Discover. Oncology最新文献

Background: During chronic liver injury, hepatic stellate cells (HSCs) lose their vitamin-A-rich lipid droplets (LDs), yet whether these organelles are merely degraded or released via vesicles and functionally relevant remains unclear. We investigated the fate of HSCs LDs and their impact on hepatic macrophage phenotype and hepatocellular carcinoma (HCC) development.

Methods: Chronic liver injury was induced in C57BL/6 mice using carbon tetrachloride (CCl₄) for up to 12 weeks. HSCs activation and lipid droplet dynamics were assessed by immunofluorescence, transmission electron microscopy, and flow cytometry. Single-cell RNA sequencing data from normal and inflamed livers were analyzed to characterize cell populations and interactions. HSC-derived LDs were isolated by gradient centrifugation and their effects on macrophage polarization were evaluated in vitro and in vivo. An orthotopic HCC model was used to assess the impact of lipid droplet-educated macrophages on tumor growth. Clinical relevance was validated using The Cancer Genome Atlas-liver hepatocellular carcinoma (TCGA-LIHC) cohort data.

Results: Activated HSCs in fibrotic livers showed progressive fragmentation and release of LDs, which were subsequently internalized by hepatic macrophages. Single-cell transcriptomic analysis revealed enhanced HSC-macrophage interactions and upregulation of lipid metabolism pathways in both cell types during liver inflammation. HSC-derived LDs acted as a direct metabolic cue to induced M2 polarization of macrophages, characterized by elevated secretion of transforming growth factor-beta (TGF-β1), interleukin-10 (IL-10), and C-C Motif Chemokine Ligand 17 (CCL17). In orthotopic HCC models, co-injection of tumor cells with lipid droplet-educated macrophages significantly enhanced tumor growth compared to control macrophages. TCGA analysis showed that high CD163 expression correlated with poor overall survival in HCC patients.

Conclusion: Our findings identifies a distinct mechanism whereby activated HSCs transfer LDs to hepatic macrophages, inducing M2 polarization and creating a pro-tumorigenic microenvironment. This HSC-macrophage crosstalk represents a potential metabolic therapeutic target for preventing HCC development in patients with chronic liver disease.

Background: Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with poor prognosis, partly due to an immunosuppressive tumor microenvironment. The immune-related gene CCDC86, selectively expressed in hematopoietic and antigen-presenting cells, has not been previously characterized in HNSCC. We aimed to delineate its expression pattern and immunological functions using integrated single-cell transcriptomic analysis.

Methods: Bulk RNA-sequencing data from The Cancer Genome Atlas (TCGA) and single-cell RNA-sequencing data (GEO: GSE139324) were integrated to assess CCDC86 expression, immune-cell specificity, and associated transcriptional programs in HNSCC. Differential expression, pathway enrichment, transcription factor regulon, and cell-cell communication analyses were conducted between CCDC86-high and CCDC86-low populations. The immune contexture and ligand-receptor interactions of CCDC86-expressing cells were evaluated to infer their roles in tumor-immune modulation. Additionally, qPCR validation following CCDC86 knockdown in FaDu cells was performed to confirm the transcriptional alterations of immune-related genes identified by bioinformatic analysis.

Results: CCDC86 was predominantly expressed in tumor-infiltrating antigen-presenting cells (APCs), including macrophages and dendritic cells. CCDC86-high APCs exhibited enhanced SPI1- and CEBPA-regulated transcriptional activity, metabolic reprogramming, and altered antigen-presentation signatures.Ligand-receptor network analysis revealed intensified interactions with T cells via both co-stimulatory (CD86-CD28) and checkpoint (PDCD1, CTLA4) pathways, suggesting dual immunomodulatory potential. Functionally, CCDC86-high APCs were associated with increased cytotoxic T-cell infiltration but concurrent T-cell dysfunction, implying that CCDC86 defines a specialized APC state that sustains chronic immune activation yet promotes tolerance within the tumor microenvironment. Additionally, qPCR validation following CCDC86 knockdown in FaDu cells was performed to confirm the transcriptional alterations of immune-related genes identified by bioinformatic analysis.

Conclusions: CCDC86 acts as a key regulator of immune communication in HNSCC, orchestrating APC-T cell interactions and shaping an immunoregulatory niche. By linking antigen presentation with checkpoint signaling, CCDC86 contributes to immune evasion while maintaining local immune activation. These findings highlight CCDC86 as a promising prognostic biomarker and potential immunotherapeutic target in HNSCC.

Prostate cancer (PCa) is the most prevalent malignancy among men with a rising mortality rate. Androgen deprivation therapy (ADT) effectively treats PCa. However, patients inevitably progress to castration-resistant prostate cancer (CRPC). There are still no effect methods for treating CRPC. The underlying mechanisms driving CRPC remain unclear. Methyl-CpG binding domain protein 3 (MBD3), a key member of the methyl-CpG binding protein family, exhibits high expression in lots of cancers. Here, we tried to find the mechanism of MBD3 in causing CRPC. We collected RNA-sequence data of PCa patients from public databases and collected CRPC samples from Tongji Hospital. Then, the expression of MBD3 in PCa samples was detected. By overexpression or knockdown MBD3, the role of MBD3 in affecting PCa cells proliferation was detected in vivo and vitro. Using public databases data, PCR, western blot and ChIP-qPCR experiments, the mechanism of MBD3 leading to PCa was analyzed. This study revealed that MBD3 is upregulated in both PCa and CRPC samples from public databases and clinical samples. Elevated MBD3 expression promotes CRPC cell proliferation by epigenetically silencing the tumor suppressor gene phosphatase and tensin homolog (PTEN). Furthermore, MBD3 is transcriptionally regulated by bromodomain-containing protein 4 (BRD4), and MBD3 knockdown enhances the sensitivity of CRPC cells to BET inhibitors. These findings suggest that the BRD4-MBD3-PTEN axis is a new pathway in CRPC, with MBD3 representing a potential therapeutic target, particularly in combination with BET inhibitors.

Background: Thyroid cancer stem cells (CSCs) have been implicated in the recurrence and metastasis of thyroid cancer. This study, therefore, explored the properties of thyroid CSC-like cells, cell-cell interactions, and genes associated with prognosis by analyzing single-cell RNA sequencing (scRNA-seq) data and clinical data.

Methods: We analyzed two independent scRNA-seq datasets (GSE191288 and GSE250521) using the Seurat R package. Tumor cells were identified based on copy number variations, and stemness^High (CSC-like) and stemness^Low cells were defined using CytoTRACE. Protein-protein interaction (PPI) networks were constructed, after which hub genes were identified using STRING and cytoHubba. Gene ontology analysis was performed using the clusterProfiler R package. CellChat was used for cell-cell interaction analysis. Furthermore, survival analysis was performed using the TCGA database.

Results: Compared to stemness^Low cells, stemness^High cells showed upregulation of 1,498 (GSE191288) or 1,274 genes (GSE250521), with 109 genes being commonly upregulated in both datasets. Furthermore, hub genes identified from the PPI network constructed from the co-upregulated genes in both two datasets were implicated in angiogenesis. Subsequent cell-cell interaction analysis revealed strong interactions between JAG1 in stemness^High cells and NOTCH1/4 in endothelial cells. Analysis of clinical data showed that thyroid cancer patients with high stemness exhibiting high JAG1 expression and that patients with high JAG1 expression had significantly poorer prognosis than did those with low JAG1 expression.

Conclusions: This study provides new insights into the gene expression profile of thyroid CSC-like cells and their interactions with cells constituting tumor tissues.

Deubiquitination(DUB) is a critical cellular process that regulates protein stability and functionality, playing essential roles in cell proliferation, migration, tumorigenesis, and various molecular signaling pathways. Within the DUB enzyme family, ubiquitin-specific protease 33 (USP33) is found to be aberrantly expressed in several cancers, including a significant reduction in colorectal cancer (CRC) tissues. The decreased expression of USP33 impairs its ability to inhibit CRC cell proliferation, migration, and invasion, potentially through its involvement in key signaling pathways such as the β-arrestin-dependent ERK pathway, Slit-Robo pathway, and Wnt/β-catenin pathway. This review highlights the interaction between USP33 and these signaling pathways, exploring its potential as a novel independent prognostic biomarker for CRC and its promise as a therapeutic target.