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Loss of LDOC1 by chromatin compaction in mesenchymal tumor cells is required for PFA1 ependymoma growth [RNA-seq]

ABSTRACT: Posterior fossa molecular subtype A (PFA) ependymoma occurs in young children and is the deadliest subtype of pediatric ependymoma. High-risk subtypes with chromosome 1q+ and/or 6q- exhibit significantly poorer outcome compared to wild-type PFA. However, 50% of wild-type PFA patients relapse and there is a high risk of gaining chromosome 1q at recurrence. We previously found constitutively active NF-kB, through loss of LDOC1, led to chronic IL-6 secretion and an overall immunosuppressive tumor microenvironment in the higher risk wild-type PFA ependymoma subset (PFA1). In this study, we delineate the mechanistic consequences of LDOC1 loss in PFA1, using our PFA ependymoma in vitro and in vivo models under normoxia and hypoxia conditions. We noted chromatin compaction by H3K27me3 at the LDOC1 loci results in loss of LDOC1 gene expression. Restoration of LDOC1 was sufficient to reduce proliferation, NF-kB signaling and significant decrease in IL-6 secretion. Furthermore, tumors implanted with LDOC1- transduced cells in vivo were out competed by non-transduced cells, suggesting loss of LDOC1 is required for PFA tumor growth. These findings shed further light on the biology of PFA1 ependymoma and the role LDOC1 loss has on the tumor and immunobiology of high risk pediatric ependymoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE274879 | GEO | 2025/08/06

REPOSITORIES: GEO

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Project description:Ependymoma (EPN) posterior fossa group A (PFA) has the highest rate of recurrence and the worst prognosis of all EPN types. At relapse, it is typically incurable even with re-resection and re-irradiation. The biology of recurrent PFA EPN remains largely unknown, which hinders clinical advances. In this large longitudinal multicenter study, we examined matched samples of primary and recurrent disease from PFA EPN patients (n=95) to investigate the biology of recurrence. DNA methylomic data was used to measure copy number variants (CNVs), revealing progressive large scale chromosome gains and losses in successive recurrences. These CNV changes were dominated by chromosome 1q gain and/or 6q loss (1q+/6q-), both previously identified as high-risk factors in PFA EPN, which were present in ~20% at presentation but increased to ~60% at 1st recurrence. These CNV changes were correlated with hypomethylation of heterochromatin associated DNA at presentation. Evolution of chromosomal aberrations was further explored using CNV analysis of single-nuclei RNAseq on approximately 46,000 PFA EPN cells from 6 matched pairs of primary and 1st relapse tumors that harbored CNV changes at recurrence. No evidence of rare subclones in primary tumors was observed, suggesting that chromosomal rearrangement events occur after initial presentation. Cellular and molecular characteristics associated with CNVs were examined by single-nuclei RNAseq, bulk transcriptomic analysis and immunohistochemistry, revealing that 1q+/6q- PFA have a significantly higher mitotic index, increased proportions of proliferative epithelial progenitors and decreased differentiated neoplastic subpopulations. Multivariate survival analyses showed that cases with 1q gain or 6q loss at 1st recurrence were significantly more likely to recur than cases with no 1q or 6q change. The high prevalence of 1q+/6q- at recurrence and the associated shortened survival, suggest that both these abnormalities should be routinely tested for, and used for trial stratification.

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Loss of LDOC1 by chromatin compaction in mesenchymal tumor cells is required for PFA1 ependymoma growth [RNA-seq]

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