Molecular Oncology最新文献

Early detection of cancer is essential for effective treatment. However, current prostate cancer screening methods lack sufficient sensitivity and specificity, leading to overdiagnosis and unnecessary treatment. There is also an unmet need to distinguish clinically significant from insignificant prostate cancer. To identify complementary biomarkers for improved screening and diagnosis, we performed transcriptional profiling of cancer-associated transcripts in circulating extracellular vesicles (EVs) isolated from peripheral blood of patients with suspected prostate cancer prior to biopsy and healthy donors. Expression data for 2549 mRNAs were obtained from 28 men. CAPN5 expression was significantly lower, whereas BIRC2, CASP3, CD63, FMO5, IRF6, PFDN1, PRDX6, PSMD2, RIT1, S100A2, THBS1, and XRCC2 were significantly elevated in EVs from patients with significant prostate cancer (n = 14) compared with cancer-free individuals and patients with insignificant disease (n = 14). Candidate biomarkers were subsequently evaluated by in silico validation using the The Cancer Genome Atlas (TCGA) prostate adenocarcinoma dataset and the GEO dataset GSE70768 containing benign and malignant prostate tissues. This analysis identified CASP3, XRCC2, and RIT1 transcripts in circulating EVs as promising biomarkers for the early detection of significant prostate cancer.

Cervical cancer is one of the leading causes of tumor-related deaths among women. Chemotherapy in cervical cancer is mainly based on cisplatin, but this drug has limited efficacy; therefore, alternative treatment options are needed. Ferroptosis represents a novel form of cell death. In cervical epithelium, ferroptosis occurs in the early neoplastic stages of papillomavirus infection but shifts to evasion in carcinoma. Combination therapy has the potential to enhance cancer cell death and overcome resistance development. Herein we demonstrate that dimethyl fumarate (DMF), a Food and Drug Administration (FDA)-approved anti-inflammatory drug, induces ferroptosis in cervical cancer cells in a dose-dependent manner and inhibits growth in spheroid models. Cotreatment with DMF and cisplatin significantly decreases cell viability compared to either drug alone. Under DMF/cisplatin combination, cervical cancer cells underwent to glutathione depletion and p53 (re)activation, leading to cell death by both ferroptosis and apoptosis. We found a p53-mediated downregulation of the Solute Carrier Family 7 Member 11 (SLC7A11)/Cystine/Glutamate Transporter (xCT) expression and glutathione levels. Our results suggest that combined administration of DMF and cisplatin, by targeting the dependency of cervical cancer cells on glutathione and (re)activating p53, represents a promising anticancer therapeutic strategy.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, with poor prognosis despite multimodal therapy. Chloride cotransporters NKCC1 and KCC2 are key regulators of intracellular chloride levels and thereby determine whether GABA acts inhibitory or excitatory. In GBM, disrupted chloride homeostasis promotes proliferation, migration, and stem-like properties, but its clinical relevance is not fully understood. We analyzed NKCC1 and KCC2 expression in GBM samples, considering clinical parameters, such as age, gender, and MGMT promoter methylation. Statistical analyses included ROC-based cutoff determination, Kaplan-Meier survival analysis, and subgroup. Immunohistochemistry was performed to identify cell types expressing NKCC1. NKCC1 expression was significantly higher in older patients and emerged as a prognostic marker for recurrence-free survival, with lower levels correlating with delayed recurrence, although overall survival was unaffected. NKCC1 was expressed in stem-like, astrocytic, and neuronal progenitor cells, but not in mature neurons. These findings identify NKCC1 as a regulator of GBM progression and recurrence, linking chloride transporter imbalance to GABAergic signaling. Targeting NKCC1 and restoring chloride homeostasis may provide promising new treatment strategies.

Treatment resistance has become a major challenge in cancer research, particularly for patients with advanced castration resistant prostate cancer (CRPC) where no curative therapies are available. Epigenetic alterations play a significant role in cancer progression. In prostate cancer (PCa), where androgen receptor (AR) is the primary oncogenic driver, epigenetic coregulators, specifically lysine demethylases (KDMs), have previously been identified as factors that alter the transcriptome as cancer cells acquire resistance. KDM7A has been identified as a cancer-promoting factor in many cancers; however, its role in PCa remains largely unexplored. This study investigates the clinical relevance of KDM7A in comparison with the well-studied KDM1A in PCa. Using PCa cell line models, we confirm KDM7A as an AR coregulator. By exploiting commercially available pharmacological inhibitors, we demonstrate that in AR-positive CRPC cell lines, combinatory inhibition of KDM1A and KDM7A leads to a loss of AR and the AR-driven transcriptome, which in turn attenuates cancer-promoting cell phenotypes. These findings highlight the potential of combination-targeted therapies in tackling advanced prostate cancers.

Von Hippel-Lindau disease (vHL) predisposes to tumor development, mainly clear cell renal carcinoma and hemangioblastoma. The underlying cause is germline variants in the VHL gene, with tumorigenesis thought to require additional somatic 'second-hit' events that most commonly include loss of 3p. However, the precise mechanisms of vHL-related tumor development remain incompletely understood. Genomic investigations of familial hemangioblastoma may help elucidate the early steps of tumorigenesis and contribute to improved disease prediction, biomarker discovery, and therapeutic strategies. We performed whole exome sequencing on 22 familial hemangioblastomas from 7 patients representing 5 unrelated families, and with 4 different causative VHL genotypes. The tumors exhibited low overall mutational burden but showed frequent loss of heterozygosity on chromosome 3 or 3p and single nucleotide variants in the VHL region. Variants were significantly enriched in genes associated with GABAergic and serotonergic neuronal cell types, as well as in pathways regulating cell cycle and neurogenesis. These findings suggest that, in addition to VHL loss, dysregulation of neuronal differentiation programs and cell cycle control may play important roles in hemangioblastoma tumorigenesis.

DNA double-strand breaks (DSBs) generated from collisions of DNA replication forks with cisplatin-induced interstrand crosslinks underpin cisplatin cytotoxicity. Yet, the impact of cell-cycle-dependent cisplatin-DNA adduct (CDA) formation on cell cycle progression and interactions with DNA replication remain incompletely characterized. Also, although cisplatin enhances tumor response to ionizing radiation (IR), the underpinning radiosensitizing mechanisms remain unresolved. Here, we close this void and analyze CDAs (GpG crosslinks) and DSB (γH2AX foci) induction and repair in a strictly cell-cycle-dependent manner. We report for the first time that CDAs form in a dose- and time-dependent manner in all cell cycle phases, whereas DSBs emerge only in S-phase. Repair of IR-induced DSBs remains largely unaffected by CDAs in G₁, S, and G₂ phases, but is inhibited when S-phase-treated cells progressed to G₂. Radiosensitization occurs after prolonged cisplatin exposure, likely owing to G₂-phase accumulation and lesion evolution from S-phase, thus impairing repair of IR-induced DSBs. Cisplatin fails to radiosensitize quiescent (G₀) cells. In summary, CDA formation is similar across the cell cycle, but DSBs form only in S-phase. Whereas CDAs fail to interfere with repair of IR-induced DSBs, progression-dependent repair disruptions cause radiosensitization. Elucidation of the underpinning mechanisms may help to design improved cisplatin-radiation schedules for more efficacious therapies.

Neutrophils are abundant innate immune cells with remarkable plasticity, capable of exerting both antitumour and protumour functions. Beyond their local roles in the tumour microenvironment, recent studies highlight tumour-induced granulopoiesis as a systemic process by which cancers rewire haematopoiesis to expand immature neutrophils with immunosuppressive and tumour-promoting activity. Sustained by tumour-derived cytokines, chemokines and alarmins, tumour-induced granulopoiesis activates developmental programmes such as STAT3-C/EBPβ and RORC1, driving persistent neutrophilia and systemic immune suppression. Here, we review neutrophil maturation and heterogeneity, their dual roles in tumour initiation and progression, and the emerging recognition of tumour-induced granulopoiesis as a critical axis of tumour-host interaction with clinical and therapeutic implications.

Neuronal innervation of the pancreas has historically been characterized using marker-based classification and physiological studies, but its transcriptomic landscape remains only partially explored. A detailed molecular profile of pancreatic sensory neurons could provide insights into their role in health and disease, particularly in pancreatic ductal adenocarcinoma (PDAC), where neural remodeling influences tumor progression and pain signaling. Wild-type and PDAC mice were injected with the retrotracer Fast Blue into pancreatic or cancerous tissue. Dorsal root ganglia were dissociated, and Fast Blue-positive sensory neurons were isolated, lysed, and analyzed using single-cell RNA sequencing. Data were validated using immunofluorescence, organoid cultures and qPCR. We performed transcriptomic profiling of sensory neurons innervating the pancreatic head and tail under normal and cancer conditions. Our analysis identified neurofilament-containing neurons as the predominant sensory subtype in both contexts, while non-peptidergic neurons were underrepresented in tumor-associated innervation. Differential gene expression analysis revealed a unique subset of genes upregulated in sensory neurons innervating pancreatic tumors, many linked to mitochondrial activity. Further validation also revealed the presence of transcripts transferred via extracellular vesicles (including the Pdx1-CreERT2 transgene from the KPC mouse model), suggesting a novel mechanism of tumor-neuron interaction. Our findings provide a detailed characterization of pancreatic and pancreatic ductal adenocarcinoma sensory innervation. We identified tumor-derived RNA within sensory neurons in the PDAC mouse model, suggesting an extracellular vesicle-mediated RNA transfer mechanism that may remodel sensory signaling and open new prospects for diagnostic and therapeutic innovation in PDAC. Impact statement Transcriptomic profiling of pancreatic sensory neurons reveals shifts in neuronal populations, tumor-specific mitochondrial gene upregulation, and potential extracellular vesicle-mediated transcript transfer. Circulating tumor transcripts in KPC mice provide a reference for pancreatic innervation, tumor-nerve interactions, and therapeutic targets.

Transforming growth factor-β (TGF-β) regulates epithelial homeostasis by inducing growth arrest and apoptosis during early carcinogenesis; however, these tumor-suppressive functions are frequently lost in advanced nonsmall cell lung cancer (NSCLC) despite intact signaling. We identify the transcription factor E2A as a critical mediator of resistance to TGF-β-induced apoptosis in mutant KRAS-driven NSCLC. TGF-β induces E2A expression in a SMAD3-dependent manner in NSCLC cells harboring mutant KRAS, but not in those with wild-type KRAS. Silencing E2A restores TGF-β-induced apoptosis in mutant KRAS cell lines without affecting epithelial-mesenchymal transition. E2A depletion promotes mitochondrial apoptosis through mitochondrial outer membrane permeabilization, caspase-3 activation, and regulation of BCL-2 family and inhibitor-of-apoptosis proteins. In contrast, wild-type KRAS NSCLC cells fail to upregulate E2A in response to TGF-β and remain resistant to apoptosis following E2A silencing. Knockdown of mutant KRAS abrogates the pro-apoptotic effects of E2A silencing, establishing KRAS dependency. E2A silencing enhances radiation-induced growth inhibition, likely through increased sensitivity to TGF-β signaling. E2A is overexpressed in lung adenocarcinoma and is significantly elevated in tumors harboring mutant KRAS. These findings identify E2A as a context-specific suppressor of TGF-β-mediated apoptosis and a potential therapeutic target in mutant KRAS NSCLC.

The limited efficacy of immunotherapy in clinical trials in high-grade serous ovarian cancer (HGSOC) may improve by implementing experimental models that are more reflective of human biology into preclinical studies. To address this, we developed and validated a humanized patient-derived xenograft mouse model of HGSOC. Human hematopoietic stem cells and patient-derived HGSOC cells were engrafted into immunodeficient mice. The mice were administered durvalumab (anti-PD-L1) and/or oleclumab (anti-CD73) immunotherapy intraperitoneally twice a week for 5 weeks. The treatment showed good tolerability with no observed side effects, though it failed to elicit a measurable antitumor response. Leukocytes in primary tumors were analyzed immunohistochemically, and circulating T cells were characterized using spectral flow cytometry. All tumors exhibited an immune-excluded immunophenotype. No significant inter-group differences in disease burden, intratumoral leukocyte density, or circulating T cells were observed. In the durvalumab-only group, tumor burden significantly positively correlated with intratumoral cytotoxic and regulatory T-cell densities. This model reflects the immunotherapy resistance of human disease in line with clinical findings, providing a robust platform for studying tumor-immune interactions and immunosuppressive mechanisms in HGSOC. Impact statement Our results address the critical need for representative preclinical models for testing combination immunotherapy in HGSOC by providing a robust preclinical platform that can enhance the reliability of preclinical data and contribute to the improvement of the design and outcomes of future clinical trials.