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

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.

Transcriptomic Characteristics Associated With Aging in the Thyroid Gland

“…The aging-associated upregulation of fatty acid metabolism seen in this study may contribute to dysregulation of lipid metabolism in thyroid cancer ( 26 ). A recent single-cell RNA sequencing study confirmed a premalignant state, in which cancer-primed cells with aberrant expression programs have yet to undergo evident changes in cellular morphology ( 27 ). Hence, some caution in interpreting the results is warranted.…”

Single-Cell RNA Sequencing Revealed a 3-Gene Panel Predicted the Diagnosis and Prognosis of Thyroid Papillary Carcinoma and Associated With Tumor Immune Microenvironment

“…Single cell RNA sequencing data are extracted from the Gene Expression Omnibus (GEO) database (GSE184362) ( 11 ). The downstream analysis of scRNA-seq (namely, quality control, dimensionality reduction, clustering, differential expression analysis, etc.)…”

The Role of the Kinase Inhibitors in Thyroid Cancers

“…Single-cell transcriptome analyses depicted a more detailed genomic landscape of thyroid cancers, underlying PTC initiation and progression, identifying a premalignant thyrocyte subpopulation that evolves in different malignant states [ 23 ].…”

“…Mutation hierarchy in thyroid cancers is nicely evidenced by data generated for the most aggressive thyroid cancers, PDTC and ATC, carrying mutations in TERT promoter gene (42.3% in PTDC and 73.5% in ATC), suggesting that the initial BRAF+ve subpopulation is lost during the tumour progression and the TERT+ve cells have a positive growth selection over the others, becoming more aggressive [ 23 ].…”