Integrative proteogenomic characterization reveals therapeutic targets in poorly differentiated and anaplastic thyroid cancers
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<sup>+</sup> 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.
Authors
- Tiannan Guo (ORCID: https://orcid.org/0000-0003-3869-7651)
- Changtian Yin
- Wanyuan Chen (ORCID: https://orcid.org/0000-0002-8216-9568)
- Minghua Ge (ORCID: https://orcid.org/0000-0001-6726-6418)
- Lei Xie (ORCID: https://orcid.org/0000-0002-5751-7532)
- Zongfu Pan (ORCID: https://orcid.org/0000-0002-4054-6660)
- Zhenmei Yao
- Yulu Che (ORCID: https://orcid.org/0000-0001-7252-1508)
- Liehao Jiang
- Ping Huang (ORCID: https://orcid.org/0000-0003-1775-029X)
- Dingyi Yu
- Zhaoyu Qin (ORCID: https://orcid.org/0000-0003-4437-0268)
- Tiefeng Jin (ORCID: https://orcid.org/0000-0001-8957-696X)
- Jiafeng Wang (ORCID: https://orcid.org/0000-0002-1753-6499)
- Ning Xu (ORCID: https://orcid.org/0000-0001-7909-7025)
- Yingying Gong (ORCID: https://orcid.org/0000-0001-7965-2236)
- Chuanming Zheng
- Yaoting Sun (ORCID: https://orcid.org/0000-0001-7613-648X)
- Wei Qiang Wang (ORCID: https://orcid.org/0000-0002-1430-1360)
- Ying Li (ORCID: https://orcid.org/0000-0001-6664-0084)
- Jinbiao Shang (ORCID: https://orcid.org/0009-0004-2169-1020)
- Chen Ding (ORCID: https://orcid.org/0000-0001-8673-3464)
- Jiajie Xu
- Tong Xu (ORCID: https://orcid.org/0000-0002-7046-5917)
- Xuhang Zhu
- Xiaojun Peng
- Xiaozhou Zou
- Zhenying Guo
- Weixin Wang (ORCID: https://orcid.org/0000-0003-2807-3298)
- Zhuo Tan
- Yiwen Zhang (ORCID: https://orcid.org/0000-0003-1711-6870)
Institutions
- Fudan University (CN)
- Sir Run Run Shaw Hospital (CN)
- Westlake University (CN)
- Zhejiang Cancer Hospital (CN)
- Wisdom Health (United States) (US)
- Pudong Medical Center (CN)
- Zhejiang Provincial People's Hospital (CN)
- Hangzhou Medical College (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-16
- DOI
- https://doi.org/10.1038/s41467-025-58910-3
- Citations
- 18
- Primary Topic
- Thyroid Cancer Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 23.31
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Fudan University
- Chinese Pharmaceutical Association
- Zhejiang Medical Association