MedComm – Oncology最新文献

Imatinib (IM) is the first-line therapy for high-risk gastrointestinal stromal tumor (GIST) patients; however, over 50% of those with advanced stage or metastasis develop IM resistance within 2 years, and effective strategies to overcome this resistance remain elusive. In this study, we identified that decreased N6-methyladenosine (m6A) modification by the demethylase FTO regulated GIST progression and IM resistance. Long noncoding RNA XIST (XIST) was identified as the main demethylated RNA by FTO in GIST. FTO leaded to a decrease in m6A modification at the 10517-10633 site of XIST, thereby protecting it from degradation mediated by YTHDF2's recognition and binding. Stabilized XIST enhanced IM resistance by acting as a posttranscriptional regulator of KIT, the primary oncogenic driver in GIST. In vitro and in vivo functional assays confirmed the roles of both FTO and XIST in promoting GIST progression and IM resistance. Importantly, pharmacological inhibition of FTO using FB23-2 effectively restored IM sensitivity in murine xenograft models of GIST. Together, our findings establish a mechanistic link among FTO-mediated m6A demethylation, XIST stabilization, and posttranscriptional regulation of KIT in GIST. These insights highlight the therapeutic potential of targeting m6A-FTO axis to overcome IM resistance in GIST treatment.

Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer, accounting for approximately 50% of global lung cancer-related mortality, which underscores the urgent need for identifying novel biomarkers and therapeutic targets. Long noncoding RNAs (lncRNAs) have been increasingly recognized as pivotal regulators in cancer development; however, the specific function of lncRNA small nucleolar RNA host gene 5 (SNHG5) in LUAD remained unclear. This study aimed to investigate the clinical significance, biological roles, and molecular mechanisms of SNHG5 in LUAD pathogenesis. Through integrated bioinformatics analysis and experimental validation, we found that SNHG5 was significantly upregulated in LUAD tissues and cell lines. Functional in vitro and in vivo assays—including gain-/loss-of-function studies, luciferase reporter assays, RNA immunoprecipitation, co-immunoprecipitation, and tumor xenograft models—demonstrated that SNHG5 promoted malignant phenotypes by acting as a competing endogenous RNA (ceRNA) for miR-363-3p. This sponge activity elevated the expression of ubiquitin-specific peptidase 28 (USP28), which in turn stabilized β-catenin and activated oncogenic signaling. Rescue experiments confirmed the functional importance of the SNHG5/miR-363-3p/USP28/β-catenin axis. In conclusion, these results indicate that SNHG5 drives LUAD progression through a novel ceRNA mechanism, highlighting its potential as both a prognostic biomarker and a therapeutic target.

Metabolic reprogramming is a core hallmark of malignant tumors. It facilitates the rapid growth of tumor cells and significantly modulates antitumour immune responses through metabolic interactions, affecting the success of immunotherapy. Despite recent breakthroughs in immunotherapy, most patients exhibit limited responses, and the underlying mechanisms are closely related to metabolic dysregulation within the tumor immune microenvironment. However, a comprehensive review of how to systematically leverage metabolic interventions to enhance immunotherapy efficacy is lacking. This review examines the competitive interactions between tumor and immune cells within essential metabolic pathways, including those involving glucose, amino acids, lipids, and nucleotides. This metabolic stress leads to the functional exhaustion of effector immune cells and activation of immunosuppressive cells, thereby promoting immune escape. Based on these mechanisms, we further summarize therapeutic strategies that target key metabolic enzymes to reshape the immune microenvironment and discuss their integration with strategies and clinical advances such as immune checkpoint blockade or CAR-T cell therapy. This review systematically integrates the core mechanisms and cutting-edge strategies at the intersection of metabolism and immunity, provides a theoretical framework and methodological reference for basic research and clinical translation in this area, and offers a theoretical basis and translational perspective for the development of synergistic metabolic–immunological therapeutic strategies.

There is a complex pathological association between neurodegenerative diseases and cancer. The epidemiological negative correlation between Parkinson's disease (PD) and brain tumor is particularly noteworthy. PD is characterized by the loss of dopaminergic neurons and the formation of Lewy bodies, while glioma, the representative of brain tumors, originates from the malignant transformation of glial cells. The molecular interaction network between these two diseases is elusive, limiting the development of cross-disease treatment strategies. This review systematically summarizes the associations between PD and glioma in genetic predispositions, epigenetic modifications, alterations in subcellular compartments, and cellular mechanisms concerning neurons, glial cells, and stem cells. Additional links arise from circadian rhythm regulation, oxidative stress, and gut microbiota, underscoring the importance of systemic pathways that connect neurodegeneration and tumorigenesis. Within this context, cancer neuroscience emerges as a critical framework, demonstrating how neuronal activity drives cancer progression by shaping the tumor microenvironment. Therapeutic opportunities build upon these mechanistic insights, including engineering neuron types to suppress cancer growth, modulating synaptic genes, inducing neuronal cell death cascades, and controlling inflammation to disrupt tumor-nerve crosstalk. Emerging neuroscience-inspired technologies may drastically expand the treatment landscape. This review tries to unveil a potential theoretical paradigm for developing precise therapies with both neuroprotection and antitumor effects.

Breast cancer brain metastasis (BCBrM) remains a major clinical challenge with limited therapeutic options and poor prognosis. Despite advances in systemic therapy, the incidence of BCBrM is rising due to prolonged survival of patients with advanced breast cancer, yet effective brain-targeted strategies remain scarce, underscoring a critical research gap. This review integrates recent mechanistic insights that illuminate the complex biology underpinning BCBrM and explores how these discoveries are driving therapeutic innovation. We detail the metastatic cascade from local invasion to brain colonization, and examine key signaling pathways orchestrating brain-specific metastasis. Emphasis is placed on the dynamic crosstalk between tumor cells and the brain microenvironment, including astrocytes, microglia, and neurons, as well as metabolic reprogramming and immune evasion. We critically evaluate current preclinical models and their translational relevance, highlighting recent advances in humanized and imaging-based systems. Emerging therapies, such as central nervous system-penetrant kinase inhibitors, antibody–drug conjugates, and immunotherapies, are discussed alongside persistent challenges in drug delivery and resistance. Finally, we outline future directions, calling for cross-disciplinary collaboration and innovative clinical trial designs to personalize care and improve patient outcomes. Together, this review underscores the urgent need to bridge biology and therapy to transform the management of BCBrM.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major risk factor for hepatocellular carcinoma (HCC), yet treatment options for advanced disease remain limited. O-GlcNAc transferase (OGT), the enzyme catalyzing O-GlcNAcylation, has been implicated in tumorigenesis, but its pro-cancer mechanism in MASLD-HCC remains poorly defined. Here, we show that OGT expression is significantly upregulated during MASLD-HCC progression and negatively regulates the tumor suppressor phosphatase and tensin homolog deleted on chromosome ten (PTEN) both in vivo and in vitro. Mechanistically, OGT catalyzes O-GlcNAcylation of PTEN at T382, which competitively inhibits the phosphorylation at the same residue. This modification promotes PTEN ubiquitination and accelerates its degradation. Importantly, O-GlcNAcylation of PTEN simultaneously impairs its intrinsic phospholipase activity. These dual effects compromise PTEN function, leading to activation of PI3K/Akt signaling pathway and enhanced tumor cell proliferation and migration. Moreover, pharmacological inhibition of OGT suppresses tumor growth and, when combined with PI3K/Akt pathway inhibitors, produces additive antitumor effects. These findings reveal a novel mechanism by which OGT-mediated O-GlcNAcylation destabilizes and inactivates PTEN, driving MASLD-HCC progression. They also highlight OGT and PTEN as promising therapeutic targets for developing novel strategies against HCC.

Aging is a complex biological process that significantly influences human health, including susceptibility to cancer. Although aging and cancer are distinct phenomena, they intersect through shared molecular mechanisms such as genomic instability, telomere attrition, epigenetic alterations, and chronic inflammation. Despite increasing recognition of these connections, how aging-related changes influence cancer development and treatment remains poorly understood. This review explores the intricate relationship between aging and cancer, highlighting how age-related changes in the tumor microenvironment, systemic inflammation and cellular senescence contribute to oncogenesis and tumor progression. We also assess the impact of aging on cancer treatment outcomes, as well as how cancer and its therapies may contribute to the acceleration of biological aging. Furthermore, we discuss potential intervention strategies that target the aging-related mechanisms that drive cancer development and progression. We review current progress and future directions in aging and cancer research, emphasizing that, with continuous technological advances and deepening insights, incorporating aging biology into oncology is both timely and necessary. By integrating recent advances in cancer biology and geroscience, this review offers insights critical for designing age-adapted therapeutic strategies. It underscores the need to shift toward personalized oncology approaches that account for the biological and clinical heterogeneity of aging.

The DEAD-box RNA helicase 17 (DDX17) is strongly linked to the occurrence and development of specific human cancers, emphasizing its previously unrecognized biological roles in cancer progression and metastasis. However, the precise mechanisms by which DDX17 regulates liver cancer metastasis have not been thoroughly explored. In this study, increased DDX17 expression levels showed a robust association with the invasive potential of hepatocellular carcinoma (HCC) cells. Silencing DDX17 expression resulted in substantial reduction of HCC cell migration and invasion potentials, while DDX17 overexpression had the opposite effect. Silencing DDX17 also attenuated epithelial–mesenchymal transition (EMT) in HCC cells and significantly reduced metastatic lesions in an orthotopic HCC nude mouse model. Mechanistically, chromatin immunoprecipitation assays revealed that TCF4 physically interacts with the DDX17 promoter, activating its transcriptional expression. Immunoprecipitation results demonstrated that DDX17-mediated nuclear input of β-catenin is dependent on its helicase functional domain. Furthermore, we demonstrated that β-catenin/TCF4 is essential for DDX17-induced migration and invasion in HCC cells. Taken together, these findings emphasize the significance of DDX17 in the malignant progression and metastasis of HCC, revealing a novel mechanism involving the β-catenin/TCF4/DDX17 pathway.

Epstein–Barr virus-associated gastric cancer (EBVaGC) is a unique subtype of gastric cancer (GC) with distinct molecular characteristics that generally has a better prognosis. BamHI-A leftward frame 4 (BALF4), an envelope glycoprotein encoded by the Epstein-Barr virus (EBV), plays an important role in EBV infection. However, its biological function and potential molecular mechanisms in EBVaGC remain unclear. This study aimed to investigate the impact of the highly expressed viral gene BALF4 on the progression of EBVaGC. Here, we detected the expression of BALF4 in GC tissue chips and validated that the presence of BALF4 might be associated with a favorable prognosis in EBVaGC. The results showed that BALF4 inhibited the proliferation, migration, and invasion of GC cells in vitro and in vivo. In addition, we discovered that BALF4 interacts with N-acetyltransferase 10 (NAT10). High expression of NAT10 in GC tissues promotes the malignant phenotype of GC cells. We discovered that BALF4 could inhibit the malignant progression of GC by promoting the ubiquitination and degradation of NAT10. In summary, our study revealed a possible mechanism explaining the favorable prognosis of the EBVaGC subtype, which contributes to a better understanding of this special type of GC.

A groundbreaking study published in Cell Metabolism reveals how lactate promotes cancer stemness and therapy resistance by reshaping epigenetic landscapes [1]. By employing advanced single-cell tracking and machine learning in tumor organoids, the authors demonstrate that lactate suppresses differentiation and induces dedifferentiation of cancer cells into stem-like states through MYC activation. This discovery underscores lactate as a key regulator of tumor dynamics and identifies bromodomain protein 4 (BRD4) inhibitors as a promising therapeutic strategy to prevent relapse.

Tumor cells typically rely on glycolysis (the Warburg effect) for rapid energy supply, producing a large amount of lactate. Traditionally viewed as a metabolic byproduct, lactate is now recognized as a signaling molecule with multiple roles in the tumor microenvironment. The accumulation of lactate is closely associated with tumor proliferation, invasion, and drug resistance [2]. In gastric cancer, lactate promotes NBS1 K388 lactylation, enhancing MRN complex formation and recruitment to DNA double-strand breaks, thereby improving homologous recombination repair and mediating chemoradiotherapy resistance [3]. Lactate metabolism has thus emerged as a key focus in cancer research.

Cancer recurrence and metastasis remain major clinical challenges, driven largely by cancer stem cells (CSCs). CSCs exhibit self-renewal, multi-directional differentiation, and drug resistance, enabling survival post-therapy and tumor regeneration. Cancer differentiated cells (CDCs), as an important component of the tumor cell population, exhibit significant functional differences from CSCs. Research by the Rodríguez Colman team at the University Medical Center Utrecht revealed that murine intestinal stem cells and differentiated cells display distinct metabolic profiles and interact via lactate [4]. This suggests similar metabolic heterogeneity may exist between CSCs and CDCs in human intestinal tumors, with lactate playing a potential role in tumor progression. Further investigation into lactate's functional impact in these interactions is warranted.

Immunostaining of clinical samples showed that the expression level of monocarboxylate transporter 4 (MCT4), a lactate transporter, was significantly higher in CDCs than in CSCs. This indicates that CDCs have a higher glycolysis level. This finding demonstrates that, although tumor metabolism is generally characterized by the Warburg effect, there are notable differences in aerobic glycolysis levels among different tumor cell populations. Single-cell analysis further confirmed that the lactate level was elevated in CDCs relative to CSCs, indicating a higher glycolytic rate in CDCs. However, no significant differences were observed in basal glucose levels or glucose uptake between CDCs and CSCs. Interestingly, CSCs exhibited a greater capacity for lactate uptake compared to