Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Chronic Disease Laboratory, Institutes for Life Sciences, South China University of Technology, Guangzhou, China.
Clin Transl Med. 2024 Mar;14(3):e1594. doi: 10.1002/ctm2.1594.
Papillary thyroid carcinoma (PTC) is the most common malignant endocrine tumour, and its incidence and prevalence are increasing considerably. Cellular heterogeneity in the tumour microenvironment is important for PTC prognosis. Spatial transcriptomics is a powerful technique for cellular heterogeneity study.
In conjunction with a clinical pathologist identification method, spatial transcriptomics was employed to characterise the spatial location and RNA profiles of PTC-associated cells within the tissue sections. The spatial RNA-clinical signature genes for each cell type were extracted and applied to outlining the distribution regions of specific cells on the entire section. The cellular heterogeneity of each cell type was further revealed by ContourPlot analysis, monocle analysis, trajectory analysis, ligand-receptor analysis and Gene Ontology enrichment analysis.
The spatial distribution region of tumour cells, typical and atypical follicular cells (FCs and AFCs) and immune cells were accurately and comprehensively identified in all five PTC tissue sections. AFCs were identified as a transitional state between FCs and tumour cells, exhibiting a higher resemblance to the latter. Three tumour foci were shared among all patients out of the 13 observed. Notably, tumour foci No. 2 displayed elevated expression levels of genes associated with lower relapse-free survival in PTC patients. We discovered key ligand-receptor interactions, including LAMB3-ITGA2, FN1-ITGA3 and FN1-SDC4, involved in the transition of PTC cells from FCs to AFCs and eventually to tumour cells. High expression of these patterns correlated with reduced relapse-free survival. In the tumour immune microenvironment, reduced interaction between myeloid-derived TGFB1 and TGFBR1 in tumour focus No. 2 contributed to tumourigenesis and increased heterogeneity. The spatial RNA-clinical analysis method developed here revealed prognosis-associated cellular heterogeneity in the PTC microenvironment.
The occurrence of tumour foci No. 2 and three enhanced ligand-receptor interactions in the AFC area/tumour foci reduced the relapse-free survival of PTC patients, potentially leading to improved prognostic strategies and targeted therapies for PTC patients.
甲状腺乳头状癌（PTC）是最常见的恶性内分泌肿瘤，其发病率和患病率显著增加。肿瘤微环境中的细胞异质性对 PTC 的预后很重要。空间转录组学是研究细胞异质性的强大技术。
结合临床病理学家的鉴定方法，利用空间转录组学来描述组织切片中 PTC 相关细胞的空间位置和 RNA 谱。提取每个细胞类型的空间 RNA-临床特征基因，并应用于勾勒出整个切片上特定细胞的分布区域。通过 ContourPlot 分析、monocle 分析、轨迹分析、配体-受体分析和基因本体论富集分析，进一步揭示了每个细胞类型的细胞异质性。
在所有五例 PTC 组织切片中，准确全面地鉴定了肿瘤细胞、典型和非典型滤泡细胞（FCs 和 AFCs）和免疫细胞的空间分布区域。AFCs 被鉴定为 FCs 和肿瘤细胞之间的过渡状态，与后者更为相似。在观察到的 13 个肿瘤病灶中，有 3 个肿瘤病灶在所有患者中共享。值得注意的是，2 号肿瘤病灶显示出与 PTC 患者无复发生存率降低相关的基因表达水平升高。我们发现了关键的配体-受体相互作用，包括 LAMB3-ITGA2、FN1-ITGA3 和 FN1-SDC4，这些相互作用涉及 PTC 细胞从 FCs 向 AFCs 再向肿瘤细胞的转变。这些模式的高表达与无复发生存率降低相关。在肿瘤免疫微环境中，2 号肿瘤病灶中髓系衍生的 TGFB1 和 TGFBR1 之间的相互作用减少导致肿瘤发生和异质性增加。这里开发的空间 RNA-临床分析方法揭示了 PTC 微环境中与预后相关的细胞异质性。
2 号肿瘤病灶的发生和 AFC 区/肿瘤病灶中三个增强的配体-受体相互作用降低了 PTC 患者的无复发生存率，可能为 PTC 患者提供了改进的预后策略和靶向治疗。
