Journal Article

Single-Cell Transcriptome Analysis Reveals Inter-Tumor Heterogeneity in Bilateral Papillary Thyroid Carcinoma

Zhang, Hui, Li, Luchuan, Zhang, Xiaofang, Zhou, Xiaoming, Liu, Lian, Shi, Jinyuan, Sheng, Lei, Wang, Tiantian, Wang, Yong

2022

Overview

The tumor microenvironment (TME) plays a pivotal role in cancer progression in papillary thyroid carcinoma (PTC), yet the composition and the phenotype of cells within the TME in bilateral PTC are poorly understood. We performed unbiased transcriptome-wide single-cell RNA sequencing (scRNA-seq) analysis on 29,561 cells from 3 pairs of bilateral PTC and 1 non-tumor thyroid sample. The results of the analysis were validated by a large-scale bulk transcriptomic dataset deposited in The Cancer Genome Atlas (TCGA) database. Our integrative analysis of thyroid follicular cells revealed 42 signaling pathways enriched in malignant follicular cells, including cytokine-cytokine receptor interaction, PI3K/Akt signaling pathway, mitogen-activated protein kinase (MAPK) signaling pathway, and tumor necrosis factor (TNF) signaling pathway. A 6-gene signature ( , , , , , and ) in the cytokine-cytokine receptor interaction pathway was constructed to predict the prognosis of patients with PTC, with high risk scores being associated with decreased overall survival [hazard ratio (HR) = 3.863, 95% CI = 2.233-6.682, < 0.001]. Gene set variation analysis (GSVA) indicated that the pathways enriched in bilateral PTC were significantly different, indicating great heterogeneity in bilateral PTC, even with the same mutation. Comprehensive analysis of T cells revealed that the proportion of CD8 tissue-resident memory T cells expressing decreased in tumor samples with advanced N stage. Within the myeloid compartment, the ratio of suppressive M2-like to pro-inflammatory M1-like macrophages increased with advanced disease stage, which was confirmed in the bulk dataset using transcriptomic profiles. In addition, we also identified numerous biologically critical interactions among myeloid cells, T cells, and follicular cells, which were related to T-cell recruitment, M2-like macrophage polarization, malignant follicular cell progression, and T-cell inhibitory signaling. Our integrative analyses revealed great inter-tumor heterogeneity within the TME in bilateral PTC, which will offer assistance for precise diagnosis and treatment.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: 1-Phosphatidylinositol 3-kinase / AKT protein / Approximation / bilaterality / CD8 antigen / Cells / Cytokines / Cytokines - genetics / Gene expression / Gene Expression Profiling / Genomes / Genomics / Humans / immune dysfunction / Immunological memory / Immunology / Kinases / Ligands / Lymphocytes T / Macrophages / MAP kinase / Medical prognosis / Memory cells / Mutation / Myeloid cells / Papillary thyroid carcinoma / Patients / Phenotypes / Phosphatidylinositol 3-Kinases - metabolism / Receptors, Cytokine - genetics / scRNA-seq / Signal transduction / Single-Cell Analysis / Thyrocytes / Thyroid cancer / Thyroid Cancer, Papillary - metabolism / Thyroid Neoplasms - pathology / Transcriptome / Transcriptomes / Transcriptomics / Tumor microenvironment / Tumor Microenvironment - genetics