Loss of LDOC1 by chromatin compaction in mesenchymal tumor cells is required for PFA1 ependymoma growth.

Abstract

Background: 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 outcomes 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-κB, 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).

Methods: 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.

Results: 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-κB signaling, and a 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.

Conclusion: 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.