de Sousa Graziella Ribeiro, Calzadilla Annaliese J, Grimaldo Enrique, Donson Andrew M, Sobral Lays Martin, Jones Kendra M, Liu Tian, Amani Vladimir, Venkataraman Sujatha, Dahl Nathan A, Levy Jean M Mulcahy, Phang Tzu, Vibhakar Rajeev, Hankinson Todd, Handler Michael, Valera Elvis Terci, Foreman Nicholas K, Griesinger Andrea M
Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Neuro Oncol. 2025 Jul 30;27(6):1597-1610. doi: 10.1093/neuonc/noaf029.
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).
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-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.
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.
后颅窝分子亚型A（PFA）室管膜瘤发生于幼儿，是小儿室管膜瘤中最致命的亚型。与野生型PFA相比，具有1q +和/或6q -染色体的高危亚型预后明显较差。然而，50%的野生型PFA患者会复发，且复发时获得1q染色体的风险很高。我们之前发现，通过LDOC1缺失导致的组成型激活的NF-κB会导致慢性IL-6分泌以及高危野生型PFA室管膜瘤亚组（PFA1）中整体免疫抑制性肿瘤微环境的形成。
在本研究中，我们利用常氧和低氧条件下的PFA室管膜瘤体外和体内模型，阐述PFA1中LDOC1缺失的机制后果。
我们注意到H3K27me3在LDOC1基因座处导致染色质压缩，从而导致LDOC1基因表达缺失。LDOC1的恢复足以减少增殖、NF-κB信号传导，并显著降低IL-6分泌。此外，体内植入LDOC1转导细胞的肿瘤被未转导细胞竞争淘汰，这表明LDOC1缺失是PFA肿瘤生长所必需的。
这些发现进一步揭示了PFA1室管膜瘤的生物学特性以及LDOC1缺失在高危小儿室管膜瘤的肿瘤和免疫生物学中的作用。
