Identification and characterization of metastasis-initiating cells in esophageal squamous cell carcinoma in a pulmonary metastasis mouse model
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE249058 | GEO | 2024/08/21
REPOSITORIES: GEO
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Project description:Background and aims: Cancer metastasis is the biggest obstacle to esophageal squamous cell carcinoma (ESCC) treatment. At present, understanding of its mechanism remains insufficient. Therefore, an in-depth exploration of the mechanisms of metastasis is crucial for early detection and intervention to reduce metastasis-related mortality. Methods: This study applied single-cell RNA sequencing analysis to investigate lung metastatic ESCC cells isolated from a pulmonary metastasis mouse model at multiple timepoints to characterize early metastatic microenvironment. Results: We identified a small population of parental ESCC KYSE30 cell line (Cluster S) resembled metastasis-initiating cells (MICs) because they could survive and colonize at lung metastatic sites. By comparing differential expression profiles between Cluster S and other subpopulations, we identified a panel of 7 metastasis-initiating signature genes (MIS), including CD44 and TACSTD2, to represent MICs of ESCC. Functional studies demonstrated that Cluster S cells (CD44high) exhibited significantly enhanced cell survival (resistances to oxidative stress and apoptosis), cell migration, invasion, stemness, and in vivo lung metastasis capabilities. Multiplex immunohistochemistry (mIHC) staining of 4 MISs (CD44, S100A14, RHOD, and TACSTD2) in ESCC cell lines and clinical samples found that differential MIS expression scores (dMISs) could predict lymph node metastasis, overall survival and risk of carcinothrombosis. GO and KEGG analyses revealed that CD44high cells were enriched in cell migration, organ development, stress responses, and neuron development, which might be related to the establishment of early metastatic microenvironment. Conclusion: This study identified CD44, S100A14, RHOD, and TACSTD2 as MISs to represent the MICs in ESCC populations and predict patient outcomes. Keywords: ESCC, metastasis-initiating cells, metastasis-initiating signatures, biomarker, scRNA-seq.
2024-08-21 | GSE249057 | GEO
Project description:Background and aims: Cancer metastasis is the biggest obstacle to esophageal squamous cell carcinoma (ESCC) treatment. At present, understanding of its mechanism remains insufficient. Therefore, an in-depth exploration of the mechanisms of metastasis is crucial for early detection and intervention to reduce metastasis-related mortality. Methods: This study applied single-cell RNA sequencing analysis to investigate lung metastatic ESCC cells isolated from a pulmonary metastasis mouse model at multiple timepoints to characterize early metastatic microenvironment. Results: We identified a small population of parental ESCC KYSE30 cell line (Cluster S) resembled metastasis-initiating cells (MICs) because they could survive and colonize at lung metastatic sites. By comparing differential expression profiles between Cluster S and other subpopulations, we identified a panel of 7 metastasis-initiating signature genes (MIS), including CD44 and TACSTD2, to represent MICs of ESCC. Functional studies demonstrated that Cluster S cells (CD44high) exhibited significantly enhanced cell survival (resistances to oxidative stress and apoptosis), cell migration, invasion, stemness, and in vivo lung metastasis capabilities. Multiplex immunohistochemistry (mIHC) staining of 4 MISs (CD44, S100A14, RHOD, and TACSTD2) in ESCC cell lines and clinical samples found that differential MIS expression scores (dMISs) could predict lymph node metastasis, overall survival and risk of carcinothrombosis. GO and KEGG analyses revealed that CD44high cells were enriched in cell migration, organ development, stress responses, and neuron development, which might be related to the establishment of early metastatic microenvironment. Conclusion: This study identified CD44, S100A14, RHOD, and TACSTD2 as MISs to represent the MICs in ESCC populations and predict patient outcomes. Keywords: ESCC, metastasis-initiating cells, metastasis-initiating signatures, biomarker, scRNA-seq.
2024-08-21 | GSE249056 | GEO
Project description:Identification and characterization of metastasis-initiating cells in esophageal squamous cell carcinoma in a pulmonary metastasis mouse model
| PRJNA1047094 | ENA
Project description:Metastasis is the biggest obstacle to esophageal squamous cell carcinoma (ESCC) treatment. Single-cell RNA sequencing analyses are applied to investigate lung metastatic ESCC cells isolated from pulmonary metastasis mouse model at multiple timepoints to characterize early metastatic microenvironment. A small population of parental KYSE30 cell line (Cluster S) resembling metastasis-initiating cells (MICs) is identified because they survive and colonize at lung metastatic sites. Differential expression profile comparisons between Cluster S and other subpopulations identified a panel of 7 metastasis-initiating signature genes (MIS), including CD44 and TACSTD2, to represent MICs in ESCC. Functional studies demonstrated MICs (CD44high) exhibited significantly enhanced cell survival (resistances to oxidative stress and apoptosis), migration, invasion, stemness, and in vivo lung metastasis capabilities, while bioinformatics analyses revealed enhanced organ development, stress responses, and neuron development, potentially remodel early metastasis microenvironment. Meanwhile, early metastasizing cells demonstrate quasi-epithelial-mesenchymal phenotype to support both invasion and anchorage. Multiplex immunohistochemistry (mIHC) staining of 4 MISs (CD44, S100A14, RHOD, and TACSTD2) in ESCC clinical samples demonstrated differential MIS expression scores (dMISs) predict lymph node metastasis, overall survival, and risk of carcinothrombosis.
| S-EPMC11321633 | biostudies-literature
Project description:Identification and characterization of metastasis-initiating cells in esophageal squamous cell carcinoma in a pulmonary metastasis mouse model [scRNA-Seq]
| PRJNA1047099 | ENA
Project description:Identification and characterization of metastasis-initiating cells in esophageal squamous cell carcinoma in a pulmonary metastasis mouse model [bulk RNA-Seq]
| PRJNA1047098 | ENA
Project description:BackgroundEvaluation of biological changes at the molecular level has important clinical implications for improving the survival rate of esophageal squamous cell carcinoma (ESCC). Therefore, we plan to analyze and elucidate the expression of microRNA-133b (miR-133b), M2 pyruvate kinase (PKM2), and signal transducer and activator of transcription 3 (STAT3) in ESCC and their associated clinicopathological significance.MethodsThe 72 patients with ESCC were selected as the experimental study group. Normal adjacent tissues (NAT) were matched as the control group. In this study, in situ hybridization was used to detect the expression of miR-133b in ESCC, and tissue expressions of PKM2 and STAT3 were detected by immunohistochemistry, and literature review was conducted.ResultsStudies had shown that the positive expression of miR-133b in NAT was significantly higher than that in ESCC (χ2 = 9.007, P = .003). PKM2 and STAT3 in ESCC had a significantly higher positive expression levels than those of NAT (χ2 = 56.523, P = .000; χ2 = 72.939, P = .000). From correlation analysis, there was a negative correlation between miR-133b and PKM2(r = -0.515, P < .001), a negative correlation between miR-133b and STAT3(r = -0.314, P = .007), and a positive correlation between PKM2 and STAT3(r = 0.771, P < .001).ConclusionsIn ESCC, our study demonstrated that downregulation of miR-133b and upregulation of PKM2 and STAT3. We predict that miR-133b may inhibit the STAT3 pathway by downregulating PKM2.
| S-EPMC10748682 | biostudies-literature
Project description:Primary human squamous cell carcinomas (SCCas) are heterogeneous invasive tumors with proliferating outer layers and inner differentiating cell masses. To determine if tumor-initiating cells (TICs) are present in SCCas, we utilized newly developed reliable in vitro and in vivo xenograft assays that propagate human SCCas, and demonstrated that a small subset of SCCa cells (∼1%) expressing Prominin-1 (CD133) in the outer layers of SCCas were highly enriched for TICs (∼1/400) compared with unsorted SCCa cells (TICs ∼1/10(6)). Xenografts of CD133+ SCCas recreated the original SCCa tumor histology and organizational hierarchy, whereas CD133- cells did not, and only CD133+ cells demonstrated the capacity for self-renewal in serial transplantation studies. We present a model of human SCCas in which tumor projections expand with outer leading edges that contain CD133+ TICs. Successful cancer treatment will likely require that the TICs identified in cancers be targeted therapeutically. The demonstration that TICs are present in SCCas and are enriched in a CD133- expressing subpopulation has not been, to our knowledge, previously reported.
| S-EPMC3258300 | biostudies-literature
Project description:Chronic inflammation is integral to the development of esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), although the latter has not been associated with reflux esophagitis. The L2-IL-1β transgenic mice, expressing human interleukin (IL)-1β in the oral, esophageal and forestomach squamous epithelia feature chronic inflammation and a stepwise development of Barrett's esophagus-like metaplasia, dysplasia and adenocarcinoma at the squamo-columnar junction. However, the functional consequences of IL-1β-mediated chronic inflammation in the oral and esophageal squamous epithelia remain elusive. We report for the first time that in addition to the previously described Barrett's esophagus-like metaplasia, the L2-IL-1β mice also develop squamous epithelial dysplasia with progression to squamous cell carcinoma (SCC) in the esophagus and the tongue. L2-IL-1β showed age-dependent progression of squamous dysplasia to SCC with approximately 40% (n = 49) and 23.5% (n = 17) incidence rates for esophageal and tongue invasive SCC respectively, by 12-15 months of age. Interestingly, SCC development and progression in L2-IL-1β was similar in both Germ Free (GF) and Specific Pathogen Free (SPF) conditions. Immunohistochemistry revealed a T cell predominant inflammatory profile with enhanced expression of Ki67, Sox2 and the DNA double-strand break marker, γ-H2AX, in the dysplastic squamous epithelia of L2-IL-1β mice. Pro-inflammatory cytokines, immunomodulatory players, chemoattractants for inflammatory cells (T cells, neutrophils, eosinophils, and macrophages) and oxidative damage marker, iNOS, were significantly increased in the esophageal and tongue tissues of L2-IL-1β mice. Our recent findings have expanded the translational utility of the IL-1β mouse model to aid in further characterization of the key pathways of inflammation driven BE and EAC as well as ESCC and Oral SCC.
| S-EPMC10404242 | biostudies-literature
Project description:BackgroundEsophageal squamous cell carcinoma (ESCC) is a leading malignancy with both high incidence and mortality worldwide. However, the molecular mechanisms of the poor prognosis in ESCC are still unclear.MethodsWe conducted differential expression analysis between ESCC and normal tissues and between ESCC samples with and without CNAs in a given gene. Overrepresentation enrichment and gene set enrichment analyses were used to identify the oncogenic pathways and abnormal transcription factors (TFs). The survival analysis was employed to identify the genes associated with overall survival.ResultsIn this study, we aimed to identify and interpret the driver genes triggered by the copy number alterations (CNAs), including CCND1, TEAD4, EIF4EBP1, EGFR, FGFR3, and FZD6. Furthermore, we identified oncogenic pathways, including RTK-RAS, WNT, PI3K, Hippo, and cell cycle, and key TFs including TEAD4, a transcription factor in the Hippo signaling pathway, and LEF1 in the WNT signaling pathway. Furthermore, we observed that upregulations of FGFR3 and EIF4EBP1 were significantly associated with shorter overall survival in ESCC.ConclusionIn conclusion, the driver genes triggered by CNAs not only exhibited critical functionality but also were clinically relevant in ESCC, which greatly improved our understanding of the molecular mechanisms in ESCC.
| S-EPMC7463369 | biostudies-literature