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Dissecting esophageal squamous-cell carcinoma ecosystem by single-cell transcriptomic analysis

ABSTRACT: Esophageal squamous-cell carcinoma (ESCC), one of the most prevalent and lethal malignant disease, has a complex but unknown tumor ecosystem. Here, we decipher for the first time the full compositions of ESCC tumor based on analyzing 208,659 single-cell transcriptomes in ESCC derived from 60 individuals. We identify 8 essential expression programs from malignant epithelial cells and discovered 43 cell types including 26 immune cell and 17 nonimmune stromal cell subtypes in the tumor microenvironment (TME), and also explicate the interactions between cancer cells and other cells and the interactions among different cell types in the TME. Moreover, we have linked the cancer cell transcriptomes to the somatic mutations and identified several markers significantly associated with survival time in patients, which may be relevant to precision cares of ESCC patients. These results renew our understanding of ESCC and provide a valuable example and resource for investigating other types of solid tumor.

ORGANISM(S): Homo sapiens

PROVIDER: GSE160269 | GEO | 2020/10/29

REPOSITORIES: GEO

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Dissecting esophageal squamous-cell carcinoma ecosystem by single-cell transcriptomic analysis

Project description:Esophageal squamous-cell carcinoma (ESCC), one of the most prevalent and lethal malignant disease, has a complex but unknown tumor ecosystem. Here, we decipher for the first time the full compositions of ESCC tumor based on analyzing 208,659 single-cell transcriptomes in ESCC derived from 60 individuals. We identify 8 essential expression programs from malignant epithelial cells and discovered 43 cell types including 26 immune cell and 17 nonimmune stromal cell subtypes in the tumor microenvironment (TME), and also explicate the interactions between cancer cells and other cells and the interactions among different cell types in the TME. Moreover, we have linked the cancer cell transcriptomes to the somatic mutations and identified several markers significantly associated with survival time in patients, which may be relevant to precision cares of ESCC patients. These results renew our understanding of ESCC and provide a valuable example and resource for investigating other types of solid tumor.

2020-11-03 | PRJEB41091 | EVA

Mesothelioma-associated fibroblasts enhance proliferation and migration of malignant pleural mesothelioma cells via Met/PI3K and WNT signaling but do not protect against cisplatin

Project description:Malignant pleural mesothelioma (MPM) is an aggressive malignancy with poor prognosis. Unlike many other cancers, MPM is mostly characterized by inactivation of tumor suppressor genes. Its highly malignant nature in absence of tumor driving oncogene mutations indicates an extrinsic supply of stimulating signals by cells of the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are an abundant cell type of the TME and have been shown to drive the progression of several cancer types. The aim of the current study was to isolate and characterize patient-derived mesothelioma-associated fibroblasts (Meso-CAFs), and evaluate their impact on MPM cells.

2022-12-31 | E-MTAB-12179 | biostudies-arrayexpress

Profiling transcriptional heterogeneity of epithelium, fibroblasts and immune cells in esophageal squamous cell carcinoma by single-cell RNA sequencing

Project description:We generated single-cell RNA sequencing (scRNA-seq) of 25,796 immune and 8,197 non-immune cells from three primary tumor and paired normal samples in ESCC patients. The results revealed that transcriptional signatures of malignant epithelium could be effectively distinguished from that of non-malignant epithelium by scRNA-seq data. The infiltration of myofibroblasts, one subtype of fibroblasts, might play important roles in the progression of ESCC. Diverse cell subtypes of T cells and myeloid cells were identified, including tumor-enriched HAVCR2+ CD4+ T cells with significantly exhausted signature. We also found that epithelium and myeloid cells had more frequent cell-cell communication compared with epithelium and T cells. Taken together, this study provided in-depth insights into the cellular heterogeneity of TME in ESCC and highlighted potential therapeutic targets including for immunotherapy.

2023-02-14 | GSE196756 | GEO

Single cell RNA-sequence reveals the effect of neoadjuvant chemotherapy on immune cells in human esophageal squamous cell carcinoma.

Project description:In this study, we comprehensively investigated the impact of neoadjuvant chemotherapy (NAC) on immune cells in the tumor microenvironment (TME) of esophageal squamous cell carcinoma (ESCC) using single cell RNA sequence. CD8+ T cells, CD4+ T cells, dendritic cells, and macrophages in TME of ESCC all showed higher levels of anti-tumor immune response in the NAC(+) group than in the NAC(-) group. Furthermore, the immune cells in the TME of the NAC(+) group interacted with each other to enhance the anti-tumor immune response. Our results suggest that NAC potentially enhance the anti-tumor immune response of immune cells in the TME.

2023-03-31 | GSE197677 | GEO

A Single-Cell Atlas of the Multicellular Ecosystem of Primary and Metastatic Hepatocellular Carcinoma

Project description:Hepatocellular carcinoma (HCC) represents a paradigm of the relation between tumor microenvironment and tumor development. Here, we generated > 70,000 single-cell transcriptomes for 10 HCC patients from four relevant sites: primary tumor, portal vein tumor thrombus (PVTT), metastatic lymph node and non-tumor liver. We discovered a cluster of antitumor central memory T cells enriched in intratumoral tertiary lymphoid structures (TLSs) of HCC. We found chronic HBV/HCV infection increases the infiltration of CD8+ T cells in tumors but aggravates the exhaustion of tumor-infiltrating lymphocytes. We identified MMP9+ macrophages to be terminally differentiated tumor-associated macrophages (TAMs) and two distinct differentiation trajectories are related to their accumulation. We further demonstrated MMP9+ TAMs can promote HCC cells migration, invasion and angiogenesis. Our data also revealed the heterogeneous population of malignant hepatocytes and found they might play multifaceted roles in shaping the immune microenvironment of HCC. Finally, we identified seven TME subtypes of HCC that can predict patient prognosis. Collectively, this large-scale, single-cell atlas deepens our understanding of the ecosystem in primary and metastatic HCCs, might facilitating identification of new immune therapy strategies for this malignancy.

2020-04-30 | GSE149614 | GEO

Single-cell dissection of the multicellular ecosystem and molecular feature sunderlying microvascular invasion in hepatocellular carcinoma

Project description:Microvascular invasion (MVI) is a significant pathological feature of hepatocellular carcinoma (HCC) associated with poor outcomes, early recurrence, and intrahepatic metastasis in post-surgical resection and transplant patients. However, the tumor microenvironment (TME) and transcriptional programs underlying MVI remain poorly understood. In this study, we conducted single-cell RNA sequencing of 46,789 individual cells from 10 samples of MVI+ (MVI present) and MVI- (MVI absent) HCC patients, providing a comprehensive single-cell atlas of MVI. Single-cell dissection of the multicellular ecosystem revealed the emergence or expansion of cycling T cells, LAMP3+ dendritic cells, TREM2+ macrophages, myofibroblasts, and tumor-promoting arterial i endothelial cells within the MVI+ TME. MVI+ malignant cells are characterized by high proliferation rates and the ability to evade immune detection through the upregulation of non-classical MHC class I molecules. In contrast, MVI-malignant cells exhibit an inflammatory milieu. Furthermore, we identified the CCL16/CCR1 interaction between TREM2+ macrophages and malignant cells as a contributing factor in MVI formation and tumor progression. Notably, we identified a unique multicellular module that plays the dominant role in shaping the immunosuppressive microenvironment of MVI and correlates with poor prognosis. In summary, these findings enhance our understanding of the underlying cellular and molecular mechanisms driving MVI and provide valuable insights for improving clinical diagnosis and developing more effective treatment strategies.

2023-09-12 | GSE242889 | GEO

Immune suppressive landscape in a human esophageal squamous cell carcinoma microenvironment

Project description:Properly applying current immunotherapies or developing novel therapeutic strategies relies on a comprehensive understanding of the immune elements of the tumor microenvironment (TME). In this study, we aim to map at single-cell resolution the immune landscape of esophagus squamous cell carcinoma (ESCC), a common, aggressive, but understudied cancer of the gastrointestinal tract. We obtained a detailed immune cell atlas of the ESCC-associated transcriptome from a total of 80,787 tumor-infiltrating immune cells. Significant intertumoral heterogeneity was found among individual ESSC tumors. Exhausted T cells, exhausted NK cells, regulatory T cells, alternatively activated macrophages, and tolerogenic dendritic cells were discovered as the dominant portions of the immune cells in the TME. Dysfunctional T cells were the major proliferative cell compartment among tumor-infiltrating immune cells. In addition, strong potential interactions of immune cells in tumors may contribute to the immunosuppressive status and the progress of tumor development; a six-gene signature, comprising IFNGR1, IFNGR2, IDO1, IL10, CD163, and CD274, were associated with ESCC survival. Our results provided a comprehensive characterization of tumor-infiltrating immune cells in ESCC, indicating that immunosuppression of various kinds was synchronously responsible for the failure of immunosurveillance in ESCC. Specifically targeting the immunosuppressive pathways could reverse the immune-suppressive status and reactivate anti-tumor immune responses in ESCC.

2020-10-19 | GSE145370 | GEO

Bone marrow-derived multipotent mesenchymal stromal cells promote tongue cancer invasion by inducing collagen production

Project description:Tumor microenvironment (TME) is an active player in malignant growth and spread. Changes in the composition and structure of TME and extracellular matrix can result in either suppression or facilitation of malignant tumor growth. Carcinoma‐associated fibroblasts, bone marrow-derived multipotent mesenchymal stromal cells (BMMSCs), tumor associated macrophages and other inflammatory cells all affect the composition of TME, proliferation and survival of cancer cells, angiogenesis, invasion and metastasis. The objective of this work was to investigate the effect of the interaction between bone marrow-derived BMMSCs and human oral tongue squamous cell carcinoma (OTSCC) cells in the processes of invasion and gene expression. Co-cultures of OTSCC cancer cells and BMMSCs in 3D organotypic invasion assay were used in addition to cell culture, immunological, microarray, and RNA interference techniques. Total number of 4 samples were analyzed. 2 replicates of cultured human oral tongue squamous cell carcinoma (OTSCC) cells, and 2 replicates of OTSCC cells co-cultured with bone marrow-derived multipotent mesenchymal stromal cells

2013-12-01 | E-GEOD-44458 | biostudies-arrayexpress

Comprehensive Landscape of Resistance Mechanisms for Neoadjuvant Therapy in Esophageal Squamous Cell Carcinoma by single-cell Transcriptomics

Project description:Neoadjuvant therapy has been shown to improve survival for locally advanced esophageal squamous cell carcinoma (ESCC). However, some cases may acquire therapy resistance and the mechanism is still unclear. Here, we applied single-cell RNA sequencing on 7 ESCC patients with neoadjuvant therapy and 2 ESCC patients underwent general surgery alone to delineate the tumor heterogeneity, tumor microenvironment (TME) and potential hallmarks of therapy resistance. In total, 13 tumor cell lineages and its corresponding lineage-specific gene signatures, pathway activities, and transcription factors were identified, representing different mechanisms and hallmarks of neoadjuvant therapy resistance, such as oxidative stress response, hypoxia, DNA repair, ECM and EMT. Typically, tumor cell lineage Ep-C2 with signatures of oxidative stress response showed the strongest resistance to neoadjuvant therapy, particularly under chemoradiotherapy and immunotherapy combination. Excepting for the resistance mechanisms associated with tumor cell lineages, we also investigated three TME characteristics response to neoadjuvant therapy resistance, including the infiltration of cytotoxic-insufficient GZMK+ effector memory T cells, angiogenesis-promoting effect of myeloid lineages and the cell-cell communication of tumor-associated fibroblasts. These hallmarks of neoadjuvant therapy will help us to understand the therapy resistance in ESCC and provide important clues to identify potential targets to improve therapy sensitivity.

2023-08-14 | GSE221561 | GEO

Development and Validation of a Comprehensive Analysis of the Competing Endogenous CircRNA/miRNA/mRNA Network for Identification of Immune-Related Therapeutic Targets in Esophageal Squamous Cell Carcinoma

Project description:Esophageal squamous cell carcinoma (ESCC) immunotherapy exhibits limited efficacy, prompting the investigation of its molecular mechanisms. Circular RNAs (circRNAs) are believed to play a significant role in the development of the tumor microenvironment (TME) in ESCC, but their role in ceRNA regulation remains indeterminate. In this study, we identified the expression of mRNA, circRNA in four tumor samples and their pair normal samples noting their paired samples by high-throughput sequencing to validate the correlation analysis.

2023-09-03 | GSE226192 | GEO

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