Institute of Clinical Medicine, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China.
Department of Pharmacy, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China.
Neuro Oncol. 2024 Feb 2;26(2):295-308. doi: 10.1093/neuonc/noad173.
With cancer-associated fibroblasts (CAFs) as the main cell type, the rich myxoid stromal components in chordoma tissues may likely contribute to its development and progression.
Single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, bulk RNA-seq, and multiplexed quantitative immunofluorescence (QIF) were used to dissect the heterogeneity, spatial distribution, and clinical implication of CAFs in chordoma.
We sequenced here 72 097 single cells from 3 primary and 3 recurrent tumor samples, as well as 3 nucleus pulposus samples as controls using scRNA-seq. We identified a unique cluster of CAF in recurrent tumors that highly expressed hypoxic genes and was functionally enriched in endoplasmic reticulum stress (ERS). Pseudotime trajectory and cell communication analyses showed that this ERS-CAF subpopulation originated from normal fibroblasts and widely interacted with tumoral and immune cells. Analyzing the bulk RNA-seq data from 126 patients, we found that the ERS-CAF signature score was associated with the invasion and poor prognosis of chordoma. By integrating the results of scRNA-seq with spatial transcriptomics, we demonstrated the existence of ERS-CAF in chordoma tissues and revealed that this CAF subtype displayed the most proximity to its surrounding tumor cells. In subsequent QIF validation involving 105 additional patients, we confirmed that ERS-CAF was abundant in the chordoma microenvironment and located close to tumor cells. Furthermore, both ERS-CAF density and its distance to tumor cells were correlated with tumor malignant phenotype and adverse patient outcomes.
These findings depict the CAF landscape for chordoma and may provide insights into the development of novel treatment approaches.
软骨肉瘤组织中丰富的黏液样基质成分以癌相关成纤维细胞（CAFs）为主要细胞类型，可能有助于其发展和进展。
使用单细胞 RNA 测序（scRNA-seq）、空间转录组学、批量 RNA-seq 和多重定量免疫荧光（QIF）来剖析软骨肉瘤中 CAF 的异质性、空间分布和临床意义。
我们使用 scRNA-seq 对 3 个原发性和 3 个复发性肿瘤样本以及 3 个作为对照的髓核样本进行了测序，共获得了 72097 个单细胞。我们在复发性肿瘤中鉴定出一个独特的 CAF 簇，该簇高度表达低氧基因，并且在内质网应激（ERS）中具有功能富集。拟时轨迹和细胞通讯分析表明，这个 ERS-CAF 亚群起源于正常成纤维细胞，并与肿瘤和免疫细胞广泛相互作用。分析来自 126 名患者的批量 RNA-seq 数据，我们发现 ERS-CAF 特征评分与软骨肉瘤的侵袭和不良预后相关。通过将 scRNA-seq 的结果与空间转录组学相结合，我们证明了 ERS-CAF 存在于软骨肉瘤组织中，并揭示了这种 CAF 亚型与周围肿瘤细胞最为接近。在随后涉及 105 名额外患者的 QIF 验证中，我们证实 ERS-CAF 在软骨肉瘤微环境中丰富，并靠近肿瘤细胞。此外，ERS-CAF 的密度及其与肿瘤细胞的距离均与肿瘤恶性表型和不良患者结局相关。
这些发现描绘了软骨肉瘤的 CAF 图谱，并可能为开发新的治疗方法提供思路。
