Single-cell transcriptomic analysis of the tumor ecosystems underlying initiation and progression of papillary thyroid carcinoma.
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ABSTRACT:
SUBMITTER: Pu W
PROVIDER: S-EPMC8523550 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background Despite extensive research, the papillary thyroid carcinoma (PTC) ecosystem is poorly characterized and, in particular, locoregional progression. Available evidence supports that single-cell transcriptome sequencing (Sc-RNA seq) can dissect tumor ecosystems. Methods Tissue samples from one PTC patient, including matched primary tumor (Ca), lymph node (LN) metastasis, and paracancerous tissue (PCa), were subjected to Sc-RNA seq with 10×Genomics. Dual-label immunofluorescence and immunohistochemistry were used to confirm the existence of cell subtypes in a separate cohort. Results 11,805 cell transcriptomes were profiled, cell landscapes of PTC were composed of malignant follicular epithelial cells (MFECs), CD8+ and CD4+ T cells, B cells, vascular endothelial cells, fibroblasts and cancer-associated fibroblasts (CAFs). Between Ca and LN ecosystems, the proportions of MFEC and interstitial cells were similar, less than 1/25(229/6,694, 361/3,895), while the proportion of normal follicular epithelial cells (NFECs) and interstitial cells was > 2 in PCa (455/171). NFECs in PCa formed a separate cluster, while MFECs in Ca and LN exhibited a profound transcriptional overlap, and the interstitial cells among these samples had an overall concordance in their identity and representation, albeit with some distinctions in terms of the cell percentage per subset. A fraction of the B cell subpopulation in Ca expressed inhibitory receptors, while their respective ligand genes were clearly transcribed in T cell and malignant epithelial cell clusters, while some CD8+ T cells in both Ca and LN produced high levels of inhibitory receptors whose respective ligands were overexpressed in some CD4+ T cells. Three CAF subtypes in Ca and LN were identified, which may be due to mutual transitions. Conclusions Our data provide new insights into the PTC ecosystem and highlight the differences in ecosystems in PTC progression, which updates our understanding of PTC biology and will improve individualized patient treatment.
| S-EPMC8591202 | biostudies-literature
Project description:The tumor ecosystem of papillary thyroid carcinoma (PTC) is poorly characterized. Using single-cell RNA sequencing, we profiled 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 study illuminates a comprehensive landscape of PTC ecosystem that suggests potential prognostic and therapeutic implications. Our work not only adds dimensions to the biological underpinnings of PTC heterogeneity, but also provides a benchmark dataset for this malignancy.
2021-09-19 | GSE184362 | GEO
Project description:Single-cell sequencing of tumor ecosystems in papillary thyroid carcinoma
| PRJNA764217 | ENA
Project description:Background: Tumor-associated calcium signal transducer 2 (TROP2) is over expressed in various kinds of human cancers and plays important roles in the proliferation, invasion and metastasis of tumor cells. However, the expression and molecular mechanism of TROP2 in thyroid papillary carcinoma (PTC) are unclear. Methods: The expressions of TROP2 in PTC and control tissue were detected by real-time reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. The proliferation and invasion of PTC cell lines were examined by cell cloning and transwell assays. RNA sequencing analysis and public data analysis were assessed to investigate the potential mechanisms of TROP2 in PTC. Gene correlation analysis was conducted to explore the association between TROP2 and the related gene ISG15 in patients with PTC. Results: The expression of TROP2 was significantly higher in PTC than control. The high expression of TROP2 protein was associated with lymph node metastasis, tumor size and capsular infiltration (P<0.05). SiRNA-mediated TROP2 gene expression silencing can significantly inhibit proliferation and migration of PTC cells. ISG15 decreased in TROP2 siRNA PTC cells and increased in PTC patients significantly. There was a significant correlation between the expression of TROP2 and ISG15 in PTC patients. TROP2 interacted directly with ATP6V1A, CEBPA and SOX5 and then further interacted with the immune genes. TROP2 expression and tumor-infiltrating immune cells were also correlated in thyroid cancer microenvironment. Conclusions: TROP2 promotes the development of PTC. TROP2 expression was correlated with ISG15 and tumor-infiltrating immune cells in thyroid cancer.
| S-EPMC8518010 | biostudies-literature
Project description:The signaling pathway involving the R-spondins and its cognate receptor, GPR48/LGR4, is crucial in development and carcinogenesis. However, the functional implications of the R-spondin-GPR48/LGR4 pathway in thyroid remain to be identified. The aim of this study was to investigate the role of R-spondin-GPR48/LGR4 signaling in papillary thyroid carcinomas. We retrospectively reviewed a total of 214 patients who underwent total thyroidectomy and cervical lymph node dissection for papillary thyroid carcinoma. The role of GPR48/LGR4 in proliferation and migration was examined in thyroid cancer cell lines. R-spondin 2, and GPR48/LGR4 were expressed at significantly higher levels in thyroid cancer than in normal controls. Elevated GPR48/LGR4 expression was significantly associated with tumor size (P=0.049), lymph node metastasis (P=0.004), recurrence (P=0.037), and the BRAFV600E mutation (P=0.003). Moreover, high GPR48/LGR4 expression was an independent risk factor for lymph node metastasis (P=0.027) and the BRAFV600E mutation (P=0.009). in vitro assays demonstrated that elevated expression of GPR48/LGR4 promoted proliferation and migration of thyroid cancer cells, whereas downregulation of GPR48/LGR4 decreased proliferation and migration by inhibition of the β-catenin pathway. Moreover, treatment of thyroid cancer cells with exogenous R-spondin 2 induced activation of the β-catenin pathway through GPR48/LGR4. The R-spondin 2-GPR48/LGR4 signaling axis also induced the phosphorylation of ERK, as well as phosphorylation of LRP6 and serine 9 of GSK3β. Our findings demonstrate that upregulation of the R-spondin 2-GPR48/LGR4 pathway contributes to tumor aggressiveness in papillary thyroid carcinoma by promoting ERK phosphorylation, suggesting that this pathway represents a novel therapeutic target for treatment of differentiated thyroid cancer.
| S-EPMC5777747 | biostudies-literature
Project description:Papillary thyroid carcinoma (PTC) is the fastest-growing disease caused by numerous molecular alterations in addition to previously reported DNA mutations. There is a compelling need to identify novel transcriptomic alterations that are associated with the pathogenesis of PTC with potential diagnostic and prognostic implications. Methods: We gathered and compared 242 expression profiles between paired PTC and adjacent normal tissues and identified and validated the coding and long non-coding RNAs (lncRNAs) associated with the extrathyroidal extension (ETE) of 655 PTC patients in two independent cohorts, followed by predicting their interactions with drugs. Co-expression, RNA interaction, Kaplan-Meier survival and multivariate Cox proportional regression analyses were performed to identify dysregulated lncRNAs and genes that correlated with clinical outcomes of PTC. Alternative splicing (AS), RNA circularization, and editing were also compared between transcriptomes to expand the repertoire of molecular alterations in PTC. Results: Numerous genes related to cellular microenvironment and steroid hormone response were associated with the ETE of PTC. Drug susceptibility predictions of the expression signature revealed two highly ranked compounds, 6-bromoindirubin-3'-oxime and lovastatin. Co-expression and RNA interaction analysis revealed the essential role of lncRNAs in PTC pathogenesis by modulating extracellular matrix and cell adhesion. Eight genes and two novel lncRNAs were identified that correlated with the aggressive nature and disease-free survival of PTC. Furthermore, this study provided the transcriptome-wide landscape of circRNAs in PTC and uncovered dissimilar expression profiles among circRNAs originating from the same host gene, suggesting the functional complexity of circRNAs in PTC carcinogenesis. The newly identified AS events in the SERPINA1 and FN1 genes may improve the sensitivity and specificity of these diagnostic biomarkers. Conclusions: Our study uncovered a comprehensive transcriptomic signature associated with the carcinogenesis and aggressive behavior of PTC, as well as presents a catalog of 10 potential biomarkers, which would facilitate PTC prognosis and development of new therapeutic strategies for this cancer.
| S-EPMC6134936 | biostudies-literature
Project description:Lymph node metastasis, the leading cause of mortality in esophageal squamous carcinoma (ESCC) with a highly complex tumor microenvironment, remains underexplored. Here, the transcriptomes of 85 263 single cells are analyzed from four ESCC patients with lymph node metastases. Strikingly, it is observed that the metastatic microenvironment undergoes the emergence or expansion of interferon induced IFIT3+ T, B cells, and immunosuppressive cells such as APOC1+ APOE+ macrophages and myofibroblasts with highly expression of immunoglobulin genes (IGKC) and extracellular matrix component and matrix metallopeptidase genes. A poor-prognostic epithelial-immune dual expression program regulating immune effector processes, whose activity is significantly enhanced in metastatic malignant epithelial cells and enriched in CD74+ CXCR4+ and major histocompatibility complex (MHC) class II genes upregulated malignant epithelia cells is discovered. Comparing with primary tumor, differential intercellular communications of metastatic ESCC microenvironment are revealed and furtherly validated via multiplexed immunofluorescence and immunohistochemistry staining, which mainly rely on the crosstalk of APOC1+ APOE+ macrophages with tumor and stromal cell. The data highlight potential molecular mechanisms that shape the lymph-node metastatic microenvironment and may inform drug discovery and the development of new strategies to target these prometastatic nontumor components for inhibiting tumor growth and overcoming metastasis to improve clinical outcomes.
| S-EPMC9982558 | biostudies-literature
Project description:CD73 is involved in tumor immune escape and promotes the growth and progression of cancer cells. The functional role of CD73 expression in papillary thyroid carcinoma (PTC) has not yet been established. In 511 patients with PTC, immunohistochemistry for CD73 on tissue microarrays showed that the high expression of CD73 was associated with an aggressive histologic variant (p = 0.002), extrathyroidal extension (p < 0.001), lymph node metastasis (p < 0.001), and BRAFV600E mutation (p = 0.015). Survival analysis results showed that patients with high CD73 expression had worse recurrence-free survival (p = 0.023). CD73 inhibitors induced G1 cell cycle arrest and apoptosis, inhibited the migration and invasion of PTC cells, and suppressed tumor growth in PTC xenograft nude mice. High expression of CD73 (NT5E) mRNA was associated with unfavorable clinicopathologic characteristics, the abundance of Tregs and dendritic cells, depletion of natural killer (NK) cells, and high expression of immune checkpoint genes and epithelial-to-mesenchymal transition-related genes in The Cancer Genome Atlas (TCGA) dataset. Taken together, CD73 expression promotes tumor progression and predicts low recurrence-free survival. Targeting the CD73-adenosine axis in the tumor microenvironment offers an attractive pathway for therapeutic strategies aimed at advanced PTC.
| S-EPMC7603384 | biostudies-literature
Project description:The prevalence of thyroid carcinoma is increasing and represents the most common endocrine malignancy, with papillary thyroid carcinoma (PTC) being the most frequent subtype. The genetic alterations identified in PTCs fail to distinguish tumors with different clinical behaviors, such as extra-thyroidal extension and lymph node metastasis. We hypothesize that the immune microenvironment may play a critical role in tumor invasion and metastasis. Computational immunogenomic analysis was performed on 568 PTC samples in The Cancer Genome Atlas using CIBERSORT, TIMER and TIDE deconvolution analytic tools for characterizing immune cell composition. Immune cell infiltrates were correlated with histologic type, mutational type, tumor pathologic T stage and lymph node N stage. Dendritic cells (DCs) are highly associated with more locally advanced tumor T stage (T3/T4, odds ratio (OR) = 2.6, CI = 1.4-4.5, P = 5.4 × 10-4). Increased dendritic cells (OR = 3.4, CI = 1.9-6.3, P = 5.5 × 10-5) and neutrophils (OR = 10.5, CI = 2.7-44, P = 8.7 × 10-4) significantly correlate with lymph node metastasis. In addition, dendritic cells positively correlate with tall cell morphology (OR = 4.5, CI = 1.6-13, P = 4.9 × 10-3) and neutrophils negatively correlate with follicular morphology (OR = 1.3 × 10-3, CI = 5.3 × 10-5-0.031, P = 4.1 × 10-5). TIDE analysis indicates an immune-exclusive phenotype that may be mediated by increased galectin-3 found in PTCs. Thus, characterization of the PTC immune microenvironment using three computational platforms shows that specific immune cells correlate with mutational type, histologic type, local tumor extent and lymph node metastasis. Immunologic evaluation of PTCs may provide a better indication of biologic behavior, resulting in the improved diagnosis and treatment of thyroid cancer.
| S-EPMC8279427 | biostudies-literature
Project description:Background:Papillary thyroid carcinoma (PTC) is one of the most frequent malignancies of the endocrine system, whose mechanisms of pathogenesis, progression and prognosis are still far from being clearly elucidated. Despite an increasing body of evidences highlights ribosome biogenesis regulator homolog (RRS1) as a ribosome biogenesis protein in yeast and plants, little is known about human RRS1 function. Methods:Proliferation, cell cycle and apoptosis of PTC cells were assessed following the knockdown of RRS1 expression though MTT, colony formation assay, and flow cytometry. Then, transcriptome profiling was conducted to explore pathway changes after RRS1 silencing in PTC cells. Receiver operating characteristic curve and Youden's index were performed in twenty-four thyroid carcinoma samples to assess their potential clinical diagnostic value. Results:Firstly, we found that silencing RRS1 significantly reduced cell proliferation, inhibited cell cycle, and promoted apoptosis in PTC cell line. The result also showed that knock-down of RRS1 could up-regulate genes involving apoptosis and metabolism, while, down-regulate genes relative to cell proliferation and blood vessel development. Notably, the present study confirmed the diagnostic value of RRS1 for thyroid carcinoma in both children and adults. Conclusions:In conclusion, these data afford a comprehensive view of a novel function of human RRS1 by promoting cell proliferation and could be a potential indicator for papillary thyroid carcinoma.
| S-EPMC5812111 | biostudies-literature