We were delighted to have had the chance to sit down with Cigall Kadoch, Professor at the Dana-Farber Cancer Institute recently. In this interview, Cigall discusses her research into chromatin remodelling complexes and their role in health and disease, and how emerging technologies are enabling deeper insights.
Cigall Kadoch is a Professor of Pediatric Oncology at the Dana-Farber Cancer Institute and Harvard Medical School, Affiliate Faculty of Biological Chemistry and Molecular Biology at Harvard Medical School, and Institute Member and Epigenomics Program Co-Director at the Broad Institute of MIT and Harvard. She established her independent laboratory in 2014, at age 28, one of the youngest scientists ever appointed to the Harvard Medical School faculty. She has quickly become a leading expert in chromatin and gene regulation and is internationally recognized for her groundbreaking studies in these areas.
Please note transcript has been edited for brevity and clarity.
FLG: Hi everybody. Today, I’m here with Cigall Kadoch, Professor at the Dana-Farber Cancer Institute, ahead of her talk at The Festival of Genomics, Biodata and AI in Boston next month. Cigall, thank you so much for joining me today. How are you?
Cigall Kadoch: Thank you very much for having me, and very much looking forward to this event in June.
FLG: Could you tell us a bit about yourself and your background?
Cigall Kadoch: I am a professor here at Harvard Medical School and the Dana-Farber Cancer Institute in the Department of Paediatric Oncology. I’ve had my lab here for just over 10 years, and I’m also an investigator of the Howard Hughes Medical Institute. Our laboratory is centred in understanding the mechanisms of chromatin and gene regulation, with a specific emphasis on large protein complexes known as chromatin remodelling complexes.
FLG: Great. And how would you describe your work to a non-specialist audience?
Cigall Kadoch: So, the past decade has been extremely exciting, and we’ve learned, through the lens of human genetics, the most frequently disrupted genes in human cancer. We’ve also used DNA-based technologies, CRISPR screening and so on, to identify the top and actionable vulnerabilities or dependencies in human cancer and other diseases. I think what has been most exciting is that those efforts have repeatedly identified chromatin regulatory entities, and in particular these chromatin regulatory complexes, known as mSWI/SNF or BAF complexes, which we study as central determinants of disease and central dependencies that are responsible for upholding the oncogenic types of these cancers. And we have been excited to understand their properties, their functions, their structure, and we spent a great deal of time trying to understand how these complexes look inside a cell, what they interact with, and how they work to govern very specialised gene expression patterns in both normal and cancer settings.
FLG: What first drew you to work in this field of epigenetics and chromatin biology?
Cigall Kadoch: As a graduate student, I was in my interview, and my to-be mentor described how his lab focused on mechanisms that can incorporate changes from outside the cell all the way into the nucleus of the cell, and how cells can collect cellular and extracellular information, ultimately to change gene expression. And he was explaining to me that overall, the topology of our genomes is dependent on regulatory entities, proteins that run around inside the nucleus of our cells to dictate chromatin architecture. It just seemed like a process that’s so fundamental in the development of virtually every cell type he and his team had studied. It would be exactly the kind of process that goes awry or is perturbed in cancer and other diseases. And I was particularly interested in cancer, and so among the earliest studies we linked these chromatin regulatory entities to human cancer. We did that by way of a very rare but genomically well characterised and extremely aggressive paediatric cancer known as synovial sarcoma, and we learned from that one rare lens exactly how these complexes can be co-opted and dragged around the genome to different sites to activate, in a very cancer-specific manner, oncogenic gene regulatory processes.
FLG: What are some of the most important implications of your work for patients?
Cigall Kadoch: So, we can understand the mechanisms that govern gene regulation in cancer, and if we can learn how to modulate those very mechanisms that turn on and turn off the key pathways and key gene regulatory programmes that govern the cancer state, I think we have a myriad of new opportunities. As an example, it’s become very clear over the past decade that a number of human cancers are dependent on these chromatin regulatory complexes, these chromatin remodelling machines we study, known as Maf complexes. If we can specifically understand why and at what interfaces they are most dependent, and for what reasons they are most dependent on these complexes, we can design and develop therapeutics that specifically address those dependencies, and that’s what I’m most excited about.
FLG: Do you think that these insights are going to translate into real world treatments in the near future?
Cigall Kadoch: Yes, we’re very excited about that. And indeed, they already are. So, taking the insights of the whole field at large, from the genetics to the structure and function work to the biochemistry to the dependency work, now, several clinical agents have made their way into the clinic in phase one studies. It’s still very early days. We have a lot to learn about how these types of remodelling inhibitors and modulators are going to work in different cancer types. But what’s very exciting is that now this is a whole new first in class, and this is now, for the very first time, crossing the bridge into patients with many different types of cancer.
FLG: What are some emerging discoveries that you find particularly groundbreaking and exciting?
Cigall Kadoch: One of the exciting discoveries we’re going to be talking about at The Festival of Genomics is a new study from our laboratory that addresses a long-standing question in the field. You know, these are large chromatin and modelling complexes. They’re two megadaltons. They’re very big. They’re pieced together from multiple components, and they play critical roles in governing the accessibility of specialised sites across the genome. A huge question, though, has been, how do they get to specific sites on chromatin? We have two metres of DNA. What’s their navigation system? How do they know where to go, both in the normal setting, for example, during development and in the maintenance of our normal cells and tissues, but also, how do they know where to go, sometimes in a very aberrant way? How do they know where to go in cancer?
Some new work from our laboratory revealed a specialised domain present on the SMARCD family of subunits within this chromatin or modular complex called the SWIFT domain. And this little SWIFT domain is an out pouching of the complex that is essentially a platform for the binding of mammalian, in this case, human transcription factors that bind and dock at the site. They help dictate where these complexes go and do their activities. They’re largely activating activities on chromatin. So, this is very exciting, because this starts to help answer why many cancers that are dependent on transcription factors – oncogenic transcription factor dependence, oncogenic addiction, if you will – are so dependent on these complexes. And if we make a single residue mutation to break how a transcription factor binds to these complexes, in some cases, we can completely collapse the oncogenic phenotype of that cancer. We’re excited about now bringing in additional information to try to take this toward a path to develop new therapeutics, specifically for these transcription factor addicted, BAF complex, chromatin remodeling complex addicted cancer types that are being upheld by this one interaction.
FLG: And what are some of the biggest unanswered questions that you hope might be tackled next?
Cigall Kadoch: You know, I think there’s a big group of questions about how broad spanning these patterns are. I just described to you a little bit about our work on how transcription factors engage with these complexes. That’s one bucket, if you will, as to how these complexes are major dependencies in certain cancers. Our lab has a major interest to understand all the buckets. What are all the ways by which these complexes can be moved around in the cell, by what mechanisms? How do they get where they need to go? How do they respond to external cues? And these are major areas of active inquiry in the lab.
FLG: What new technologies would most accelerate your work?
Cigall Kadoch: We’ve been very fortunate to benefit from a wide range of sequencing technologies. I think, definitely over the past decade, a wide number of our discoveries have been certainly aided by DNA sequencing and DNA sequencing-based technologies, CRISPR screening, for example. The dependency map led by the Broad Institute has been extremely enabling to identify, in high throughput, the top synthetic lethal vulnerabilities and cancers. Of course, sequencing in general has allowed us to do our work much faster. We can now take any protein, or domain thereof, of these complexes and map their occupancy on chromatin quite readily. Similarly, single cell technologies that enable identification of protein abundance and identification in single cells is also extremely enabling for us. So, we are continuing to leverage technology. Certainly on the other side, there is also artificial intelligence, AI-based technologies, both for the protein structure function work that we do, as well as the more epigenomics based work that we do, and it has also been very forwarding. We are constantly integrating more and more of these types of approaches.
