Unlike adult cancers, certain pediatric cancers have few genetic mutations and instead are driven by fusion oncoproteins with altered DNA and protein interactions. Ewing sarcoma, a pediatric and young adult cancer of bone and surrounding tissue, arises from a single chromosomal rearrangement to generate the EWS-FLI1 fusion protein. EWS-FLI1 levels stratify cells into proliferative and aggressively metastatic cell subpopulations. Patient outcomes remain poor for metastatic disease as treatments have been unchanged for decades: harsh combination chemotherapy, crude tumor removal surgeries and radiation therapy. We are motivated by imagining a future in which more patients survive Ewing sarcoma and other fusion oncoprotein-driven pediatric cancers without long-term mobility impairment, secondary cancers and heart damage.
Our overarching goal is to advance the treatment of Ewing sarcoma, leukemias, brain tumors and other pediatric/young-adult cancers caused by fusion oncoproteins and their molecular interactions. We engineer quantitative biochemical and biophysical tools to uncover heterogeneity in protein interactions, conformations and mechanical states that underpin tumor growth and metastasis. Thus, with novel microtechnologies on the scale of the biology we study, we will gain insight into molecular mechanisms and uncover potential therapeutic targets.
Significance: Many childhood cancers arise from changes in the physics and composition of protein binding partners in cells. Cells are tiny–less than half the width of a human hair–while proteins are over 10,000 times smaller than cells. Thus, we design miniaturized tools to study protein binding. We ask questions like: “which proteins bind together in cancer cells that spread”?
Single-cell analysis of metastasis and engineered tumor-immune microenvironments
Understanding the molecular underpinnings of metastatic cell subpopulations and tumor-immune cell interactions will inform design of targeted therapies to prevent recurrences as distant metastases. We design microfluidic tools to quantify the protein-complex profiles of metastasis in Ewing sarcoma at the single-cell level. Furthermore, we are engineering novel measurement methods for probing how metastasizing Ewing sarcoma cells evade the immune system during metastasis. We have established collaborations to study cytoskeleton and glycosylation targeting therapeutics with the labs of physician-scientist Jason Yustein, M.D., Ph.D. (Professor of Pediatrics at Emory University School of Medicine) and Kevin Yarema, Ph.D. at Johns Hopkins.
Cancer systems biology assay design
Ewing sarcoma and other pediatric cancers are diseases of aberrant protein interactions. The ability to study interactions will reveal how key networks of cell function change in cancer cell subpopulations. We are interested in networks implicated in cancer progression including cytoskeletal, chromatin remodeling, chaperone and fusion oncoprotein interactions. Such changing networks of interaction, or ‘interactomes’, represent sets of molecular targets for combination therapies that have yet to be tested. To advance cancer systems biology and network-targeted therapeutics, we will innovate in design of separation materials and assays for single-cell and low-cell number protein complex identification and quantification. To perform research innovating in sample preparation for mass spectrometry-based proteomics, we have initiated collaborations with the Mass Spectrometry Core at the Baylor College of Medicine and the DNA nanomaterials lab of Matt Jones, Ph.D. (Rice Chemistry Department)
Structural biology and biophysics nanotechnology:
Fusion oncoproteins are tantalizing, but elusive therapeutic targets, particularly when they are the sole mutation driving disease, such as in Ewing sarcoma. The fusion of a DNA binding and intrinsically disordered domain results in a protein that interacts with chromatin remodeling complexes and also phase separates into protein condensates. As a result, fusion oncoproteins can alter the mechanics of gene expression. To elucidate the role of specific conformations and mechanical states in fusion oncoprotein biology, we design nanoscale methods to visualize structures and interactions. Our findings will inform the design of therapeutics tailored to change the physical states that are essential to fusion oncoprotein function.
We are grateful to the following organizations for their support of our research:
