Cellular Oncology最新文献

Background: Pancreatic cancer is typically accompanied by fibrosis, forming a dense stromal matrix. This dense matrix restricts drug penetration, making it difficult for drugs to effectively reach tumor cells. Additionally, pancreatic cancer has inadequate local blood supply and "vascular irregularity," which makes it challenging for drugs to reach the core of the tumor. Even if some drugs reach the pancreas through systemic circulation, poor vascular permeability prevents them from effectively entering tumor cells, resulting in suboptimal therapeutic effects. Statins were initially used to treat high cholesterol levels and prevent cardiovascular diseases, but recent studies suggest that they may also have potential therapeutic effects on cancer, particularly certain types of cancer such as pancreatic cancer. However, clinical research on the use of statins for pancreatic cancer treatment is still ongoing, and the results are inconsistent. The effects of statins on pancreatic cancer may vary depending on the dose. Due to the aforementioned limitations of fibrosis and lack of blood supply in pancreatic cancer, simvastatin only exerts its effect on pancreatic cancer cells at low doses.

Purpose: This study aimed to explore the effects of low-dose simvastatin on pancreatic cancer cells and the underlying mechanisms. We investigated the effects of different concentrations of simvastatin on pancreatic cancer cells.

Methods: The vitality of the cells was evaluated by CCK8, EDU staining, and the level of ferroptosis in pancreatic cancer cells was detected by flow cytometry detection of C11, MDA, ROS.

Results: We found that small doses of simvastatin can resist the toxicity of Erastin against pancreatic cancer cells. Under the transmission electron microscope, more mitophagosomes were produced in pancreatic cancer cells treated with small dose of simvastatin, and immunofluorescence revealed increased co-localization of lysosomes and mitochondria, indicating that simvastatin promoted the occurrence of mitophagy. At the same time, immunofluorescence confirmed that simvastatin promoted the nuclear translocation of TFEB, and chromatin immunoprecipitation and dual-luciferase gene report confirmed that TFEB is the transcription factor of P62/SQSTM1. This study clarified that a small dose of simvastatin, in the event of mitochondrial stress in pancreatic cancer cells, induces mitophagy to clear damaged mitochondria, protecting pancreatic cancer cells from ferroptosis and apoptosis, by promoting the transcription of P62/SQSTM1 through the nuclear translocation of TFEB.

Conclusion: These findings may explain one of the reasons for the suboptimal efficacy of simvastatin in the treatment of pancreatic cancer, while also providing new insights for research on the antitumor effects of statins.

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.