Sung Ji-Yong, Kim Jin-Hong, Kim Yi-Jun
Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, 08826, South Korea.
Department of Environmental Medicine, College of Medicine, Ewha Womans University, Seoul, 07804, South Korea.
J Transl Med. 2025 May 12;23(1):536. doi: 10.1186/s12967-025-06539-7.
Cancer cells achieve replicative immortality through telomere maintenance mechanisms (TMMs), primarily via telomerase activation or alternative lengthening of telomeres (ALT). Sarcomas frequently employ the ALT pathway, which traditionally correlates with adverse clinical outcomes. However, chondrosarcomas represent a unique context where the role and prognostic significance of ALT remain largely unexplored.
We performed comprehensive analyses of single-cell RNA-sequencing data from patients with chondrosarcoma and integrated this with 90 bulk RNA-seq datasets. This approach enabled detailed characterization of TMM at single-cell resolution, identification of ALT-specific signatures, and evaluation of the tumor microenvironment in chondrosarcomas.
Patients with ALT-like chondrosarcomas exhibited significantly improved survival compared to those with non-ALT-like chondrosarcomas. Analysis of the tumor immune microenvironment revealed distinct metabolic and immune landscapes between the ALT-like and non-ALT-like groups. Single-cell analysis showed that high-entropy stem-like cells in high-grade chondrosarcomas predominantly adopted telomerase activation over the ALT pathway as their TMM. Additionally, we identified a 100-gene signature that reliably distinguishes ALT-like chondrosarcomas, providing a robust molecular marker for classification and prognosis.
Our study reveals ALT-like state as a marker of favorable prognosis in chondrosarcomas-contrasting with its typically adverse implications in other sarcomas. We establish a robust 100-gene signature that reliably identifies ALT-like chondrosarcomas and characterize their distinct immune microenvironment profile.
癌细胞通过端粒维持机制（TMMs）实现复制永生，主要是通过端粒酶激活或端粒的替代延长（ALT）。肉瘤经常采用ALT途径，传统上这与不良临床结果相关。然而，软骨肉瘤是一个独特的情况，其中ALT的作用和预后意义在很大程度上仍未得到探索。
我们对软骨肉瘤患者的单细胞RNA测序数据进行了全面分析，并将其与90个批量RNA测序数据集整合。这种方法能够在单细胞分辨率下对TMM进行详细表征，识别ALT特异性特征，并评估软骨肉瘤中的肿瘤微环境。
与非ALT样软骨肉瘤患者相比，ALT样软骨肉瘤患者的生存率显著提高。对肿瘤免疫微环境的分析揭示了ALT样和非ALT样组之间不同的代谢和免疫格局。单细胞分析表明，高级别软骨肉瘤中的高熵干细胞样细胞主要采用端粒酶激活而非ALT途径作为其TMM。此外，我们确定了一个100基因特征，可可靠地区分ALT样软骨肉瘤，为分类和预后提供了一个强大的分子标志物。
我们的研究揭示了ALT样状态是软骨肉瘤预后良好的标志物，这与它在其他肉瘤中通常的不良影响形成对比。我们建立了一个强大的100基因特征，可可靠地识别ALT样软骨肉瘤，并表征其独特的免疫微环境特征。
