Single-cell transcriptomic analysis of the tumor ecosystems underlying initiation and progression of papillary thyroid carcinoma.

Wenjun Wei, Yu-Long Wang, Xiaoming Zhang, Jiucun Wang, Qinghai Ji, Huajun Li, Zaili Luo, Xiaohua Hu, Jiaqian Hu, Ning Qu, Zhongwu Lu, Weilin Pu, Hualei Gan, Dongmei Ji, Yu Wang, Peizhen Han, Licheng Tan, Zhiyan Liu, Meiying Zhang, Pengcheng Yu, Xiao Shi

Journal: Nature communications 2021;12(1):6058

PMID: 34663816

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Abstract

The tumor ecosystem of papillary thyroid carcinoma (PTC) is poorly characterized. Using single-cell RNA sequencing, we profile transcriptomes of 158,577 cells from 11 patients' paratumors, localized/advanced tumors, initially-treated/recurrent lymph nodes and radioactive iodine (RAI)-refractory distant metastases, covering comprehensive clinical courses of PTC. Our data identifies a "cancer-primed" premalignant thyrocyte population with normal morphology but altered transcriptomes. Along the developmental trajectory, we also discover three phenotypes of malignant thyrocytes (follicular-like, partial-epithelial-mesenchymal-transition-like, dedifferentiation-like), whose composition shapes bulk molecular subtypes, tumor characteristics and RAI responses. Furthermore, we uncover a distinct BRAF-like-B subtype with predominant dedifferentiation-like thyrocytes, enriched cancer-associated fibroblasts, worse prognosis and promising prospect of immunotherapy. Moreover, potential vascular-immune crosstalk in PTC provides theoretical basis for combined anti-angiogenic and immunotherapy. Together, our findings provide insight into the PTC ecosystem that suggests potential prognostic and therapeutic implications.

Address: Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.; State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, 200438, China.; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.; The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China.; Department of Pathology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.; Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.; Phase I Clinical Trial Center, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.; Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.; Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.; Department of Clinical Research & Development, Jiangsu Hengrui Pharmaceuticals Co., Ltd., Shanghai, 201210, China.; Human Phenome Institute, Fudan University, Shanghai, 200438, China.; The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China. [email protected].; Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. [email protected].; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. [email protected].

DOI: 10.1038/s41467-021-26343-3

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Medical:

https://medlineplus.gov/thyroidcancer.html

Molecular Biology Databases:

https://data.niaid.nih.gov/resources?id=gse184362

Research Materials:

https://antibodies.cancer.gov/detail/CPTC-BRAF-6

MeSH Terms: Adolescent, Carcinoma, Ecosystem, Gene Expression Regulation, Neoplastic, Humans, Iodine Radioisotopes, Lymph Nodes, Male, Single-Cell Analysis, Thyroid Cancer, Papillary, Thyroid Epithelial Cells, Thyroid Neoplasms, Transcriptome