Hendrickson, P. G. | bioRxiv Science

bioRxiv2023

Expression of the CIC-DUX4 fusion oncoprotein mimics human CIC-rearranged sarcoma in genetically engineered mouse models

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.

cancer biology↗

bioRxiv2023

p53 and RB Cooperate to Suppress Transposable Elements

Accumulating data suggest that the long interspersed nuclear element 1 (LINE1), a major class of transposable elements, can promote tumorigenesis by causing deletions of tumor suppressor genes, amplifications of oncogenes, and chromosomal translocations(1). LINE1 and other transposable elements such as short interspersed nuclear elements (SINEs) can be activated during cancer development. Aberrant transposon expression has been correlated with loss of p53, however, how the loss of p53 or other tumor suppressors leads to activation of transposons during tumorigenesis remains to be fully understood. Here, we investigate the link between loss of the p53 and RB tumor suppressors and derepression of transposable elements. We observe that loss of p53 and RB in mouse embryonic fibroblasts leads to epigenetic changes, such as loss of DNA and histone methylation, which correlate with marked upregulation of LINE and SINE transposable elements. These results suggest that p53 and RB may utilize epigenetic mechanisms that work in tandem to suppress transposons, which may contribute to tumor suppression. SignificanceThe two most commonly mutated genes in human cancer are p53 and the retinoblastoma (RB) tumor suppressors. Together, these genes regulate complex interconnecting pathways responsible for the regulation of cell growth, cell death, and genomic integrity. Studies in genetically engineered mouse models demonstrate that the canonical functions of these two tumor suppressors fail to fully explain their tumor suppressive capabilities. Individually, p53 and RB have each been implicated in repressing transposons. Here we show that combined loss of p53 and RB, which rapidly transforms cells, also results in cooperative upregulation of transposable elements and coincides with decreased methylation of DNA and H3K9. Our results present a framework by which p53 and RB work together to restrain the expression of LINE1 and SINEs, which may contribute to tumor suppression.

cancer biology↗