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Jedlicka Lab

Research Interests:

Cancers of childhood have unique pathobiology, including origins in developing or otherwise immature tissues, relative paucity of mutations, extensive epigenetic dysregulation, and clinically aggressive behavior, including early and frequent metastasis. Ewing Sarcoma is a prototypical pediatric cancer arising in a stem or stem-like cell, usually in bone, with a high propensity for metastatic dissemination. A subset of patients presenting with clinically localized disease can be cured with multi-agent conventional chemotherapy, but patients presenting with metastasis or recurrence face poor outcomes and currently have few treatment options. The need to identify new therapeutic approaches for this disease is thus easy to justify. Ewing Sarcoma has a largely quiescent genome, save for recurrent chromosomal translocations that yield fusion proteins with potent oncogenic activity. Such fusions generally consist of the N-terminus of the EWS protein and the C-terminus, including the DNA-binding domain, of an Ets transcription factor. EWS/Ets fusions, EWS/Fli1 being the most common, result in profound alterations of gene expression in the cell, through transcriptional, as well as other, mechanisms.

EWS/Ets fusions represent logical therapeutic targets in Ewing Sarcoma. However, to date, such targeting has proven difficult. Moreover, while EWS/Ets fusions are established drivers of oncogenic transformation and tumorigenesis, recent studies suggest that they are not the chief drivers of metastasis. Indeed, at present, the mechanistic basis of the known high metastatic propensity of Ewing Sarcoma is poorly understood. Recently, our laboratory has identified the Jumonji-domain histone demethylase KDM3A as a new, therapeutically targetable, pro-tumorigenic and pro-metastatic factor downstream of EWS/Fli1. KDM3A is an epigenetic regulator belonging to the histone mark “eraser” class, with specificity for H3K9 methyl 1 and 2 histone marks. These marks are generally associated with transcriptional repression, but molecular mechanistic details of how they contribute to control of gene expression are not well understood.

Currently, our laboratory is broadly interested in further understanding the biology of Jumonji-domain histone demethylases in regulation of gene expression and cancer phenotypes in Ewing Sarcoma, and in leveraging this information to try to improve patient outcomes. Specific questions include: 1) How do KDM3A and other JHDMs impact relevant cancer phenotypes, and what pathways are involved? 2) Is pharmacologic inhibition of JHDMs a viable therapeutic strategy, and if so, which JHDMs are key to inhibit? 3) What are the molecular mechanisms by which KDM3A, and other JHDMs, control target gene expression? 4) Are these effects/mechanisms of relevance in other pediatric cancers? To answer these questions, our laboratory uses a variety of molecular, biochemical, cell culture and in vivo approaches, with the ultimate goals of advancing the understanding of Ewing Sarcoma pathogenesis and harnessing such knowledge to lessen the clinical burden of this disease.



Selected Publications:
  • Jedlicka P. Ewing Sarcoma, an Enigmatic Malignancy of Likely Progenitor Cell Origin, Driven by Transcription Factor Oncogenic Fusions. International Journal of Clinical and Experimental Pathology (2010) 3: 338-347.
  • McKinsey EL, Parrish JK, Irwin AE, Niemeyer BF, Kern HB, Birks DK and Jedlicka P. A novel oncogenic mechanism in Ewing Sarcoma involving IGF pathway targeting by EWS/Fli1-regulated microRNAs. Oncogene (2011).​
  • ​Robin TP, Smith A, McKinsey E, Reaves L, Jedlicka P and Ford HL. EWS/Fli1 regulates Eya3 in Ewing's sarcoma via modulation of microRNA-708, resulting in increased cell survival and chemoresistance. Molecular Cancer Research (2012).
  • Dylla L, Moore C and Jedlicka P. MicroRNAs in Ewing Sarcoma. Frontiers in Oncology (2013).
  • Dylla L and Jedlicka P. Growth-promoting role of the miR-106a~363 cluster in Ewing Sarcoma. PLoS One (2013).
  • Parrish JK, Sechler M, Winn RA and Jedlicka P. The histone demethylase KDM3A is a microRNA-22-regulated tumor promoter in Ewing Sarcoma. Oncogene (2013).
  • Niemeyer BF, Parrish JK, Spoelstra NS, Joyal T, Richer JK and Jedlicka P. Variable expression of PIK3R3 and PTEN in Ewing Sarcoma impacts oncogenic phenotypes. PLoS One (2015).
  • Sechler M, Parrish JK, Birks DK and Jedlicka P. The histone demethylase KDM3A, and its downstream target MCAM, promote Ewing Sarcoma cell migration and metastasis. Oncogene (2017).
  • Moore C, Parrish JK and Jedlicka P. MiR-193b, downregulated in Ewing Sarcoma, targets the ErbB4 oncogene to inhibit anchorage-independent growth. PLoS ONE (2017).
  • Jedlicka P. The potential of KDM3A as a therapeutic target in Ewing Sarcoma and other cancers. Expert Opinion on Therapeutic Targets (2017).
  • Parrish JK, McCann TS, Sechler M, Sobral LM, Ren W, Jones KL, Tan AC and Jedlicka P. The Jumonji-domain histone demethylase inhibitor JIB-04 deregulates oncogenic programs and increases DNA damage in Ewing Sarcoma, resulting in impaired cell proliferation and survival, and reduced tumor growth. Oncotarget (2018).
  • McCann TS, Sobral LM, Self C, Hsieh J, Sechler M and Jedlicka P. Biology and targeting of the Jumonji-domain histone demethylase family in childhood neoplasia: a preclinical overview. Expert Opinion on Therapeutic Targets (2019).​