Zhang Wenqian, Zhang Ye, Liu Zhu, Wang Zhiyuan, Wang Huaqin, Ji Xiaoyu, Su Hongyue, Yang Fan, Yan Lirong, Xu Ying, Zhang Hao, Sun Wei
Department of Head and Neck Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital, Shenyang, 110042, China.
The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, 110001, China.
Adv Sci (Weinh). 2025 Aug;12(30):e13474. doi: 10.1002/advs.202413474. Epub 2025 May 28.
The incidence of papillary thyroid carcinoma (PTC) has been rising annually, with papillary thyroid microcarcinoma (PTMC) accounting for more than half of the cases. While most PTMCs exhibit indolent growth and a favorable prognosis, some undergo clinical progression with poor outcomes. Thus, identifying biomarkers associated with PTC, particularly those related to PTMC progression, is crucial for precise risk stratification and treatment planning. This study utilized single-cell RNA sequencing on 19 surgical tissue specimens from 15 patients, including four para-tumor tissues, four non-progressive PTMCs, five progressive PTMCs, and six progressive PTCs. Key findings are corroborated through in vivo and in vitro experiments. Single-cell RNA sequencing and spatial transcriptomics characterized the cellular ecosystem within PTC, revealing multi-directional evolutionary patterns as PTMC progresses. Analysis of progression-specific alterations in intercellular communication networks highlighted the PROS1-MERTK signaling interaction as pivotal in PTMC progression. In vitro and in vivo models confirm that the PROS1-MERTK axis accelerates PTMC progression via paracrine and autocrine signaling. Furthermore, NFYB and FOXP2 are identified as activators of PROS1 transcription in fibroblasts, promoting PTMC progression through the MERTK/WNT/TGF-β signaling. These findings underscore the PROS1/MERTK axis as a critical component of the cellular microenvironment and a key regulatory mechanism in PTMC progression.
甲状腺乳头状癌（PTC）的发病率逐年上升，其中甲状腺微小乳头状癌（PTMC）占病例的一半以上。虽然大多数PTMC生长缓慢且预后良好，但有些会发生临床进展，预后较差。因此，识别与PTC相关的生物标志物，特别是那些与PTMC进展相关的生物标志物，对于精确的风险分层和治疗规划至关重要。本研究对15例患者的19个手术组织标本进行了单细胞RNA测序，包括4个肿瘤旁组织、4个非进展性PTMC、5个进展性PTMC和6个进展性PTC。关键发现通过体内和体外实验得到了证实。单细胞RNA测序和空间转录组学对PTC内的细胞生态系统进行了表征，揭示了PTMC进展过程中的多向进化模式。对细胞间通信网络中进展特异性改变的分析突出了PROS1-MERTK信号相互作用在PTMC进展中的关键作用。体外和体内模型证实，PROS1-MERTK轴通过旁分泌和自分泌信号加速PTMC进展。此外，NFYB和FOXP2被确定为成纤维细胞中PROS1转录的激活因子，通过MERTK/WNT/TGF-β信号促进PTMC进展。这些发现强调了PROS1/MERTK轴是细胞微环境的关键组成部分，也是PTMC进展中的关键调节机制。
