Park Junseong, Kim Dokyeong, Park Hyeon-Chun, Park Minyoung, Zhang Songzi, Na Okcho, Lee Youn Soo, Lee Minho, Ahn Stephen, Chung Yeun-Jun
Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.
Precision Medicine Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
J Transl Med. 2025 Aug 14;23(1):915. doi: 10.1186/s12967-025-06952-y.
Gliosarcoma (GS) is a rare variant of glioblastoma (GBM), characterized by biphasic glial and sarcomatous histology and poor prognosis. Despite its distinct clinical features, GS remains underrepresented in glioma research due to the lack of biologically faithful and experimentally tractable models.
We established patient-derived gliosarcoma organoids (GSOs) from freshly resected tumors using a suspension culture system without enzymatic dissociation. Histological, molecular, and functional properties were evaluated using H&E staining, immunohistochemistry, whole-exome sequencing, 3D invasion assays, and single-cell RNA sequencing (scRNA-seq). Drug response assays were performed using temozolomide and ANA-12 (NTRK2 inhibitor).
GSOs preserved key histological features, genetic alterations, and tumor microenvironmental cell populations from the original tumors. They stable growth and viability over extended culture periods and maintained integrity following cryopreservation and recovery, supporting their long-term utility. 3D invasion assays further revealed infiltrative behavior, consistent with the aggressive nature of GS. Histological and molecular analyses revealed that GSOs retained glial and mesenchymal differentiation, diverse non-malignant stromal cells, and case-specific somatic alterations. Comparative scRNA-seq revealed distinct transcriptional programs: GSOs were enriched for fibroblast-like and oligodendrocyte progenitor-like states, while glioblastoma organoids (GBOs) displayed astrocyte-like differentiation and high connectivity signatures. Functional assays confirmed consistent sensitivity of GSOs to temozolomide, and selective therapeutic response to NTRK2 inhibition was observed in the GSO harboring an NTRK2 alteration, supporting the utility for genomic-context-guided therapy.
Together, GSOs constitute a tractable and translationally relevant model that faithfully reflects the cellular complexity, genetic landscape, and tumor-specific heterogeneity. This model addresses a critical gap in GS biology and supports its integration into precision oncology.
胶质肉瘤（GS）是胶质母细胞瘤（GBM）的一种罕见变体，其特征为具有双相性胶质和肉瘤样组织学表现且预后较差。尽管GS具有独特的临床特征，但由于缺乏生物学上可靠且实验上易于操作的模型，其在胶质瘤研究中的代表性仍然不足。
我们使用无酶解离的悬浮培养系统，从新鲜切除的肿瘤中建立了患者来源的胶质肉瘤类器官（GSO）。使用苏木精和伊红染色、免疫组织化学、全外显子测序、三维侵袭试验和单细胞RNA测序（scRNA-seq）对组织学、分子和功能特性进行了评估。使用替莫唑胺和ANA-12（NTRK2抑制剂）进行药物反应试验。
GSO保留了原始肿瘤的关键组织学特征、基因改变和肿瘤微环境细胞群体。它们在延长的培养期内稳定生长且具有活力，在冷冻保存和复苏后保持完整性，这支持了它们的长期实用性。三维侵袭试验进一步揭示了浸润行为，这与GS的侵袭性本质一致。组织学和分子分析表明，GSO保留了胶质和间充质分化、多种非恶性基质细胞以及特定病例的体细胞改变。比较性scRNA-seq揭示了不同的转录程序：GSO富含成纤维细胞样和少突胶质细胞祖细胞样状态，而胶质母细胞瘤类器官（GBO）表现出星形胶质细胞样分化和高连接性特征。功能试验证实了GSO对替莫唑胺的一致敏感性，并且在携带NTRK2改变的GSO中观察到对NTRK2抑制的选择性治疗反应，这支持了其在基因组背景指导治疗中的实用性。
总之，GSO构成了一个易于操作且与转化相关的模型，忠实地反映了细胞复杂性、基因图谱和肿瘤特异性异质性。该模型填补了GS生物学中的一个关键空白，并支持将其整合到精准肿瘤学中。
