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 () and Minghua Ge ()
Additional contact information
Zongfu Pan: Hangzhou Medical College
Zhuo Tan: Hangzhou Medical College
Ning Xu: Fudan University
Zhenmei Yao: Fudan University
Chuanming Zheng: Hangzhou Medical College
Jinbiao Shang: Zhejiang Cancer Hospital
Lei Xie: Zhejiang University School of Medicine
Jiajie Xu: Hangzhou Medical College
Jiafeng Wang: Hangzhou Medical College
Liehao Jiang: Hangzhou Medical College
Xuhang Zhu: Zhejiang Cancer Hospital
Dingyi Yu: Hangzhou Medical College
Ying Li: Hangzhou Medical College
Yulu Che: Hangzhou Medical College
Yingying Gong: Hangzhou Medical College
Zhaoyu Qin: Fudan University
Yiwen Zhang: Hangzhou Medical College
Xiaozhou Zou: Hangzhou Medical College
Tong Xu: Hangzhou Medical College
Zhenying Guo: Hangzhou Medical College
Tiefeng Jin: Hangzhou Medical College
Tiannan Guo: Westlake University
Wei Wang: Hangzhou Medical College
Wanyuan Chen: Hangzhou Medical College
Yaoting Sun: Westlake University
Weixin Wang: Hangzhou Cosmos Wisdom Biotechnology Co. Ltd
Xiaojun Peng: Hangzhou Cosmos Wisdom Biotechnology Co. Ltd
Changtian Yin: Hangzhou Medical College
Chen Ding: Fudan University
Ping Huang: Hangzhou Medical College
Minghua Ge: Hangzhou Medical College

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58910-3

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