Deltex E3 ubiquitin ligase 3L (DTX3L) is a well-established ubiquitin ligase implicated in various cancers, but its role in nasopharyngeal carcinoma (NPC) progression remains elusive. In this study, we confirmed for the first time that DTX3L was highly expressed in C666-1 and NPC/HK1 NPC cells. DTX3L overexpression promoted NPC cell proliferation, invasion, and migration. Conversely, DTX3L knockdown suppressed these malignant phenotypes. Notably, DTX3L activated the β-catenin pathway, as evidenced by increased β-catenin nuclear translocation, increased transcriptional activity, and elevated expression of its downstream target c-Myc. Mechanistically, we identified an upstream regulatory axis in which the oncogenic long noncoding RNA H19 acted as a molecular sponge for miR-423-5p, thereby alleviating the miR-423-5p-mediated repression of DTX3L. Dual-luciferase reporter assays confirmed that miR-423-5p directly targeted both DTX3L and H19, supporting the presence of a competitive endogenous RNA (ceRNA) network. Furthermore, rescue experiments demonstrated that DTX3L knockdown largely abolished the proliferative advantage conferred by H19 overexpression. Collectively, the results of our study revealed that the H19/miR-423-5p/DTX3L axis is a novel ceRNA-driven mechanism that promotes NPC progression via activation of β-catenin signaling.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality globally; however, the molecular drivers remain unclear. Dysregulated cholesterol metabolism is a hallmark of HCC and contributes to tumor progression. The Niemann-Pick type C1 protein (NPC1), a lysosomal cholesterol transporter, is overexpressed in cancers; however, its oncogenic mechanisms in HCC remain unclear. In this study, we identified NPC1 as a critical regulator of HCC progression through dual mechanisms involving p53 destabilization and modulation of cholesterol metabolism. Analysis of the clinical data revealed that NPC1 was significantly upregulated in HCC tissues and correlated with poor prognosis. Functional studies have demonstrated that NPC1 silencing suppresses HCC cell proliferation, both in vitro and in vivo. Mechanistically, NPC1 interacts with deubiquitinase ubiquitin-specific protease 7 (USP7), disrupting its binding to p53 and enhancing p53 ubiquitination and proteasomal degradation. Concurrently, NPC1 modulates cholesterol synthesis and distribution via the p53-SREBP2 axis, and p53 knockdown reverses the cholesterol reduction caused by NPC1 silencing. The pharmacological activation of p53 reversed the decrease in cholesterol levels mediated by the overexpression of NPC1. These findings reveal that NPC1 is a multifaceted oncoprotein in HCC, linking cholesterol metabolism to p53 regulation and highlighting its potential as a therapeutic target for HCC intervention.

S-palmitoylation, a reversible lipid-based post-translational modification, is notably elevated in colorectal cancer (CRC) due to common lipid metabolism disorders. It has been reported to play crucial roles in regulating membrane composition, cell proliferation, and metastasis in various malignancies such as pancreatic and breast cancers. However, its role in the progression of CRC remains poorly understood. ZDHHC9, a member of the palmitoyl transferase family, is significantly upregulated in CRC patients and correlates with poor prognosis. Knockdown of ZDHHC9 impairs CRC cell proliferation and migration both in vitro and in vivo. RNA sequencing revealed that ZDHHC9 depletion markedly downregulates the cAMP signaling pathway. Mechanistically, ZDHHC9 knockdown impairs ADCY4 activity by reducing S-palmitoylation of KLF5 at cysteine 438, thereby modulating the ZDHHC9/KLF5/ADCY4 axis and downstream cAMP/PKA/CREB signaling to influence CRC cell proliferation and migration. Our findings demonstrate that ZDHHC9 promotes CRC progression by regulating intracellular cAMP levels through KLF5 palmitoylation, providing a novel therapeutic perspective targeting palmitoylation in CRC. The mechanism diagram of this study. ZDHHC9 mediates palmitoylation of KLF5 at cysteine 438, thereby enhancing ADCY4 activity and increasing intracellular cAMP levels. This elevation in cAMP promotes PKA and phosphorylation of CREB, ultimately activating the cAMP/PKA/CREB signaling pathway, which contributes to the regulation of CRC cell proliferation, migration, and resistance to 5-FU. (Created with BioRender.com).

Malignant cancers exhibit distinct lipid metabolic features that support tumor initiation and progression. Glioblastoma (GBM) is an aggressive brain tumor driven by GBM stem cells (GSCs), which are responsible for tumor development and therapy resistance. However, effective treatments targeting vulnerable metabolic pathways in GSCs have not yet been developed. Here, we demonstrate that the ATP-binding cassette transporter A3 (ABCA3) maintains lipid metabolic balance in GSCs. ABCA3 is highly expressed in GSCs, where lipid biosynthesis is particularly active. Knocking down ABCA3 significantly reduces cell growth, self-renewal, viability, and tumor growth after intracranial implantation. These changes are caused by a profound disruption of lipid metabolic balance, as demonstrated by RNA sequencing and liquid chromatography-time-of-flight mass spectrometry, which revealed widespread alterations in lipid metabolism genes and lipid composition. Mechanistically, ABCA3 knockdown inhibits sterol regulatory element-binding protein 1 (SREBP1) signaling by accumulating acylcarnitines (ACs) caused by phospholipid breakdown. The increased ACs induce the production of mitochondrial reactive oxygen species, which activate adenosine monophosphate-activated protein kinase (AMPK), resulting in the inhibition of SREBP1 signaling and reduced GSC fitness. Overall, these findings suggest that ABCA3 maintains lipid metabolic balance in GSCs, and disrupting this function triggers AMPK-dependent suppression of SREBP1 signaling.

Acute myeloid leukemia (AML) remains challenging to treat due to extensive genetic heterogeneity, high relapse rates, and treatment-related toxicity. Although drug combinations offer therapeutic promise, their selection is often empirical. Here, we introduce Combinatorial Proteome Integral Solubility/Stability Alteration analysis (CoPISA), a high-throughput proteomics workflow that captures protein solubility/stability alterations uniquely induced by drug combinations. We applied CoPISA to two rationally designed AML drug pairs, LY3009120-sapanisertib (LS) and ruxolitinib-ulixertinib (RU), previously identified as the most effective and least toxic combinations among many candidates and validated in AML cell lines, patient-derived samples and zebrafish xenograft models. We uncovered an emergent mechanism termed "conjunctional targeting", in which combinatorial drug action induces combination-exclusive protein targets consistent with an AND-gate logic model. LS-specific converged on SUMOylation, chromatin condensation, and VEGF-linked adhesion, while RU-specific targets disrupted DNA-damage checkpoints, mitochondrial bioenergetics, and RNA-splicing. Post-translational modification analysis revealed combination-induced acetylation, methylation, and phosphorylation of key AML proteins, including NPM1. Network analysis demonstrated that a substantial fraction of AML-associated proteins targeted by CoPISA are unique to combinations, including DNMT3A, NPM1, and TP53. By uncovering a mechanistic layer beyond classical synergy, CoPISA provides a robust framework for the precision-guided design of combinatorial therapies in heterogeneous cancers.

High-grade serous ovarian cancer (HGSOC) is characterized by a complex, immunosuppressive tumor microenvironment (TME) that contributes to poor clinical outcomes and resistance to therapy. To replicate the human TME in vitro, we develop a 3D pentaculture model incorporating five human cell types: malignant HGSOC cells and primary fibroblasts, mesothelial cells, adipocytes, monocytes. Monocytes differentiate into macrophages without exogenous cytokines in the pentacultures. Bulk RNA sequencing and deconvolution with single-cell RNA data from patient biopsies reveal that macrophage clusters within the pentacultures replicate those found in human HGSOC metastases, and proportions of individual clusters vary according to the malignant cell line. The pentacultures enable detailed analysis of malignant cell-macrophage interactions and highlight the influence of malignant cell genomic, transcriptomic and proteomic heterogeneity on the TME. Furthermore, targeting of "do-not-eat-me" signals with anti-CD47 and anti-CD24 monoclonal antibodies demonstrate differential effects on macrophage activity and cancer cell viability, again depending on the individual malignant cell line. Real-time microscopic monitoring of the pentacultures confirms dynamic modulation of macrophage behavior. We conclude that this pentaculture model offers a platform to study malignant cell control of TME elements and in particular their interactions with myeloid cells.

Gastric cancer (GC) is a highly aggressive malignancy with a poor prognosis. Transfer RNA-derived small RNAs (tsRNAs) are implicated in tumorigenesis, but their precise mechanistic roles in GC progression remain incompletely understood. We performed high-throughput sequencing in four paired GC/normal tissues to profile tsRNAs. The functional and mechanistic role of a candidate tsRNA was systematically investigated, alongside a suite of techniques including fluorescence in situ hybridization, RNA immunoprecipitation, RNA pull-down, chromatin immunoprecipitation, and luciferase reporter assays. We identified a novel tsRNA, tRF-Ser, that was significantly downregulated in GC tissues and cell lines, and its expression was correlated with favorable survival. Functionally, tRF-Ser acted as a tumor suppressor by inhibiting epithelial-mesenchymal transition (EMT), inducing ferroptosis, and enhancing sensitivity to 5-fluorouracil chemotherapy. Mechanistically, tRF-Ser directly bound to the cellular nucleic acid-binding protein CNBP (a transcription factor), promoting its accumulation in the cytoplasm and preventing its binding to the HSPA8 promoter to downregulate HSPA8. Then, the tRF-Ser/CNBP/HSPA8 axis suppressed EMT by inhibiting β-catenin nuclear translocation and promoted ferroptosis by facilitating STUB1-mediated ubiquitination degradation of GPX4. Our study unveils that the tRF-Ser/CNBP/HSPA8 axis may constrain GC progression by regulating energy metabolism, which highlights the therapeutic potential of targeting this axis for GC treatment.

Reactive oxygen species (ROS) act as critical secondary messengers in various intracellular signaling pathways that regulate cellular proliferation, differentiation, and survival under normal physiological conditions. However, dysregulation of redox signaling-driven by genetic mutations, epigenetic alterations, and posttranscriptional or posttranslational modifications-plays a central role in malignant transformation and cancer progression. Cancer cells typically exhibit elevated basal ROS levels due to increased metabolic activity, mitochondrial dysfunction, and oncogene activation. This moderate oxidative stress promotes tumorigenesis by inducing DNA damage, genomic instability, and aberrant activation of proliferative and survival pathways, while also contributing to resistance to conventional therapies. Paradoxically, excessive ROS accumulation can overwhelm antioxidant defenses, triggering oxidative stress-induced programmed cell death (PCD) mechanisms, including apoptosis, autophagy, and ferroptosis. Owing to its dual role-facilitating both tumor progression and suppression-ROS have emerged as compelling yet complex targets in cancer therapy. Therapeutic strategies aimed at modulating ROS homeostasis, such as enhancing ROS production, inhibiting antioxidant systems, or targeting downstream redox-regulated signaling nodes, hold promise for selectively eliminating cancer cells. Furthermore, integrating redox profiling or "redox signatures" into personalized medicine approaches may optimize therapeutic efficacy while minimizing off-target toxicity. In this review, we critically examine the Janus-faced role of ROS in carcinogenesis, dissect the molecular pathways regulated by ROS in tumor biology, and explore current advancements, limitations, and future directions in redox-based anticancer therapeutic approaches.

Hepatocellular carcinoma (HCC) is the most prevalent hepatic malignancy worldwide, accounting for approximately 90% of all primary liver cancer cases. However, the mechanisms involving in liver tumorigenesis and drug resistance remain unclear, largely restricting the clinical management of HCC. Here, we first evaluated the clinical significance of malic enzyme 1 (ME1) in HCC patients and revealed that ME1 was significantly upregulated in tumor tissues and positively correlated with poor prognosis. Gain- and loss-of-function experiments suggested that ME1 promoted HCC cell viability in vitro. Consistently, hepatocyte-specific Me1 knockout (Me1HKO) mice treated with diethylnitrosamine (DEN) showed reduced tumor burden as compared to Me1Flox mice. In addition, ME1 overexpression conferred resistance to the first-line therapeutic drug lenvatinib, while knockout of ME1 restored drug sensitivity in lenvatinib-resistant HCC cells. Mechanistically, we showed that ME1 could regulate ferroptosis of HCC cells through its function on NADPH production. We further identified ferroptosis suppressor protein 1 (FSP1) as a key downstream effector, which utilized ubiquinol (CoQH2) as a lipophilic radical-trapping antioxidant to block the accumulation of lipid peroxides to pro-ferroptotic levels. In summary, our findings demonstrated that ME1 promotes HCC progression by activating the NADPH-FSP1-CoQH2 axis and thereby inhibiting ferroptosis, suggesting a promising therapeutic strategy for HCC treatment.

Metastasis remains the primary cause of mortality in pancreatic ductal adenocarcinoma (PDAC). Circulating tumor cells (CTCs) are key players in metastasis, yet the mechanisms governing CTCs formation and survival are incompletely understood. Here, we identify ITGA3 as a key driver of CTCs generation and metastatic progression in PDAC. Integrated proteomic and transcriptomic analyses, coupled with clinical specimen validation, revealed that ITGA3 expression positively correlates with CTCs abundance and poor prognosis. Mechanistically, ITGA3 promotes epithelial-mesenchymal transition (EMT), enhances matrix metalloproteinase expression, and facilitates tumor cell detachment, thereby initiating CTCs formation. Importantly, cancer-associated fibroblasts (CAFs) secrete laminin-332 (LAM332), which engages ITGA3 on PDAC cells to promote proliferation and invasion, drive homotypic CTC clustering, and suppress apoptosis, collectively sustaining CTCs' survival. Neutralization of CAFs-derived LAM332 impaired tumor cell proliferation and invasion, disrupted CTC cluster formation, increased apoptosis, reduced hepatic and pulmonary metastasis, and prolonged survival in mouse models. These findings uncover a CAFs-LAM332-ITGA3 axis that orchestrates CTCs formation and survival, and highlight this stromal-tumor interaction as a promising therapeutic target to mitigate metastatic progression in PDAC.

The cGAS-STING pathway is crucial for recognizing aberrant DNA in the cytoplasm and activating the innate immune response. After detecting aberrant DNA in the cytoplasm, cGAS can catalyze the synthesis of cGAMP from ATP and GTP, which acts as a second messenger to engage STING and unleash type I interferons, thereby eliciting a robust antitumor immune cascade. In recent years, the role of the cGAS-STING pathway in tumor immunity has attracted widespread attention. Paradoxically, it not only activates antitumor immune responses but also promotes tumor progression under certain circumstances. This review untangles the safeguards that prevent cGAS from recognizing nuclear self-DNA, delineates the antitumor and pro-tumor mechanisms of the cGAS-STING axis, and surveys tumor immunotherapy strategies targeting this pathway.

Glioblastoma (GBM), the most common malignant brain tumor in adults, remains a highly lethal and incurable cancer, with a 5-year survival rate below 10%. Standard-of-care involves surgical resection followed by concurrent temozolomide chemotherapy and radiation treatment. While these interventions can effectively shrink tumors, they fail to eradicate all malignant cells. Small populations of GBM cells invariably survive and seed recurrent disease, leading to near-universal relapse and the formation of fatal recurrent tumors, typically within 1-2 years of treatment. Here, we investigated the metabolic features that define these surviving cell populations using ten patient-derived GBM models and matched orthotopic xenograft models exposed to a clinically relevant chemoradiotherapy regimen. By sampling living cells at defined treatment intervals and integrating 13C-glucose tracing, quantitative untargeted metabolomics, and nCounter metabolic gene expression profiling, we reconstructed the temporal evolution of glucose metabolism from therapy-naïve to post-treatment states. Across all models, GBM cells that evaded therapy-induced death exhibited a conserved and coordinated reorganization of glycolytic flux. These cells showed enhanced glucose uptake and elevated abundance of upper glycolytic enzymes such as HK1, while lower glycolytic enzymes, including ALDOA, GAPDH, ENO1, and LDHA, were suppressed, resulting in reduced lactate output. This bifurcation of glycolytic metabolism redirected carbon flux toward the pentose phosphate pathway and nucleotide biosynthesis, as well as mitochondrial metabolism, supported by the increased abundance of tricarboxylic acid cycle enzymes. Notably, these adaptations were conserved in recurrent patient-derived orthotopic xenograft tumors in vivo. Together, these findings reveal a fundamental and conserved metabolic state that defines GBM cells surviving chemoradiotherapy. This study deciphers a core metabolic architecture that enables tumor cell survival, persistence, and recurrence following therapy by shifting glycolytic flux away from lactate production to balance biosynthetic demands with mitochondrial metabolism.

Isocitrate dehydrogenase (IDH)-mutant low-grade and high-grade gliomas are primary brain cancers with slower growth rates and longer survival than IDH-wildtype counterparts. However, these tumors are fatal and because of the younger age of patients, result in significant morbidity and loss of productivity. Several management options are available at initial diagnosis for IDH-mutant gliomas (including close surveillance, surgery, radiation therapy, chemotherapy and/or targeted therapies either alone or in combination), however, there is limited data about optimal timing and sequencing. When considering treatment, the risks associated with uncontrolled disease should be weighed against potential treatment-associated toxicities given the expected long overall survival times for many patients. Preservation of cognition, neurological function and quality of life remain a priority. Treatment decisions should therefore be made in the context of a neuro-oncology multidisciplinary team, and incorporating the patient's wishes and expectations. The management of recurrent IDH-mutant glioma is not well defined. This expert position statement aims to provide an Australian perspective on the evidence base and available treatments for contemporaneous management of IDH-mutant glioma in adults.

ACTB is a cytoskeletal protein involved in intracellular trafficking. In recent years, it has become evident that, in addition to its established roles in these compartments, ACTB also participates in the regulation of transcription. However, the molecular mechanisms underlying this function remain poorly understood. The methyltransferase SETD3 has previously been shown to methylate ACTB at H73, thereby regulating ACTB polymerization and smooth muscle contraction. Here, we show that the genomic distribution of ACTB is SETD3-dependent and that this regulation modulates the transcription of genes involved in cell adhesion and mRNA translation in colorectal cancer cells. Proteomic analyses reveal that ACTB and SETD3 interact with multiple large protein complexes, including complexes associated with transcriptional regulation. Specifically, we demonstrate that SETD3-mediated ACTB methylation is required for the colocalization of SMARCA4, a subunit of the SWI/SNF BAF complex, at specific genomic loci. Genomic analyses further show that this colocalization enables the coordinated occupancy of SMARCA4 and H73-methylated ACTB at genes involved in cell adhesion and mRNA translation. Finally, phenotypic assays confirm these regulatory effects. Together, these findings uncover a new mechanistic layer of selective transcriptional regulation mediated by an ACTB-SETD3-SMARCA4 axis in colorectal cancer cells.

DEAD-box RNA helicase 3 (DDX3) is a key regulator of RNA metabolism whose role in cancer extends beyond canonical RNA unwinding and translational control. Emerging evidence indicates that DDX3 functions as a context-dependent post-transcriptional integrator coordinating adaptive programs essential for malignant progression. Rather than acting as a classical oncogene or tumor suppressor, DDX3 shapes cancer phenotypes by synchronizing immune regulation and mitochondrial plasticity at the RNA level. This review summarizes recent mechanistic and translational studies illustrating how DDX3 orchestrates tumor immune evasion, metabolic adaptation, and therapy resistance through post-transcriptional regulation. We highlight DDX3-mediated modulation of immune signaling and immune checkpoint dynamics, particularly its 3' untranslated region-dependent control of PD-L1 cell-surface presentation, which critically influences tumor immune surveillance and responsiveness to immunotherapy. In parallel, we discuss how DDX3 governs mitochondrial homeostasis, dynamics, and bioenergetic flexibility by selectively regulating stress-responsive transcripts, enabling cancer cells to withstand metabolic and oxidative stress. We further propose an integrative framework in which immune escape and mitochondrial plasticity are coordinately regulated by DDX3-centered RNA regulatory networks. This model reconciles the context-dependent roles of DDX3 across cancer types and disease stages and highlights DDX3 as a systems-level regulator and a potential target for precision combination therapies.

Fanconi anemia (FA) is a genetic disorder typically characterized by progressive bone marrow failure (BMF) during childhood, leading to diagnosis at that stage. In adolescence or adulthood, patients are predisposed to myelodysplastic syndrome (MDS), acute myeloid leukemia, and solid tumors. However, some individuals present atypically, delaying FA recognition and resulting in life-threatening complications. This study describes the distinctive phenotype associated with biallelic FANCM pathogenic variants.

To describe and compare patient characteristics, treatment patterns, and survival outcomes of patients with human epidermal growth factor receptor 2 (HER2)-low and HER2 immunohistochemistry 0 (IHC 0) stage IV breast cancer.

Gastroesophageal carcinoma (GEC) is increasingly managed using biomarker-guided therapies. Although both tissue DNA (tDNA) and circulating tumor DNA (ctDNA) testing are used clinically, the concordance of genomic alterations between primary tumors, metastatic sites, and liquid biopsy remains incompletely understood.

Succinate dehydrogenase (SDH) gene variants are the most common cause of the neuroendocrine tumour hereditary paraganglioma, which is associated with an over 20% metastasis risk as well as significant morbidity. There are currently no relevant human tumour cell lines or mouse models, and molecular understanding of downstream tumourigenic pathways is still rudimentary despite over two decades of concerted effort worldwide. These tumours generally show extremely slow in vivo doubling times (4-12 years), presumably existing in a primarily semi-quiescent state with little cell cycling or DNA replication. This characteristic makes deriving a useful tumour cell line impractical. A better alternative would be a cell line in which cell proliferation can be turned on and off at will, allowing expansion to generate sufficient cell numbers and experimentation once tumour cells have returned to their natural semi-quiescent state. The closest models currently available, highly-proliferating rat and mouse adrenal paraganglioma cell lines, are molecularly unrelated to SDH tumours. In this pilot study, we investigated whether primary SDH-derived paraganglioma tumour cells can be made to proliferate in vitro. We successfully transduced primary paraganglioma tumour cells with a lentiviral construct, using the proven strategy of c-MYC¬T58A (c-MYC) controlled by a Tet-On doxycycline-inducible expression system. We present the first evidence that primary paraganglioma chromaffin cells can be induced to proliferate in vitro, even in later passage cultures. Without any prior selection for chromaffin tumour cells, passaged cultures were obtained with over 80% synaptophysin-expressing chromaffin tumour cells, suggesting that this highly promising strategy deserves further exploration.

Standard adjuvant chemotherapy for stage III colon cancer consists of a fluoropyrimidine-plus-oxaliplatin regimen. Whether the addition of atezolizumab (an anti-programmed death ligand 1 agent) to a modified FOLFOX6 regimen (fluorouracil, oxaliplatin, and leucovorin; called mFOLFOX6) would improve outcomes in patients with stage III colon cancer with mismatch repair-deficient (dMMR) status is unclear.