This week we profile a recent publication in Molecular Cell from the lab of Dr. Cigall Kadoch (pictured)
at Dana-Farber Cancer Institute and Broad Institute with first author Dr. Hayley Zullow.
Can you provide a brief overview of your lab’s current research focus?
The Kadoch Lab is centered in understanding chromatin and gene regulatory mechanisms that underlie human disease, specifically, human cancer. The group takes a multidisciplinary, highly integrative scientific approach to understanding the structure and function of large molecular machines called chromatin remodeling complexes, which help dictate which stretches of our genome are accessible and hence poised for active gene expression. The Kadoch Lab has found that perturbations in these complexes are present in over 20% of human cancers, and in some rare but genomically well-characterized cancer types, this type of perturbation represents the key driving feature. Over the years, their work has led to the founding of Foghorn Therapeutics, Inc. (NASDAQ:FHTX) and the development of several clinical and drug discovery programs.
What is the significance of the findings in this publication?
Here, we explored the impact of the fusion oncoprotein hallmark to a rare sarcoma, myxoid liposarcoma, and its impact on the activities of chromatin remodeling complexes. We previously showed that fusions such as SS18-SSX and EWS-FLI1 in synovial sarcoma and Ewing sarcoma, respectively, interact with BAF complexes and direct their genomic occupancy in a cancer-specific, gain-of-function manner. Surprisingly, the fusion protein underlying myxoid liposarcoma, FUS-DDIT3, acts by sequestering BAF complexes away from key target sites, which are critical for proper adipogenic (fat cell) differentiation, resulting in stalled adipogenesis. Interestingly, the gene regulatory mechanisms we uncovered closely mirrors those of BAF loss-of-function in SMARCB1-deficient cancers and others driven by BAF complex compromise in cell lines and primary tumors, suggesting that a fusion protein can act by “inactivating” or functionally compromising a major chromatin regulator.
What are the next steps for this research?
These findings help point toward new potential therapeutic opportunities for this rare cancer (and others related) and identify a new mechanistic category for fusion oncoproteins.
