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Published on: January 7, 2019
Expression of the CIC-DUX4 fusion oncoprotein mimics human CIC-rearranged sarcoma in genetically engineered mouse
Peter G Hendrickson1, Kristianne M Oristian1, MaKenna R Browne2
1Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA.
Abstract:
CIC-DUX4 sarcoma (CDS) is a rare but highly aggressive undifferentiated small round cell sarcoma driven by a fusion between the tumor suppressor Capicua (CIC) and DUX4. Currently, there are no effective treatments and efforts to identify and translate better therapies are limited by the scarcity of tissues and patients. To address this limitation, we generated three genetically engineered mouse models of CDS (Ch7CDS, Ai9CDS, and TOPCDS). Remarkably, chimeric mice from all three conditional models developed spontaneous tumors and widespread metastasis in the absence of Cre-recombinase. The penetrance of spontaneous (Cre-independent) tumor formation was complete irrespective of bi-allelic CIC function and loxP site proximity. Characterization of primary and metastatic mouse tumors showed that they consistently expressed the CIC-DUX4 fusion protein as well as other downstream markers of the disease credentialing these models as CDS. In addition, tumor-derived cell lines were generated and ChIP-seq was preformed to map fusion-gene specific binding using an N-terminal HA epitope tag. These datasets, along with paired H3K27ac ChIP-seq maps, validate CIC-DUX4 as a neomorphic transcriptional activator. Moreover, they are consistent with a model where ETS family transcription factors are cooperative and redundant drivers of the core regulatory circuitry in CDS.
Insights
New mouse models of CIC-DUX4 sarcoma (CDS) spontaneously develop tumors and metastasis. These models advance research into effective therapies for this rare and aggressive cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- CIC-DUX4 sarcoma (CDS) is a rare, aggressive cancer with limited treatment options.
- Research is hindered by the scarcity of patient tissues and limited therapeutic strategies.
- Understanding the molecular drivers of CDS is crucial for developing targeted therapies.
Conclusions:
- The developed GEMMs accurately recapitulate key features of human CDS, including spontaneous tumorigenesis and metastasis.
- These models provide valuable tools for studying CDS pathogenesis and for preclinical therapeutic testing.
- The study validates CIC-DUX4 as a driver of oncogenesis and identifies potential therapeutic targets within the regulatory circuitry.
