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  3. Spatial Transcriptomics Reveals Transcriptomic and Immune Microenvironment Reprogramming during Thyroid Carcinoma Dedifferentiation

Spatial Transcriptomics Reveals Transcriptomic and Immune Microenvironment Reprogramming during Thyroid Carcinoma Dedifferentiation

  • Adv Sci (Weinh). 2025 Sep 4:e06925. doi: 10.1002/advs.202506925.
Kang Ning 1 2 3,  Bu Zou 1 2 3,  Yongchao Yu 1 2 3,  Taonong Cai 1 2 3,  Zhenyu Luo 1 2 3,  Yu Guo 2 4,  Yi Wu 5,  Xiujiao Shen 2 3 6,  Hao Li 7,  Mengyuan Fang 8,  Jian Bu 9,  Han Hong 9,  Zan Jiao 1 2 3,  Tong Wu 1 2 3,  Yulong Wang 10,  Tianrun Liu 2 4,  Weichao Chen 1 2 3,  Wanming Hu 2 3 6,  Mingjie Jiang 1 2 3,  Ankui Yang 1 2 3
Affiliations

Affiliations

  • 1 Department of Head and Neck Surgery, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
  • 2 State Key Laboratory of Oncology in Southern China, Guangzhou, 510060, China.
  • 3 Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.
  • 4 Department of Thyroid Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510220, China.
  • 5 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong, 510060, China.
  • 6 Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
  • 7 The Second Clinical College of Hainan Medical University, Haikou, 570216, China.
  • 8 Department of Ultrasound, Changsha Hospital for Maternal & Child Health Care Affiliated to Hunan Normal University, Changsha, 410007, China.
  • 9 Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510030, China.
  • 10 Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200003, China.
PMID: 40908584 DOI: 10.1002/advs.202506925
Abstract

Anaplastic thyroid carcinoma (ATC) is one of the most lethal human malignancies, often evolving from differentiated thyroid carcinoma (DTC) through a poorly understood dedifferentiation process. To elucidate this transition, spatial transcriptomic Sequencing (spRNAseq) is performed on seven samples containing coexisting regions of ATC, poorly differentiated thyroid carcinoma, and DTC. SpRNAseq revealed that ATC regions were characterized by upregulated genes involved in immune suppression, angiogenesis, and extracellular matrix remodeling. Whole-exome Sequencing and inferCNV analysis confirmed that adjacent DTC regions harbored mutational burdens comparable to those of ATC regions, suggesting early genomic priming for dedifferentiation. Trajectory analysis delineated a stepwise reprogramming process and identified four gene modules associated with the loss of thyroid differentiation, among which PDCD4 and TYMP emerged as key regulators. Notably, TYMP⁺ tumor-associated macrophages (TAMs) were highly enriched in ATC regions and contribute to an immunosuppressive microenvironment. Mechanistic experiments demonstrated that loss of PDCD4 led to eIF4A-dependent overexpression of immunosuppressive effectors, promoting the high infiltration of TYMP⁺TAMs in ATC. These findings support that coexisting DTC regions with ATC-like genomic alterations undergo sequential transcriptomic reprogramming and immune microenvironment remodeling to evolve into a full ATC pathological phenotype, in which PDCD4 loss-induced TAMs formation plays a critical role.

Keywords

M2 macrophage; PDCD4; anaplastic thyroid carcinoma; differentiated thyroid carcinoma; spatial transcriptomics.

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