Cellular Oncology最新文献

Purpose: CDK9, in complex with cyclin T1 or T2, is essential for mRNA transcription by enabling paused RNA polymerase II to proceed into elongation. Increasing evidence highlights CDK9's involvement in transcriptional addiction in cancer. Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype for which effective targeted therapies remain limited. Here, we aimed to define the therapeutic potential of novel CDK9 inhibitors in TNBC.

Methods: We explored the efficacy and mechanism of action of novel CDK9 inhibitors, alone or in combination with EGFR inhibitors, using TNBC cell lines and in vivo xenograft models.

Results: Targeting CDK9 significantly impaired proliferation and induced apoptosis in multiple TNBC cell lines. Transcriptomic analyses revealed that CDK9 inhibitors induced downregulation of genes involved in transcription, cell cycle progression, and oncogenic signalling pathways, including TGF-β and Wnt/β-catenin signalling. Combined CDK9 and EGFR inhibition disrupted transcriptional programs, enhanced TNBC cell death in vitro, and acted synergistically to reduce tumour growth in PDX and Hs578T xenograft models, although this combination was also associated with increased toxicity.

Conclusion: Our results position CDK9 as a promising therapeutic target in TNBC, either alone or in combination with EGFR inhibition, provided that side effects associated with this combination treatment can be controlled.

Introduction: (Isocitrate dehydrogenase) IDH-mutant astrocytoma is classified as World Health Organization (WHO) grade 2-4 and is second only to IDH wild-type glioblastoma in the incidence of adult glioma. However, few studies use single-cell and spatial transcriptome sequencing to analyze its malignant progression.

Methods: Intraoperative navigation and yellow fluorescence visualization were utilized to accurately isolate high-grade (WHO grade 3-4) and low-grade (WHO grade 2) samples of IDH-mutant astrocytoma for single-cell and spatial transcriptome sequencing. By combining single-cell, spatial transcriptome, The Cancer Genome Atlas (TCGA), and The Chinese Glioma Genome Atlas (CGGA) data, analyses of survival, enriched pathways, transcription factors, intercellular communication, differentiation trajectories, and immune response were performed to identify the characteristics of a unique subpopulation of high-grade IDH-mutant astrocytoma.

Results: Our single-cell RNA sequencing analysis identified a distinct subpopulation (Cluster 7) present in high-grade IDH-mutant astrocytoma, which was localized to the terminus of the pseudotime trajectory. Importantly, this cluster not only exhibited an immunosuppressive phenotype correlated with poor clinical prognosis, but also demonstrated significant enrichment in Developmental Biology and Calcium Signaling pathways. Furthermore, this subpopulation engaged in prominent ligand-receptor interactions, particularly through PTN_PTPRZ1 and MIF_CD74 pairs. Notably, comparative analysis revealed that high-grade astrocytoma displayed both quantitatively and qualitatively enhanced communication networks when compared to their low-grade counterparts.

Conclusions: Our single-cell RNA sequencing analysis identifies a distinct tumor cell subpopulation present in high-grade (WHO grade 3-4) adult IDH-mutant astrocytoma. This cluster, which likely arises from malignant progression in adult astrocytoma, may provide new insights for developing therapeutic strategies against this clinically challenging disease.

Purpose: PARP7 is a negative regulator of type I interferon (IFN-I) and aryl hydrocarbon receptor (AHR) signalling and has important roles in cell proliferation and antitumor immunity. Recently, several cancer cell lines have been reported to be sensitive to the antiproliferative effect of PARP7 inhibition by RBN2397; however, the roles of AHR and IFN-I signalling in this effect are not fully understood.

Methods: Murine mammary cancer cells were treated with AHR ligands, RBN2397 and with the stimulator of interferon genes (STING) agonist, DMXAA. The impact of ligand treatments on AHR and IFN-I signalling and cell proliferation was determined.

Results: RBN2397 enhanced AHR ligand signalling and STING-induced IFN-I responses in both cell lines. Py8119 but not Py230, 4T1 or EO771 cells were sensitive to the antiproliferative effects of RBN2397. In agreement with FOS-related antigen 1 (FOSL1) being required for sensitivity to RBN2397, Py8119 but not Py230 cells expressed FOSL1. However, RBN2397 insensitive 4T1 and EO771 cell lines also expressed FOSL1, suggesting that the role of FOSL1 in RBN2397-mediated growth inhibition exhibits cell line specificity. In Py8119 cells, RBN2397 induced apoptosis which was independent of AHR ligand treatment and DMXAA-induced STING activation. Although Py230 cells were resistant to the antiproliferative effects RBN2397 alone, combined treatment of DMXAA with RBN2397 reduced their proliferation, which was further reduced by AHR loss or its inhibition.

Conclusion: These findings highlight the complexity of the interplay among PARP7, AHR and STING-induced IFN signalling in regulating cancer cell proliferation but also suggest that for some cell lines STING activation might increase their sensitivity to the anti-proliferative effects of RBN2397.

Purpose: High programmed death-ligand 1 (PD-L1) expression is associated with unfavorable clinical outcomes in epidermal growth factor receptor (EGFR)-mutated lung adenocarcinomas (LUAD) patients treated with tyrosine kinase inhibitors (TKIs) or anti-PD-1/PD-L1 therapy, yet the underlying mechanisms are less explored.

Methods: Bulk RNA sequencing (RNA-seq) datasets were analyzed to investigate intertumoral transcriptional variations linked to PD-L1 expression. Immunohistochemistry (IHC) was utilized to quantify PD-L1 expression on tumor cells. Digital spatial profiling (DSP) was performed on 23 EGFR-mutated LUAD tissue samples to characterize transcriptomic differences in tumor cell (TC), immune cell (IM), and macrophage (MA) compartments between PD-L1 high and low groups. Furthermore, a publicly available DSP dataset was analyzed and IHC was conducted for validation.

Results: Analysis of RNA-seq datasets identified differentially expressed genes, signaling pathways, and immune profiles associated with PD-L1 expression. Compared to low PD-L1 tumors, high PD-L1 tumors exhibited increased infiltration of T regulatory cells (Tregs) and enhanced immunosuppressive signatures. DSP analysis revealed compartment-specific molecular disparities: TC segment in high PD-L1 tumors showed upregulated signatures of cell proliferation, invasion, and metastasis. IM segment displayed increased infiltration of immunosuppressive cells, including Tregs and myeloid-derived suppressor cells and upregulated expression of inhibitory immunomodulators CD276, HAVCR2, and LGALS9C.

Conclusion: Combining bulk and spatial RNA-seq, this study characterized the molecular and immunological hallmarks of EGFR-mutated LUAD in the context of PD-L1 expression, providing new insights into the development of tailored therapeutic strategies for EGFR-mutated LUAD with high PD-L1 expression.

Purpose: Ferroptosis is a novel form of iron-dependent programmed cell death that is associated with the progression of various tumors and cancer treatment responses. However, its role in the clinical treatment of lung cancer, particularly in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), remains poorly understood. This study aims to explore the prognostic value of ferroptosis-related genes in lung cancer and establish a reliable predictive model.

Methods: We collected the GSE4573, TCGA-LUAD, and TCGA-LUSC datasets, comprising a total of 1,271 samples and a ferroptosis gene set of 717 genes. Weighted gene coexpression network analysis (WGCNA) was used to identify ferroptosis-related markers, followed by the application of 101 machine learning algorithms combining 10 different approaches to develop a ferroptosis-related signature (FRS) for lung cancer prognosis.

Results: The FRS demonstrated superior performance in predicting the survival of lung cancer patients, significantly outperforming traditional TNM and American Joint Committee on Cancer (AJCC) staging systems. External validation using the GSE13213 dataset also confirmed its robustness. Furthermore, the low-risk group exhibited higher immune microenvironment scores, suggesting a more active anti-tumor immune response, while the high-risk group showed elevated cell proliferation, migration, T-cell exclusion, and TIDE scores, indicating a more aggressive tumor phenotype. Additionally, the low-risk group demonstrated higher sensitivity to multiple drugs, including cisplatin, cyclophosphamide, paclitaxel, erlotinib, Niraparib, Rapamycin, Fulvestrant, and Venetoclax, highlighting its potential for guiding personalized treatment strategies.

Conclusion: The FRS represents a powerful and clinically relevant tool for predicting the survival of lung cancer patients, offering new insights into personalized treatment and therapeutic decision-making.