Single cell deciphering of progression trajectories of the tumor ecosystem in head and neck cancer
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ABSTRACT:
SUBMITTER: Liu Z
PROVIDER: S-EPMC10959966 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:Head and neck squamous cell carcinoma (HNSCC) undergoes stepwise progression from normal tissues to precancerous leukoplakia, primary HNSCC, and metastasized tumors. To delineate the heterogeneity of tumor cells and their interactions during the progression of HNSCC, we employ single-cell RNA-seq profiling for normal to metastasized tumors. We can identify the carcinoma in situ cells in leukoplakia lesions that are not detected by pathological examination. In addition, we identify the cell type subsets of the Galectin 7B (LGALS7B)-expressing malignant cells and CXCL8-expressing fibroblasts, demonstrating that their abundance in tumor tissue is associated with unfavorable prognostic outcomes. We also demonstrate the interdependent ligand-receptor interaction of COL1A1 and CD44 between fibroblasts and malignant cells, facilitating HNSCC progression. Furthermore, we report that the regulatory T cells in leukoplakia and HNSCC tissues express LAIR2, providing a favorable environment for tumor growth. Taken together, our results update the pathobiological insights into cell-cell interactions during the stepwise progression of HNSCCs.
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Project description:Patients with human papillomavirus-negative head and neck squamous cell carcinoma (HPV-negative HNSCC) have worse outcomes than HPV-positive HNSCC. In our study, we used a published dataset and investigated the microbes enriched in molecularly classified tumor groups. We showed that microbial signatures could distinguish Hypoxia/Immune phenotypes similar to the gene expression signatures. Furthermore, we identified three highly-correlated microbes with immune processes that are crucial for immunotherapy response. The survival of patients in a molecularly heterogenous group shows significant differences based on the co-abundance of the three microbes. Overall, we present evidence that tumor-associated microbiota are critical components of the tumor ecosystem that may impact tumor microenvironment and immunotherapy response. The results of our study warrant future investigation to experimentally validate the conclusions, which have significant impacts on clinical decision-making, such as treatment selection.
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Project description:The development of head and neck squamous cell carcinoma (HNSCC) is a multi-step process, and its survival depends on a complex tumor ecosystem, which not only promotes tumor growth but also helps to protect tumor cells from immune surveillance. With the advances of existing technologies and emerging models for ecosystem research, the evidence for cell-cell interplay is increasing. Herein, we discuss the recent advances in understanding the interaction between tumor cells, the major components of the HNSCC tumor ecosystem, and summarize the mechanisms of how biological and abiotic factors affect the tumor ecosystem. In addition, we review the emerging ecological treatment strategy for HNSCC based on existing studies.
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Project description:The diverse malignant, stromal, and immune cells in tumors affect growth, metastasis, and response to therapy. We profiled transcriptomes of ∼6,000 single cells from 18 head and neck squamous cell carcinoma (HNSCC) patients, including five matched pairs of primary tumors and lymph node metastases. Stromal and immune cells had consistent expression programs across patients. Conversely, malignant cells varied within and between tumors in their expression of signatures related to cell cycle, stress, hypoxia, epithelial differentiation, and partial epithelial-to-mesenchymal transition (p-EMT). Cells expressing the p-EMT program spatially localized to the leading edge of primary tumors. By integrating single-cell transcriptomes with bulk expression profiles for hundreds of tumors, we refined HNSCC subtypes by their malignant and stromal composition and established p-EMT as an independent predictor of nodal metastasis, grade, and adverse pathologic features. Our results provide insight into the HNSCC ecosystem and define stromal interactions and a p-EMT program associated with metastasis.
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Project description:The mechanism underlying the association between the development of head and neck squamous cell carcinoma (HNSCC) and ferroptosis is unclear. We analyzed the transcriptomes of 5902 single cells from a single-cell RNA-sequencing (scRNA-seq) dataset. They then aggregate into B cells, epithelial cells, fibroblasts, germ cells, mesenchymal cells, cancer stem cells, stem cells, T cells and endometrial cells, respectively. Our study shows that multiple pathways are significantly enriched in HNSCC development including extracellular matrix structural components, humoral immune responses, and muscle contraction. Differentially expressed genes analysis in Pseudotime analysis, pathway and biological function indicated that there was a significant correlation in the ferroptosis pathway. Furthermore, higher ferroptosis potential index (FPI) scores were significantly associated with worse overall survival prognosis in HNSCC patients. Pseudo-temporal, survival analyses and immunohistochemistry identified multiple central genes in HNSCC development, including ACSL1, SLC39A14, TFRC, and PRNP genes, and indicated associated ferroptosis. Overall, our study detected ferroptosis-related features is closely correlated with HNSCC prognosis and development, and deserved candidates suitable for immunotherapy treatment strategies determination for HNSCC patients.
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| S-EPMC10998855 | biostudies-literature
Project description:IntroductionDespite improvements in treatment strategies for head and neck squamous cell carcinoma (HNSCC), outcomes have not significantly improved; highlighting the importance of identifying novel therapeutic approaches to target this disease. To address this challenge, we proceeded to evaluate the role of iron in HNSCC.Experimental designExpression levels of iron-related genes were evaluated in HNSCC cell lines using quantitative RT-PCR. Cellular phenotypic effects were assessed using viability (MTS), clonogenic survival, BrdU, and tumor formation assays. The prognostic significance of iron-related proteins was determined using immunohistochemistry.ResultsIn a panel of HNSCC cell lines, hemochromatosis (HFE) was one of the most overexpressed genes involved in iron regulation. In vitro knockdown of HFE in HNSCC cell lines significantly decreased hepcidin (HAMP) expression and intracellular iron level. This in turn, resulted in a significant decrease in HNSCC cell viability, clonogenicity, DNA synthesis, and Wnt signalling. These cellular changes were reversed by re-introducing iron back into HNSCC cells after HFE knockdown, indicating that iron was mediating this phenotype. Concordantly, treating HNSCC cells with an iron chelator, ciclopirox olamine (CPX), significantly reduced viability and clonogenic survival. Finally, patients with high HFE expression experienced a reduced survival compared to patients with low HFE expression.ConclusionsOur data identify HFE as potentially novel prognostic marker in HNSCC that promotes tumour progression via HAMP and elevated intracellular iron levels, leading to increased cellular proliferation and tumour formation. Hence, these findings suggest that iron chelators might have a therapeutic role in HNSCC management.
| S-EPMC3753261 | biostudies-literature
Project description:Head and neck squamous cell carcinoma (HNSCC) undergoes stepwise progression from normal tissue to metastasized tumors. To comprehensively delineate the heterogeneity of tumor cells and their interactions during the progression of HNSCC, we employed single-cell RNA-seq (scRNA-seq) profiling for the tissues of normal, leukoplakia, HNSCC, and metastasized HNSCC. We identified novel clones of malignant cells expressing LGALS7B and fibroblasts expressing CXCL8, and the abundance of these cells in the tumor tissue was associated with poorer prognostic outcomes. In addition, we demonstrated that fibroblasts in leukoplakia and tumor tissue express COL1A1, which interacts with CD44+ malignant cells, facilitating HNSCC progression. CD4+FOXP3+ regulatory T cells expand in leukoplakia and express LAIR2 with collagen stimulation, which may provide a favorable microenvironment for tumor progression. In conclusion, stromal and immune cell interactions play critical roles in the stepwise progression of HNSCC, and we have identified steps during HNSCC progression for possible therapeutic interventions
2022-08-31 | GSE181919 | GEO
Project description:Human papillomavirus (HPV) is a major causative factor of head and neck squamous cell carcinoma (HNSCC), and the incidence of HPV-associated HNSCC is increasing. The role of tumor microenvironment (TME) in viral infection and metastasis needs to be explored further. Thus we studied the molecular characteristics of primary tumors (PTs) and lymph node metastatic tumors (LNMTs) by stratifying them based on their HPV status using spatial transcriptomics.
2024-11-20 | GSE281978 | GEO
Project description:BackgroundHead and neck squamous cell carcinoma (HNSCC) typically present with a complex anatomical distribution, often accompanied by insidious symptoms. This combination contributes to its high incidence and poor prognosis. It is now understood that the immune features of cellular components within the tumor ecosystem and their complex interactions are critical factors influencing both tumor progression and the effective immune response.MethodsWe obtained single-cell RNA sequencing data of 26,496 cells from three tumor tissues and five normal tissues and performed subsequent analyses. Immunohistochemical staining on tumor sections was used to validate the presence of malignant cells. Additionally, we included bulk RNA sequencing data from 502 HNSCC patients. Kaplan-Meier analysis and the log-rank test were employed to assess predictors of patient outcomes.ResultsWe identified three epithelial subclusters exhibiting immune-related features. These subclusters promoted the infiltration of T cells, dendritic cells, and monocytes into the tumor microenvironment. Additionally, cancer-associated fibroblasts displayed tumor-promoting and angiogenesis characteristics, contrasting with the predominant antigen-presenting and inflammatory roles observed in fibroblasts from normal tissues. Furthermore, tumor endothelial subsets exhibited a double-sided effect, promoting tumor progression and enhancing the effectiveness of immune response. Finally, follicular helper T cells and T helper 17 cells were found to be significantly correlated with improved outcomes in HNSCC patients. These CD4+ T cell subpopulations could promote the anti-tumor immune response by recruiting and activating B and T cells.ConclusionOur findings provide deeper insights into the immune features of the tumor ecosystem and reveal the prognostic significance of follicular helper T cells and T helper 17 cells. These findings may pave the way for the development of therapeutic approaches.
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