Pan Zongfu, Tan Zhuo, Xu Ning, Yao Zhenmei, Zheng Chuanming, Shang Jinbiao, Xie Lei, Xu Jiajie, Wang Jiafeng, Jiang Liehao, Zhu Xuhang, Yu Dingyi, Li Ying, Che Yulu, Gong Yingying, Qin Zhaoyu, Zhang Yiwen, Zou Xiaozhou, Xu Tong, Guo Zhenying, Jin Tiefeng, Guo Tiannan, Wang Wei, Chen Wanyuan, Sun Yaoting, Wang Weixin, Peng Xiaojun, Yin Changtian, Ding Chen, Huang Ping, Ge Minghua
Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, China.
Otolaryngology & Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, China.
Nat Commun. 2025 Apr 16;16(1):3601. doi: 10.1038/s41467-025-58910-3.
Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) present major challenges in treatment owing to extreme aggressiveness and high heterogeneity. In this study, deep-scale analyses spanning genomic, proteomic, and phosphoproteomic data are performed on 348 thyroid-cancer and 119 tumor-adjacent samples. TP53 (48%), TERT promoter (36.5%), and BRAF (23%) are most frequently mutated in PDTC and ATC. Ribosome biogenesis is identified as a common hallmark of ATC, and RRP9 silencing dramatically inhibits tumor growth. Proteomic clustering identified three ATC/PDTC subtypes. Pro-I subtype is characterized with aberrant insulin signaling and low immune cell infiltration, and Pro-II is featured with DNA repair signaling, while Pro-III harbors high frequency of TP53 and BRAF mutation and intensive C5AR1 myeloid infiltration. Targeting C5AR1 synergistically improves antitumor effect of PD-1 blockade against ATC cell-derived tumors. These findings provide systematic insights into tumor biology and opportunities for drug discovery, accelerating precision therapy for virulent thyroid cancers.
低分化甲状腺癌（PDTC）和未分化甲状腺癌（ATC）因其极度侵袭性和高度异质性，在治疗上面临重大挑战。在本研究中，对348例甲状腺癌样本和119例肿瘤邻近样本进行了涵盖基因组、蛋白质组和磷酸蛋白质组数据的深度分析。TP53（48%）、端粒酶逆转录酶（TERT）启动子（36.5%）和BRAF（23%）在PDTC和ATC中最常发生突变。核糖体生物合成被确定为ATC的一个共同特征，RRP9沉默可显著抑制肿瘤生长。蛋白质组聚类识别出三种ATC/PDTC亚型。Pro-I亚型的特征是胰岛素信号异常和免疫细胞浸润低，Pro-II亚型的特征是DNA修复信号，而Pro-III亚型则具有高频的TP53和BRAF突变以及强烈的C5AR1髓系浸润。靶向C5AR1可协同提高PD-1阻断对ATC细胞衍生肿瘤的抗肿瘤效果。这些发现为肿瘤生物学提供了系统见解，并为药物发现提供了机会，加速了对恶性甲状腺癌的精准治疗。
