Department of Molecular Medicine
 

Dr Ignatius Myron  S. IgnatiusPh.D.

Assistant Professor


Profile and Contact Information | Research | Laboratory


RESEARCH

 

Research Program

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 major problem in the clinic where less that 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.



Ignatius Lab Work
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.


Ignatius Lab Work
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 10 days after transgene expression.


Ignatius Lab Work

Figure 3: Transgenic strategy in zebrafish to label cancer-stem cell and other tumor populations in vivo in zebrafish (left). 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.


Ignatius Lab Work
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 important molecular pathways that modulate Tumor propagating cell number 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 with the goal of identifying nodes to target with personalized medicines in children with relapsed cancer.



 

Selected Publications

  1. Nambiar, R. M., Ignatius, M. S. and Henion, P. D. (2007). Zebrafish colgate/hdac1 functions in the non-canonical Wnt pathway during axial extension and in Wnt-independent branchiomotor neuron migration. Mech. Dev. 124(9-10) , 682-98.

  2. Ignatius, M. S., Moose, H. E., El - Hodiri, H. M. and Henion, P. D. (2008). colgate/hdac1 repression of foxd3 expression is required to permit mitfa-dependent melanogenesis, Dev. Biol.313(2), 568-83.

  3. Ignatius, M. S. and Langenau, D. M. (2009). Zebrafish as a Model for Cancer Self-renewal. Zebrafish. Dec;6(4):377-87. Author, Review.

  4. Smith A. C, Raimondi A. R, Salthouse C. D, Ignatius M. S., Blackburn J. S, Mizgirev I. V, Storer N. Y, de Jong J. L, Chen A. T, Zhou Y, Revskoy S, Zon L. I, Langenau D. M. (2010). High- throughput cell transplantation establishes that tumor-initiating cells are abundant in zebrafish T-cell acute lymphoblastic leukemia. Blood. Apr 22; 115 (16):3296-303.

  5. Blackburn J. S, Liu S, Raimondi A. R, Ignatius M. S., Salthouse C. D, Langenau D. M. (2011). High-throughput imaging of adult fluorescent zebrafish. Nature Protocols. Feb; 6(2): 229-41.

  6. Ignatius M. S., Langenau D.M. (2011). Fluorescent Imaging of Cancer in Zebrafish. Methods in Cell biology.105:437-59. Author, Book Chapter.

  7. Ignatius M.S., Chen E., Elpek N.M., Fuller A., Tenente I.M., Clagg R., Liu S., Blackburn J.S., Linardic C., Rosenberg A., Neilsen P.G., Mempel T.R., Langenau D.M. (2012). In vivo imaging of tumor-propagating cells, regional tumor heterogeneity, and dynamic cell movements in embryonal rhabdomyosarcoma. Cancer Cell. 2012; 21(5):680-93.

  8. Le X., Pugach E. K., Hettmer S., Storer N.Y., Liu Z., Wills A., DiBiase A., Chen E., Ignatius M. S. Kenneth P., Wagers A., Langenau D.M., Zon L. (2013). A chemical screen to antagonize RAS induction during embryogenesis establishes pathway required for the development of rhabdomyosarcoma. Development. 2013; 140(11):2354-64.

  9. Ignatius M.S., Unal Eroglu A., Malireddy S., Gallagher G., Nambiar R.M., Henion P.D. (2013). Distinct functional and temporal requirements for zebrafish Hdac1 during neural crest-derived craniofacial and peripheral neuron development. PLoS One. 2013;8(5):e63218.

  10. Chen E.Y., Dobrinski K.P., Brown K.H., Clagg R., Edelman E., Ignatius M.S., Chen J.Y., Brockmann J., Nielsen G.P., Ramaswamy S., Keller C., Lee C., Langenau D.M. (2013). Cross- species array comparative genomic hybridization identifies novel oncogenic events in zebrafish and human embryonal rhabdomyosarcoma. PLoS Genet. 2013 Aug; 9(8):e1003727.

  11. Chen E.Y., DeRan M., Ignatius M.S., Grandinetti K.B., Ryan Clagg, McCarthy K, Lobbardi R.M., Brockmann J., Keller C., Wu X., Langenau D.M. (2014). GSK3 inhibitors induce the canonical WNT/b-catenin pathway to suppress growth and self-renewal in embryonal rhabdomyosarcoma. PNAS. 2014; 111(14):55349-54. 10. (Second Author)

  12. Tang Q., Abdelfattah N.S., Blackburn J.S., Moore J.C., Martinez S.A., Moore F.E., Lobbardi R., Tenente I.M., Ignatius M.S., Berman J.N., Liwski R.S., Houvras Y., Langenau D.M. (2014). Optimized cell transplantation using adult rag2 mutant zebrafish. Nature Methods. 2014; July 20 (EPUB).

  13. Ignatius M.S., Hayes M. S., Langenau D.M. (2016) In vivo imaging of cancer in Zebrafish. Cancer and Zebrafish: Mechanisms, Techniques, and Models. Advances in Experimental Medicine and Biology (Accepted).

  14. Tang Q., Moore J.C., Ignatius M.S., Hayes M.N., Tenente I, Bourque C., He S., Look A.T., Garcia E.C., Blackburn J.S., Houvras Y., Langenau D.M. (2015). Imaging the dynamics of tumour cell heterogeneity following cell transplantation into optically-clear rag2E450fs zebrafish. Nature Communications (Accepted November, 2015).