Integrative proteogenomic characterization reveals therapeutic targets in poorly differentiated and anaplastic thyroid cancers
Zongfu Pan, Zhuo Tan, Ning Xu, Zhenmei Yao, Chuanming Zheng, Jinbiao Shang, Lei Xie, Jiajie Xu, Jiafeng Wang, Liehao Jiang, Xuhang Zhu, Dingyi Yu, Ying Li, Yulu Che, Yingying Gong, Zhaoyu Qin, Yiwen Zhang, Xiaozhou Zou, Tong Xu, Zhenying Guo, Tiefeng Jin, Tiannan Guo, Wei Wang, Wanyuan Chen, Yaoting Sun, Weixin Wang, Xiaojun Peng, Changtian Yin, Chen Ding, Ping Huang, Minghua Ge
Abstract
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. The treatment of poorly differentiated thyroid cancer and anaplastic thyroid cancer remains challenging. Here, the authors perform multi-omic analysis of thyroid samples and identify proteomic clusters associated with distinct tumour microenvironment features.