Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA 19104, USA.
Max-Eder Research Group of Pediatric Sarcoma Biology, Institute of Pathology, LMU Munich, Munich, Germany; Hopp Children's Cancer Center (KiTZ) Heidelberg, Heidelberg, Germany; Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.
Cell Rep. 2022 Jun 14;39(11):110971. doi: 10.1016/j.celrep.2022.110971.
Ewing sarcoma (EwS) is a highly aggressive tumor of bone and soft tissues that mostly affects children and adolescents. The pathognomonic oncofusion EWSR1::FLI1 transcription factor drives EwS by orchestrating an oncogenic transcription program through de novo enhancers. By integrative analysis of thousands of transcriptomes representing pan-cancer cell lines, primary cancers, metastasis, and normal tissues, we identify a 32-gene signature (ESS32 [Ewing Sarcoma Specific 32]) that stratifies EwS from pan-cancer. Among the ESS32, LOXHD1, encoding a stereociliary protein, is the most highly expressed gene through an alternative transcription start site. Deletion or silencing of EWSR1::FLI1 bound upstream de novo enhancer results in loss of the LOXHD1 short isoform, altering EWSR1::FLI1 and HIF1α pathway genes and resulting in decreased proliferation/invasion of EwS cells. These observations implicate LOXHD1 as a biomarker and a determinant of EwS metastasis and suggest new avenues for developing LOXHD1-targeted drugs or cellular therapies for this deadly disease.
尤因肉瘤（EwS）是一种高度侵袭性的骨和软组织肿瘤，主要影响儿童和青少年。标志性的融合基因 EWSR1::FLI1 通过从头调控致癌转录程序来驱动 EwS。通过对数千个代表泛癌症细胞系、原发性癌症、转移和正常组织的转录组进行综合分析，我们确定了一个 32 个基因的特征（ESS32[尤因肉瘤特异性 32]），该特征将 EwS 与泛癌症区分开来。在 ESS32 中，编码一个立体纤毛蛋白的 LOXHD1 是通过一个替代的转录起始位点表达最高的基因。EWSR1::FLI1 结合的上游从头增强子的缺失或沉默导致 LOXHD1 短异构体的丢失，改变 EWSR1::FLI1 和 HIF1α 通路基因，导致 EwS 细胞增殖/侵袭减少。这些观察结果表明 LOXHD1 是 EwS 转移的生物标志物和决定因素，并为开发针对这种致命疾病的 LOXHD1 靶向药物或细胞疗法提供了新的途径。
