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Jedlicka Lab

 

Contacts:

Phone: 303-724-8161

Fax:     303-724-3712

E-mail: Paul.Jedlicka@ucdenver.edu

Ewing Sarcoma is an aggressive bone and soft tissue malignancy affecting children, adolescents and young adults. High-dose, multi-agent chemotherapy cures slightly more than half of patients with Ewing Sarcoma, but for the remainder no effective therapeutic options currently exist. Thus, innovative approaches are needed to improve clinical outcomes for this aggressive disease. Ewing Sarcoma originates in stem or stem-like cells of mesenchymal or neural crest origin, and, like many sarcomas, is driven by recurrent oncogenic fusions.

The vast majority of these fusions 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. While EWS/Ets fusions represent a logical therapeutic target, such targeting has proven difficult.

An alternative approach is the targeting of key pro-oncogenic mechanisms downstream of EWS/Fli1. We have taken the approach of investigating microRNA-mediated mechanisms downstream of EWS/Fli1, with the goal of identifying novel pathways amenable to targeting by microRNA or/and other means. Mechanistic understanding of microRNA-mediated pathways in Ewing Sarcoma has revealed both new regulatory mechanisms affecting established oncogenic pathways, such as receptor tyrosine kinase signaling, and a new oncogenic pathway involving modulation of the H3K9 histone methyl mark.

Our ongoing efforts are directed at further understanding of how these pathways contribute to Ewing Sarcoma pathogenesis, and how they could be manipulated for improved therapies for this aggressive cancer.

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).

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).

 

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