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<p>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. <i>TP53</i> (48%), <i>TERT</i> promoter (36.5%), and <i>BRAF</i> (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 <i>TP53</i> and <i>BRAF</i> 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.</p>

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Integrative proteogenomic characterization reveals therapeutic targets in poorly differentiated and anaplastic thyroid cancers

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月16日

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  • 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

摘要

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.