Neoplasia最新文献

Background: Mast cells (MCs) are immunometabolic sentinels, yet their heterogeneity and functional specialization in breast cancer (BRCA) remain unclear. We hypothesized that arginine metabolism defines transcriptionally and functionally distinct MC subpopulations that shape the BRCA microenvironment.

Methods: We integrated single-cell RNA-seq (GSE161529; 272,592 cells, 38 clusters), spatial transcriptomics (GSE243022) and bulk RNA-seq (TCGA, GSE42568). After harmony batch-correction and Seurat-Louvian clustering, MCs were split by median arginine score (AUCell/UCell/AddModuleScore/singscore) into high- (HAS) and low-activity (LAS) subsets. Monocle2 pseudotime, CellChat, hdWGCNA (power = 15), LASSO-Cox and MiloR were used to trace differentiation, communication, prognostic value and triple-negative breast cancer (TNBC) enrichment. Functional validation of the model-prioritized gene OAT was subsequently conducted in clinical tissues and breast cancer cell lines through loss-of-function assays.

Results: HAS cells represented 18.7 % of all MCs and were enriched in TNBC (OR = 2.4, p < 0.001). They displayed higher differentiation potential (CytoTRACE: 0.72 vs 0.41, p < 0.001) and trajectory progression (pseudotime τ = 0.68). Arginine score correlated with differentiation (r = 0.52) and tumor risk signature (TRS, r = 0.35). CellChat revealed 1.8-fold increased incoming signals in HAS; VEGF and TGF-β pathways were most active (p < 0.001). hdWGCNA identified 19 modules; cyan and green modules (kME > 0.9) contained 214 HAS-up genes driving cell-cycle and arginine/glutamine metabolism. A five-gene (ARG1, NOS2, ASL, OAT, AZIN1) LASSO model predicted 5-year survival (AUC = 0.82; HR = 1.68, p < 0.001). Spatial maps confirmed ASL⁺ MC hotspots in tumor cores (AUC = 0.89 vs normal). Experimentally, OAT expression was elevated in TNBC tissues and cell lines. Knockdown of OAT impaired proliferation, induced apoptosis, suppressed migration/invasion, and modulated apoptosis- and EMT-related protein expression, functionally supporting its role in BRCA progression.

Conclusion: Arginine metabolism stratifies MCs into pro-tumorigenic HAS and quiescent LAS subsets; ASL-high MCs constitute a metabolically wired, highly communicating population that fuels TNBC progression and furnishes an exploitable prognostic signature. OAT, a key HAS-associated gene, promotes breast cancer aggressiveness through proliferation, survival, and invasion.

Chemoresistance and immunosuppression present major challenges in gastric cancer (GC) treatment, with their interplay remaining poorly understood. We identify the Oncostatin M receptor (OSMR) as a central regulator coordinating both chemoresistance and neutrophil-mediated immunosuppression. OSMR was significantly upregulated in GC patients, correlating with poor chemotherapy response and reduced CD8⁺T cell infiltration. Mechanistically, OSMR directly recruits PI3K, amplifying PI3K/AKT signaling to increase cyclin E2 (CCNE2) expression, thereby sustaining tumor cell survival under chemotherapy-induced stress. Crucially, we uncovered a novel immunoregulatory cascade: OSMR drives BMP5 transcriptional activation, orchestrating N2-polarization of tumor-associated neutrophils (TANs) and upregulating PD-L1 expression on TANs, ultimately impairing CD8⁺T cell cytotoxicity. Dysfunctional CD8⁺T cells secreted IL31, activating the OSMR pathway in GC cells and thereby forming a self-perpetuating OSMR-BMP5-IL31 feedback circuit that sustains therapeutic resistance. Therapeutically, OSMR neutralization with vixarelimab synergized with fluorouracil to overcome chemoresistance and reinstate anti-tumor immunity in GC preclinical models. Our findings establish OSMR as a molecular linchpin connecting intrinsic tumor survival pathways (PI3K/CCNE2) with extrinsic immunosuppressive reprogramming (BMP5/TANs/CD8⁺T cells), providing a clinically actionable target to overcome treatment resistance in GC.

The presence of BRAF^V600E mutations is associated with poor prognosis in colorectal cancer (CRC). Although the FDA-approved combination of encorafenib and cetuximab provides clinical benefit in this population, only 22% of patients respond and most eventually develop resistance. This study investigated the mechanisms of resistance to PLX8394, a second-generation BRAF inhibitor. Using primary and established BRAF^V600E CRC cells, we show that the development of resistance to PLX8394 results in cross-resistance of cells to encorafenib. Moreover, the acquired resistance is associated with increased proliferation, invasion, and upregulation of lipid metabolism, including increased expression of fatty acid synthase (FASN), a key enzyme of lipid synthesis. Yet, the combination of PLX8394 and FASN inhibitor TVB3664 has a synergistic effect on cell viability and colony formation in parental CRC cells, but not in PLX-resistant cells. Importantly, we demonstrate that addition of TVB3664 to the PLX8394 or encorafenib regimen significantly postpones development of resistance to BRAF-targeted therapy by inhibiting the cell cycle progression via a decrease in pRb (Ser780) and downregulation of E2F transcription factor and Cyclin D1 expression. Consistently, clinical data show that patients with BRAF^V600E CRC who have high FASN expression in tumor tissues have higher expression of cell cycle-associated genes, including CDKs, E2F, CCDN1 (Cyclin D1), survivin, and MKI67. Collectively, these findings identify FASN-driven lipid metabolism as a critical mediator of resistance to BRAF-targeted therapy and suggest that incorporation of FASN inhibitors may enhance therapeutic efficacy and delay acquired resistance in BRAF^V600E CRC.

Introduction: Diffuse midline glioma (DMG) with the H3K27M mutation remains one of the most treatment-resistant pediatric brain tumors, in part due to limited antigen presentation and immune visibility. Exploring how glioma biology and therapeutic interventions influence immune recognition offers new opportunities to identify tumor-specific immune targets.

Materials and methods: We performed immunopeptidomics on human cell line derived tumor tissue for DMG and glioblastoma (GBM) and defined how MTX-241F, a selective EGFR/PI3K inhibitor, changes the tumor immunopeptidome. Immunopeptides were isolated from xenografted tumors by capturing MHC-I bound peptides followed by mass spectrometry. Comparative analyses were performed across tumor type (DMG vs. GBM) and treatment condition (vehicle vs. MTX-241F).

Results: Immunopeptidomic profiling revealed tumor-specific differences in peptide repertoires between DMG and GBM. GBM tumors exhibited twice as many immunopeptides as DMG, which may be due to the distinct biology of each tumor type or may be indicative of potential HLA allotype composition. We identified highly abundant H2B1K-derived immunopeptides in DMG, suggesting that the H3K27M-driven epitranscriptome may promote turnover of other histones. MTX-241F increased the number of immunopeptides in DMG but reduced them in GBM, indicating a tumor-specific change in the immunopeptidome following EGFR/PI3K inhibition. In addition, we identified brain-enriched, HLA-A*02:01-binding and MTX-241F-exclusive immunopeptides that represent treatment-induced changes and may serve as biomarkers of therapeutic response or potential targets for CAR-T cell-based approaches.

Discussion: MTX-241F changes the glioma immunopeptidome, unveiling H2B1K, brain-enriched, and treatment-induced immunopeptides as immunologically visible targets. These findings provide a rationale for integrating molecularly targeted therapy with immunotherapeutic approaches to enhance tumor recognition and treatment efficacy in DMG and GBM.

Colorectal cancer (CRC) progression is strongly influenced by the tumor immune microenvironment, yet the immunoregulatory role of tumor-associated macrophages (TAMs) remains incompletely defined. Using integrated single-cell RNA sequencing and spatial transcriptomic analyses, we identified a distinct TAM subset in CRC characterized by high expression of secreted phosphoprotein 1 (SPP1). In a macrophage-depleted murine CRC model established with clodronate (CL2MDP) liposomes and MC38 cells, macrophage depletion significantly inhibited tumor growth, accompanied by reduced SPP1 expression and increased infiltration of CD8⁺ T cells and type 1 cytotoxic T (Tc1) cells. Supplementation with recombinant SPP1 partially reversed these antitumor effects. Mechanistically, in vitro coculture experiments demonstrated that TAM-derived SPP1 suppressed CD8⁺ T cell differentiation into Tc1 cells through CD44-mediated signaling, resulting in decreased TNF-α and IFN-γ production and impaired activation of the LCK-ZAP70-LAT signaling pathway. These effects were attenuated by SPP1 neutralization or CD44 inhibition. Collectively, these findings elucidated TAM-derived SPP1 as a key mediator of immune suppression in CRC and suggested that the TAM-SPP1 axis is a potential therapeutic target.

Background: Chemokine receptor 1 (CCR1), a regulator of immune cell migration, has been implicated in various cancers but remains poorly characterized in gastric cancer's immune microenvironment. This study aimed to investigate whether CCR1 promotes or suppresses tumor progression in gastric cancer.

Methods: Utilize transcriptomic analysis to investigate the role of CCR1 in gastric cancer, and employed clinical data to examine the correlation between CCR1 expression and patient survival as well as pathological features. In vivo models with CCR1-knockout mice and macrophage depletion experiments validated functional roles, while Western blotting and qRT-PCR explored The pathways and signaling.

Results: Following patient stratification based on optimal cut-off values, Kaplan-Meier survival analysis demonstrated that patients with high CCR1 expression had longer survival times. Single-cell and spatial transcriptomics analyses revealed that CCR1 is predominantly expressed on macrophages. Immunofluorescence assays showed greater co-localization of CCR1 and CD68 in gastric cancer tissues compared to adjacent normal tissues, confirming CCR1 expression in macrophages. In vivo experiments demonstrated that CCR1 deficiency increased tumor growth by reducing T cell infiltration, an effect that was abrogated by macrophage depletion. Mechanistically, CCR1 activates the NF-κB and MAPK pathways in macrophages to upregulate CXCL9 and CXCL10, thereby promoting T cell recruitment to the tumor microenvironment.

Conclusions: CCR1 modulates T cell distribution via CXCL9/CXCL10, suggesting potential therapeutic directions.

Betel quid (BQ) chewing is a profound risk for oral squamous cell carcinoma (OSCC) in Southeast Asia. Yet, the detailed mechanisms by which BQ chewing damages the genome and creates a unique tumor niche that ultimately cause OSCC are still not fully understood. To address this, we conducted a multi-omics survey, including exome sequencing of tumor-normal pairs from 261 male patients with OSCC (129 habitual BQ chewers and 132 non-BQ users), alone with integrated single-cell and spatial transcriptomics of a set of tumors. Comparative analyses of the mutational catalog identified enrichment of significantly altered genes (e.g. mutations of TP53 and CHUK, copy gains of MAP3K13 and FADD, copy losses of CDKN2A) associated with BQ chewing. Assessment of oncogenic and co-occurring actionable alterations demonstrated frequently altered oncogenic pathways (Hippo and p53 signaling) and potential combination therapy opportunities linked to BQ use. In addition, evaluation of epithelial, immune, stromal expression programs in the corresponding tissue compartments revealed a shift of tumor microenvironment in BQ-related OSCC, characterized by induced hypoxia of tumor epithelium, altered immunosuppression of dendritic cells, and raised sprouting angiogenesis of tumor endothelium. Quantitative predictions of intercellular communications inferred a more heterogeneous cell-cell crosstalk among BQ-related OSCC, highlighted by extensive interactions of fibroblasts and dendritic cells with other non-epithelial cell types via mostly extracellular matrix-receptor signaling pathways. Collectively, these differences in genomic landscape and tumor niche suggest that OSCC caused by BQ chewing could be an etiological subtype different from their BQ-negative counterparts.

DFMO has been studied as a cancer therapeutic at doses ranging from 500 to 9,000 mg/m2/day. Lower doses are favored for cancer prevention studies while higher doses, often with chemotherapy, are studied in refractory cancers. DFMO inhibits the rate-limiting enzyme in polyamine synthesis, ornithine decarboxylase (ODC), an oncogene transcriptionally regulated by MYC. MYC genes are the principal oncogenic drivers of neuroblastoma, and ODC1 is co-amplified in a subset with dismal outcome, so DFMO is a rational therapeutic candidate. Low-dose DFMO has now been FDA-approved for high-risk patients though the mechanisms for its anti-tumor activity, and the exposures required to elicit them, remain obscure. We sought to define biomarkers of activity across exposures achieved in the clinic with low through high-dose DFMO. Polyamines support protein translation by providing spermidine, which is essential to hypusinate (and activate) the elongation factor, eIF5A. Selective binding of polyamines with tRNA and rRNA provide eIF5A-independent mechanisms of translation support. We show that low-dose DFMO does not extend survival in mouse models in vivo nor alter translation biomarkers in vitro. High-dose DFMO consistently extends survival in neuroblastoma models, and, in a subset of neuroblastoma cell lines, inhibits eIF5A hypusination and global translation at achievable concentrations. However, the concentration required to engage these changes across many cell lines exceeded that achievable even with high-dose DFMO. No correlation was seen among MYCN and/or ODC1 copy number and sensitivity to DFMO. Combining high-dose DFMO with additional agents to further deplete tumor polyamines may be necessary to fully engage polyamine-depletion effects on tumors, and more granular measures of translation, including codon-resolution ribosome profiling, may be required to define these effects.