Cigall Kadoch Tracks Down Chromatin Remodelers in Cancer

Taking unconventional paths with no fear of exploring the unknown has been a hallmark of Cigall Kadoch’s work. As a graduate student, the now biochemist and molecular biologist joined a developmental biology lab to study cancer. While the decision may have seemed counterintuitive to some, it was not to Kadoch. “Cancer, in essence, is development gone wrong,” she explained. “Cancer is a hijacking, or an aberrant modulation, of the very pathways that control development.”

This mindset guided Kadoch into the world of chromatin remodeling complexes, large protein machines that regulate chromatin accessibility and gene expression. As a postdoctoral researcher, she discovered that a single translocation of 78 amino acids to one subunit of the BRG1/BRM-associated factor (BAF) chromatin remodeler causes the loss of tumor suppression in a rare and aggressive form of pediatric cancer known as synovial sarcoma, turning cells cancerous.^1,2

Almost 10 years after The Scientist first spoke to Kadoch about her research, we reached out again to find out what uncharted scientific paths she has now forged to reveal the secrets of BAF complexes. Kadoch and her team have dissected the mechanisms that drive these complexes to act aberrantly in cancer, uncovering functional changes that are informing new therapeutic approaches.

BAF Complexes Under the Scope

BAF complexes are master regulators that modulate chromatin accessibility and binding of the transcriptional machinery that drives gene expression.³ A cell can express a variety of BAF complexes, which are assembled from a combination of 11 to 15 subunits pieced together from the products of 29 genes. These chromatin remodelers are mutated in more than 20 percent of human cancers, and Kadoch explained that this might be due to their crucial roles in maintaining cell identity and proper developmental processes.⁴

A schematic showing a protein complex bound to a nucleosome (blue) and chromatin (white). — BAF complexes are large protein machines that render the chromatin accessible to transcriptional machinery and help regulate gene expression.
Kadoch lab

In synovial sarcoma, SS18, a subunit of the BAF complex, fuses with another protein called SSX, forming a fusion oncoprotein. This SS18-SSX fusion binds to the BAF complex and expels both the wild type SS18 and a tumor suppressor subunit, causing the chromatin remodeler to act aberrantly. Even though researchers knew this fusion oncoprotein played a key role in synovial sarcoma, the exact genomic locations where the SS18-SSX containing BAF complexes went to cause the cancer-associated changes were unknown. Using both synovial sarcoma cell lines and samples from patients, Kadoch’s team found that the SS18-SSX containing chromatin remodelers targeted genes that were normally repressed by polycomb repressive complexes (PRCs), leading to the eviction of PRCs and expression of genes that should not be active.⁵ “That really established this cancer-specific hijacking of the BAF complex,” Kadoch said.

While the new findings showed where the altered BAF complexes bound to the chromatin, why these complexes moved to these sites in the first place still puzzled Kadoch. The primary difference between a regular and aberrant BAF complex is the little 78-amino acid long fusion protein tail, which drags the entire chromatin remodeler to the genomic sites it should not bind to, she explained. Her team discovered that the oncogenic fusion protein interacts with chromatin and directs the BAF complex by binding it to the acid region of nucleosomes bearing a specific mark placed by PRCs, thus unveiling the motif that attracts the fusion oncoprotein in synovial sarcoma.⁶

BAF Complexes Hijacking Beyond Synovial Sarcoma

That PRCs placed marks on nucleosomes uncovered another piece of the puzzle of how BAF remodelers navigate to specific sites on the two-meter-long human DNA, but Kadoch and her team still wondered whether other mechanisms were at play. The researchers knew that transcription factors can be overexpressed in a cancer-dependent manner, and BAF complexes often co-localized with these highly expressed factors. This evidence led the researchers to wonder whether there was a direct interaction between the chromatin remodelers and abundant transcription factors. The team found that highly expressed transcription factors bind to a specific domain on one of the core subunits of BAF complexes and that this interaction influences where the complexes land along the chromatin.⁷

Describing the roles of the different BAF subunits and tracking the mechanisms involved in the hijacking of these complexes allowed Kadoch’s team to expand their studies on chromatin remodelers to other cancers, including lung cancer and endometrial carcinomas.^8,9 It also made Kadoch realize the vast therapeutic potential of modulating the activity of these complexes—an area she has been exploring at Foghorn Therapeutics, a biotechnology company she helped found, which aims to identify components in the chromatin regulatory system, including complex subunits and associated transcription factors that can be targeted to treat cancer and other BAF complex-associated diseases.

Kadoch’s entire scientific journey has felt unexpected, but she has adopted a “no-fear approach” to pursue and discover something new. “That's what one has to be ready for in research. We have to be open and receptive to the unknown in what we find and where that leads us, and also open and receptive to the career paths that may come from certain findings and discoveries along the way.”

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