which they purified BAF complexes from human cells and incubated them with hundreds of DNA-barcoded nucleosomes, each containing histone tail or core features. These experiments lead to the discovery of several fundamental rules governing BAF complexes: how they travel, how they are targeted, and how they can be hijacked by disease-associated processes that alter navigation. Her work uncovers the tremendous therapeutic potential of targeting these mechanisms. Kadoch co-founded the biotech company Foghorn Therapeutics which now has two candidate cancer drugs in clinical trials.
“Through our Emerging Leader Awards, The Mark Foundation is committed to enabling outstanding researchers in the early stage of their careers to pursue innovative projects that might never launch without our support,” says Becky Bish, Head of Discovery and Preclinical Research at The Mark Foundation. “Cigall’s breakthrough studies in chromatin regulation and cancer exemplify the value of this program.”
For Kadoch, the HHMI Investigator award is a vindication of The Mark Foundation’s willingness to support daring, ambitious scientific initiatives. “My Emerging Leader Award proposal was essentially to pursue the equivalent of over 30,000 experiments, using all new reagents and novel purification methods,” says Cigall laughing. “The Mark Foundation took a chance on me. This is their unique strength: their ability to place bets on bold ideas that have the potential to transform our understanding and treatment of human cancer.”