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Cancer Research UK Cambridge Institute


Understanding how C11orf95-RELA drives ependymoma.


Ependymomas are rare tumours of the brain and spinal cord that are incurable in up to 40% of cases. Although ependymomas from the different regions of the central nervous system (CNS) are histologically similar, they possess site-specific prognosis, transcriptional profiles and DNA copy number alterations, suggesting that they are different diseases and that they are likely to require different treatments. We reasoned that individual subgroups of ependymoma might arise from regionally and developmentally distinct NSCs (Figure 2) that are susceptible to transformation by different gene mutations. We have generated the first murine models of supratentorial, posterior fossa and spinal ependymoma through a series of innovative, in vivo cross-species genomic and functional tumorigenesis assays1-4. As part of this work we completed a series of comprehensive genomic assays of human ependymomas, including whole-genome sequencing (WGS) experiments, and identified the C11orf95-RELA translocation as the most recurrent genetic alteration in any brain tumour2. By testing the in vivo transforming power of this translocation and genes located in ependymoma amplicons we have validated the C11orf95-RELA fusion as transforming as well as: ZNF668, which links chromatin relaxation state to DNA repair, and BCL7C, a member of the SWI/SNF chromatin-regulatory complex (both among 23 candidates in the 16p11.2 amplicon); RAB3A, which controls late-stage vesicle trafficking and exocytosis in neuronal cells (among 7 candidates in the 19p13.11 amplicon); the putative oncogene PRDX2, which regulates oxidation-induced apoptosis, and RTBDN, of unknown function (both among 25 candidates in the 19p13.13 amplicon); and the AKT2 oncogene (among 4 candidates in the 19q13.2 amplicon). We also validated TMEM129, of unknown function (among 9 candidates in a 4p16.3 amplicon), and the mitochondrial ribosomal protein MRPS17 (among 7 candidates in the 7p11.2 amplicon) as spinal and hindbrain oncogenes, respectively.  In this manner we have now generated mouse models of both main types of human supratentorial ependymoma.

To identify novel tumour suppressor genes (TSGs) of ependymoma, we assessed whether short hairpin RNAs (shRNAs) targeting 39 genes recurrently deleted in ependymoma could cooperate with EPHB2 to transform NSC. These data validated ALDH3A1, ACTR1A, SNX6, ULK2, PCMT1, DNA2, SUFU, STAG1, TET1 and ST13 as ependymoma TSGs4.  Finally, in work led by our international collaborators, we have been able to identify those patients whose tumours harbour the C11orf95-RELA translocation to have the highest risk disease.

Figure 2: Regionally, developmentally and genetically discrete neural stem cells (NSCs) match subgroups of human ependymoma: Co-immunofluorescence of neurospheres generated by NSCs from the cerebrum (C), hindbrain (HB) and spine (SP) of embryonic (E) and adult (A) Ink4a/Arf null or WT Blbp-eGFP mice. Cultured under conditions that promote stem cell growth, all distinct eGFP+ cell isolates were demonstrated to be NSCs that had a Nestin+/Prom1+/Gfap+/Blbp+ immunophenotype and self-renewed as clonal multipotent neurospheres.

Current research:

We are currently focusing on two main research questions: (1) How does the C11orf95-RELA translocation transform neural stem cells to generate ependymoma? To answer this we are using both cell biology and in vivo mouse modeling approaches to study the molecular biology and cellular biochemistry associated with C11orf95-RELA translocation expression. (2) Can we target the C11orf95-RELA translocation or its downstream pathways for therapeutic benefit in ependymoma? To answer this we using our mouse models and human derived xenografts of ependymoma to conduct high-throughput drug screens and in vivo preclinical therapy studies of new treatments5.


1) Taylor MD et al. Radial glia cells are candidate stem cells of ependymoma. Cancer Cell 8: 323–335, 20015.

2) Johnson RA et al. Cross-species genomics matches driver mutations and cell compartments to model ependymoma. Nature 466: 632–636, 2010.

3) <Parker M., Kumarasamypet MM. et. al. C11orf95-RELA fusions drive oncogenic NF-kB signalling in ependymoma. Nature 506: 451-455, 2014.

4) Mohankumar M, et al., An in vivo screen identifies ependymoma oncogenes and tumor suppressor genes. Nature Genetics 8:878-87, 2015.

5) Atkinson J, et al., An integrated in vitro and in vivo high-throughput screen identifies treatment leads for ependymoma. Cancer Cell 20:384-99, 2011.