The Ignatius laboratory is interested in understanding the effects of tumor heterogeneity on relapse and resistance to therapies in Rhabdomyosarcoma and other sarcomas. Relapse is a significant problem in the clinic where less than 40% of patients with relapse will survive their disease. Rhabdomyosarcoma is a pediatric malignancy of the muscle that is also the most common soft tissue sarcoma in children. Specifically, the Ignatius laboratory will study tumorigenic cell populations that self-renew and metastasize using a combination of zebrafish, murine xenograft, and human cell culture systems.
Figure 1: Research using a Zebrafish tumor model of Embryonal Rhabdomyosarcoma employs a combination of approaches and assays including Bioinformatic, High-throughput cell transplantation, Chemical-Genetic Screens, and In vivo imaging.
Figure 2: ERMS tumors are generated in vivo using the human kRASG12D oncogene. RAS is the major driver of this disease in children with ERMS. Tumors arise as quickly as ten days after transgene expression.
Figure 3: Transgenic strategy in zebrafish to label cancer-stem cell and other tumor populations in vivo in zebrafish (left). An example of a limit-dilution cell transplantation experiment, using the approach in the left panel, Cancer Stem Cell /Tumor-propagating cell number can be calculated by transplanting tumor cells at different dilutions into syngeneic matched recipients (Ignatius et al., Cancer Cell 2012). Only a Tumor-propagating cell/ Cancer Stem Cell will generate a new tumor.
Figure 4: Example of an in vivo drug screen performed in zebrafish, screening 110 compounds and using 2200 zebrafish (Chen E., DeRan M., Ignatius M, et al., PNAS 2014)
In addition to research on rhabdomyosarcoma, the Ignatius laboratory has also generated new syngeneic zebrafish models of aggressive Malignant Nerve Sheath Tumors, and hemangiosarcomas for which there are no effective treatments. Our research will uncover critical molecular pathways that modulate Tumor propagating cell numbers and the plasticity of the cancer stem cell state. A unique and innovative aspect of our research is the ability to visualize in live animals the evolution of tumors and to model the effects of patient-specific changes on tumor dynamics. Research in the laboratory will combine sequencing platforms with zebrafish tumor models to identify new genes or pathways that drive relapse intending to identify nodes to target with personalized medicines in children with relapsed cancer.
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