Unwavering Dedication to Understanding Biology
Cigall Kadoch, PhD, is Associate Professor of Pediatrics at the Dana-Farber Cancer Institute and Harvard Medical School and Co-Director of the Epigenomics Program at Broad Institute of MIT and Harvard. She is one of the leading researchers worldwide in dissecting the biology of chromatin remodeling complexes—groups of proteins that influence how DNA is packaged, thereby controlling when and how strongly genes are expressed.
The Early-Career Investigator Award recognizes her innovative discoveries that have become an important focus in cancer research.
Can you briefly discuss your background, and what you do in your current role?
Kadoch: I am Associate Professor in the Department of Pediatric Oncology at the Dana-Farber Cancer Institute and Harvard Medical School and Institute Member and Co-Director of the Epigenomics Program at the Broad Institute of MIT and Harvard. Our laboratory is dedicated to understanding the mechanisms governing chromatin architecture (the architecture and topology of our genomes) and gene expression and, importantly, to understanding how such mechanisms can be hijacked or malfunction in cancer and other human diseases. Specifically, our lab focuses on large, multicomponent molecular machines known as ATP-dependent chromatin remodeling complexes that regulate the accessibility of DNA, enabling timely and appropriate transcription (gene expression). Such chromatin remodeling complexes, called mammalian SWI/SNF (or BAF) complexes, are some of the most frequently disrupted entities in human cancer, neurodevelopmental disorders, immune conditions, and other diseases. As such, defining their function in normal and disease states enables the development of new insights that can serve as key foundations for new therapeutic approaches.
When did you decide to become a professor? Were you inspired by something?
Kadoch: I have had a long-standing interest and commitment to studying cancer, having been affected by the loss of close friends and family members in my early years. A genuine love and appreciation for science and the inner workings of biological systems in my childhood years morphed into a steadfast, unwavering dedication to understanding cancer, a unique constellation of diseases that teaches us how normal biology can go awry.
Your nomination includes the research you’ve conducted and published. What drew you to this field of research? What discovery are you most proud of?
Kadoch: To say I planned to study this exact field at the outset of my graduate training would be a stretch. As is often the case in biology, one works to learn and apply the areas of biology needed to understand a complex problem in great detail. In my case, I began by studying a protein linked to a highly aggressive form of sarcoma called synovial sarcoma. This protein, SS18, exists as a fusion protein, SS18-SSX, in 100 percent of cases of synovial sarcoma, by way of a chromosomal translocation that represents the pathognomonic, driving feature of the disease and which produces the fusion oncoprotein. In my graduate years, I found that this fusion protein integrates into and works in the context of the large chromatin remodeling complex family I described above, which changed our understanding of this disease from that point forward. Indeed, we later showed that the SS18-SSX fusion protein hijacks or misdirects BAF chromatin remodeling complexes to the wrong sites at the wrong times, producing aberrant, faulty programs of gene expression. The development of cancer results from poorly coordinated or mistimed gene expression.
We went from applying the insights derived from studying this rare cancer to uncovering the mechanism of many more cancers. Biology is all about pattern recognition. At roughly the same time as our efforts focused on synovial sarcoma, sequencing studies revealed that over 20 percent of cancers in total contain perturbations to the genes encoding mSWI/SNF (BAF) chromatin remodeling complexes. Further, sequencing-based dependency studies revealed that an additional group of cancers leverage the activities of these complexes for oncogenic maintenance. Our initial work, coupled with these new findings, led us to search for and ultimately discover many additional mechanisms by which these complexes are involved in human disease. We also defined the biochemical “order of assembly,” describing how the 11-15 subunits of these complexes bind to one another and work to generate a large complex with coordinated functional activities, which led to us solving a 3D structural model of the BAF complex. Such studies have immensely potentiated our interpretation and functional assignment of the many mutations in mSWI/SNF subunits and have already begun to aid in informing therapeutic stratification for patients.
What does it mean to you to receive the Excellence in Science award?
Kadoch: I am deeply honored and humbled to receive this award from FASEB. My many mentors and esteemed peers in the areas of experimental biology and biochemistry have inspired me profoundly over the years of my training and during the establishment of my young laboratory. Further, receiving this award is a testament to the brilliant trainees and collaborators with whom I have had the privilege to work in my young career and with whom I proudly share this wonderful honor.
What advice would you give to young women entering this field?
Kadoch: Stay hungry for discovery and when you stumble upon an interesting result, always take the time to stop and ask yourself, “Where else might this new concept/finding apply?” or “If true, what could we/the field do with this new understanding?” This constant “self-challenge,” especially for obscure or perplexing results, is one of the most valuable in one’s scientific career and will always keep you and your science focused on the most important and pressing goals of biology and medicine. For young women scientists, in particular, it is critically important to realize and appreciate the vital role you play in both the current state of science and in shaping future generations of scientists for years to come.
Cigall Kadoch is a member of American Society for Biochemistry and Molecular Biology, a FASEB member society.