Distal cholangiocarcinoma (dCCA) is a malignant tumor characterized by a challenging diagnosis, high invasiveness, and extremely poor prognosis. Research on dCCA is limited by the scarcity of reliable patient-derived preclinical tumor models. This study established a novel human distal cholangiocarcinoma cell line, CBC3T-3, and systematically characterized its biological properties, genomic features, and potential for clinical application. This cell line was extracted from postoperative distal cholangiocarcinoma tumor from a 54-year-old male patient. It was stably passaged (> 50 generations) through primary culture and condition optimization, preserving the same pathology as that of the primary tumor. Whole-exome sequencing (WES) confirmed somatic mutations, tumor mutation burden, single-sample clonal structure, driver genes, and drug resistance genes in CBC3T-3 cells, revealing their genomic characteristics. Functional assays demonstrated that CBC3T-3 cells exhibit strong capabilities for proliferation, migration, and invasion in vitro. In a subcutaneous xenograft model in immunodeficient mice, palpable tumor nodules developed within 4 weeks, reflecting the clinical characteristics of rapidly progressive disease. Drug sensitivity analysis revealed that, compared with TFK-1 cells, CBC3T-3 cells presented significantly greater responses to paclitaxel, gemcitabine, and oxaliplatin but relatively poor responses to 5-FU and cisplatin. The integration of drug resistance gene findings from WES suggests that TP53 missense mutations may mediate primary resistance to cisplatin. The establishment of the CBC3T-3 cell line enhances the research toolkit for dCCA. Its genomic characteristics and functional plasticity provide a reliable preclinical tumor model for developing precision therapies and investigating drug resistance mechanisms.

A disintegrin and metalloprotease with thrombospondin type 1 repeats, 1 (ADAMTS1) is a metalloproteinase essential for ovarian follicle development and ovulation. It is also involved in organizing vascular and lymphatic networks within ovary. ADAMTS1 is expressed by granulosa cells in ovarian follicles, and its expression and function are regulated by gonadotropins, follicle-stimulating hormone, and luteinizing hormone. This enzyme cleaves extracellular matrix (ECM) proteins to remodel the ECM and provide the necessary space for the growing ovarian follicles. ADAMTS1 is also essential for breaking down the follicular wall by cleaving proteoglycans, thereby releasing oocytes during ovulation. Loss of ADAMTS1 impairs remodeling of the ECM and decreases ovulation in mice. Dysregulation of ADAMTS1 is also linked to pathological conditions like polycystic ovary syndrome and premature ovarian failure, highlighting the precise activity of this enzyme. This chapter discusses the known and potential functions of ADAMTS1 in ovarian biology.

Isocitrate dehydrogenase 1 (IDH1) mutations confer distinct biological properties to gliomas, including the reshaping of the tumor immune microenvironment. While T cell dysfunction in glioblastoma has been extensively characterized, the role of innate lymphoid cells (ILCs)-critical regulators of tissue homeostasis and early immune responses- remains poorly understood.

Resistance to 5-fluorouracil (5-FU) remains a major challenge in the treatment of colorectal cancer (CRC). Here, we identify ETS variant transcription factor 7 (ETV7) as significantly upregulated in CRC tissues and cell lines, with elevated expression associated with poor clinical prognosis. Functional assays demonstrate that ETV7 enhances CRC cell proliferation, invasion, and resistance to 5-FU. Mechanistically, ETV7 transcriptionally upregulates CXCL1, leading to increased neutrophil recruitment and enhanced formation of neutrophil extracellular traps (NETs). The resulting NETs-enriched tumor microenvironment promotes tumor aggressiveness and chemoresistance. Pharmacological inhibition of CXCL1 or degradation of NETs effectively attenuates ETV7-driven malignant phenotypes in vitro and in vivo. Collectively, these findings establish an ETV7-CXCL1-NETs axis that contributes to 5-FU resistance in CRC and suggest that targeting this pathway may improve chemotherapy response.

Although targeted therapy has made significant advances in cancer treatment throughout these years, drug resistance still remains a major obstacle. Plenty of evidence has proved that abnormal expression of receptor tyrosine kinase AXL is associated with targeted therapy resistance and poor clinical outcomes. AXL drives drug resistance through diverse mechanisms, including altering tumor cell phenotypes, orchestrating DNA damage response process, promoting the activation of bypass signals, or interacting with other receptor tyrosine kinases. Preclinical and clinical studies have demonstrated that combined inhibition of AXL and the other target can enhance the efficacy of various targeted therapies and improve outcomes for patients with drug resistance. This review summarizes recent advances in the specific roles of AXL in targeted therapy resistance and AXL-targeted treatment strategies. It further explores the potential clinical value of combinatorial approaches involving AXL inhibition and discusses future directions for its application in developing novel targeted therapies and advancing precision oncology treatment. 
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Metabolic reprogramming is a hallmark of cancer, with the Warburg effect-driven aerobic glycolysis leading to a substantial accumulation of lactate in the tumor microenvironment. For a long time, lactate was considered a mere metabolic end product; however, recent studies have found that it acts as an important signaling molecule, profoundly influencing tumor progression by inducing a novel post-translational modification - lactylation. Lactylation, driven by lactate, occurs on both histones and non-histone proteins and is finely regulated by the 'writer' 'eraser' and 'reader' mechanisms, thereby altering the function of target proteins and gene expression. This review systematically explores the bidirectional regulatory network between glycolytic reprogramming and lactylation: on one hand, key glycolytic regulators promote lactate production, thereby increasing lactylation levels; on the other hand, lactylation can feedback to regulate the activity and expression of key glycolytic enzymes, forming a pro-tumor positive feedback loop. This interaction plays a central role in tumor proliferation, metastasis, DNA damage repair, and immune evasion. Consequently, targeting lactate production, lactate transport, or the lactylation process itself has emerged as a highly promising anti-cancer strategy and shows potential synergy with existing therapies such as immune checkpoint inhibitors. In-depth analysis of the glycolysis-lactylation axis will provide a crucial theoretical basis for developing novel cancer treatment approaches.
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First-line immunotherapy for advanced non-small cell lung cancer (NSCLC) shows significant survival benefits in patients without driver mutations, but the optimal duration of treatment remains controversial. Some studies support limiting immunotherapy to 2 years, arguing that longer treatment does not bring additional survival benefits; while other studies believe that treatment should continue until disease progression to maximize survival benefits. This article systematically reviews the current research progress on the duration of immunotherapy and discusses the potential predictive value of biomarkers such as circulating tumor DNA (ctDNA), the best efficacy response, and programmed cell death ligand 1 (PD-L1) expression levels in individualized treatment decisions. More prospective studies, especially biomarker-driven trials, are still needed to clarify the optimal duration of treatment and establish an individualized treatment strategy based on multidimensional indicators.
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Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related deaths worldwide, and its occurrence and development are closely related to complex molecular mechanisms. Alternative splicing of precursor mRNA is a key step in gene expression regulation, and its dysregulation is common in tumors. The serine/arginine-rich splicing factor (SRSF) family, a core protein family in splicing regulation, has been confirmed to play oncogenic roles in various cancers. However, systematic research on the SRSF family in NSCLC remains insufficient. This study aims to systematically analyze the specific expression patterns, clinical prognostic value, collaborative mechanisms and potential biological functions of SRSF individual members in NSCLC by the combination of bioinformatics analysis and experimental verification.

The prognosis for non-small cell lung cancer (NSCLC) with leptomeningeal metastasis (LM) is extremely poor. However, in oncogene addicted patients, the emergence of targeted therapies with high central nervous system (CNS) penetration is significantly reshaping the treatment landscape. Existing guidelines, which often favor conservative strategies, are no longer sufficient to meet the demands of precision medicine. To address this challenge, the Metastasis Lung Cancer Collaboration Group, Youth Specialists Committee of Beijing Medical Reward Foundation convened multidisciplinary experts from Medical Oncology, Radiology, Pathology, Radiotherapy, and Neurosurgery. Based on evidence-based medicine from the past decade and clinical practice experience, they have developed the Chinese expert consensus on clinical management of oncogene addicted NSCLC with leptomeningeal metastasis (2026 edition). This consensus emphasizes that the diagnosis of LM should be based on a comprehensive assessment of clinical symptoms, magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) cytology. It also highlights the critical role of CSF molecular liquid biopsy in clarifying driver gene status and assessing treatment efficacy. In terms of treatment, this consensus advocates for a fundamental paradigm shift: therapy should be led by a multidisciplinary team (MDT), with high-CNS-penetration targeted therapies as the first-line intervention, while local treatments (such as intrathecal injection and radiotherapy) are positioned as supplementary measures. The consensus provides a series of expert recommendations on key aspects, including the selection of high-CNS-penetration tyrosine kinase inhibitors (TKIs), the application of intrathecal chemotherapy, the timing of radiotherapy, and palliative surgery. It aims to establish proactive, individualized treatment standards for patients with NSCLC LM in China, based on molecular subtyping and MDT collaboration, thereby improving patient survival outcomes.
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Tumor mutational burden (TMB) and PD-L1 are established biomarkers for guiding immune checkpoint inhibitor (ICI) therapy in advanced non-small cell lung cancer (NSCLC). As ICI use expands into early-stage disease, we explored the feasibility of using TMB, which can be determined via a comprehensive genomic profiling assay along with EGFR and ALK genomic alterations, as a biomarker for outcomes in both neoadjuvant and adjuvant settings. TMB-high status (≥10 mut/Mb) showed a numerically higher, but not statistically significant, rate of pathological complete response among patients receiving neoadjuvant ICI and significantly associated with more favorable time to recurrence in patients receiving adjuvant ICI, particularly among patients with PD-L1 expression <50%. TMB should be considered in future early-stage NSCLC ICI clinical trials to further validate these results.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. The higher incidence and earlier onset of HCC in sub-Saharan Africa suggest a potential role for a genetic predisposition. This study evaluated the association of TERT-rs2242652-(A), a variant linked to lower HCC risk, with HCC in populations from Ghana, Nigeria, and Cameroon, compared with a population from the United States.

Gliomas exhibit significant prognostic heterogeneity, and single-omics data/existing technologies struggle to balance multi-omics integration efficiency, prediction accuracy, and clinical adaptability-hindering the clinical translation of precise prognostic assessment. Focussing on glioblastoma (GBM) and lower-grade glioma (LGG), this study proposes an integrated solution: three-step multi-omics feature selection combined with the limited random forest (FRF) model, using TCGA-derived transcriptomic, genomic, epigenomic and clinical survival data. Prognosis-related features are first screened using univariate Cox regression, refined by random forest-based feature importance for dimensionality reduction and then integrated into a multi-omics matrix through sample matching. The FRF model balances efficiency and accuracy by limiting decision tree number and depth, optimising node splitting criteria, and adding a dual-weighted correction mechanism. Results show that FRF achieves an AUC of 0.96 for GBM, outperforms logistic regression (LR) and support vector machine (SVM) across all LGG metrics, and reduces training time to minutes-meeting the 2-h clinical prognostic demand. Ablation experiments confirm that the multi-omics model improves performance by 11.63% compared with the optimal single-omics model, with core features consistent with glioma molecular mechanisms. This resolves the challenge of rapid integration and precise prediction, providing an efficient tool for glioma prognostic assessment and supporting multi-omics clinical translation.

Deciphering the mechanisms underlying antitumor immunity is critical for improving cancer immunotherapy efficacy. Here, we identify WFDC21P (lnc-DC) as a positive regulator of antitumor immunity through promoting the activation of the RNA-sensing retinoic acid-inducible gene-I (RIG-I) pathway in triple-negative breast cancer (TNBC). WFDC21P directly binds to RIG-I-interacting protein G3BP1 and is required for a rapid assembly of functional G3BP1-RIG-I-double-stranded RNAs condensates via phase separation, which enables robust activation of RIG-I. WFDC21P is downregulated in TNBC tissues and correlates with less CD8+ T cell infiltration in tumors and worse outcome of patients. WFDC21P knockdown in TNBC cells markedly dampens RIG-I activation and reduces the expression of IFN-stimulated genes, including MHC-I and PD-L1. In syngeneic tumor models, WFDC21P expression not only suppresses tumor growth by augmenting the infiltration and cytotoxic function of CD8+ T cells but also improves the response to immune checkpoint blockade, thus providing a compelling combination immunotherapy strategy for treating triple-negative breast cancer.

This study presents a nationwide infrastructure for the collection and utilization of gynecologic cancer biospecimens, established through the Korea Biobank Project. We comprehensively describe the biobanking strategy, quality control protocols, and development of secondary resources to support future translational and discovery-based research.

The distinct roles of GSK3 isoforms (GSK3α/β) in tumorigenesis and immune modulation remain poorly characterized across malignancies. We integrated multi-omics data from TCGA, GTEx, and single-cell RNA-seq to analyze GSK3α/β expression patterns in 31 cancers. Functional clustering, survival analysis (Cox regression), immune infiltration, and in vitro validation (AML cell lines treated with CHIR-99021) were performed. Integrated multi-omics analysis of 31 malignancies revealed divergent dysregulation of GSK3 isoforms: GSK3α was upregulated in 19 solid tumors but suppressed in AML, while GSK3β was elevated in 23 cancers and high-risk AML subtypes (FAB-M0/M1, P = 0.0013). GSK3β outperformed GSK3α as a pan-cancer diagnostic biomarker, achieving superior AUC in 9 tumors. Prognostically, high GSK3α predicted poor OS in ACC (HR = 8.80, P = 0.0047) and MESO (HR = 2.75, P < 0.0067), whereas GSK3β independently stratified cytogenetic-risk AML (HR = 4.22, P = 0.007). Immune profiling uncovered isoform-specific TME modulation: GSK3α correlated with protumorigenic immune infiltration (Treg/Th17, r = 0.38), contrasting GSK3β's broad negative associations with cytotoxic effectors (r = -0.27). Functional validation in AML THP-1 cells demonstrated that the GSK3 inhibitor CHIR-99021 (10 μM) significantly suppressed proliferation, induced apoptosis, and caused S-phase cell cycle arrest, concomitant with downregulation of c-Myc. These findings establish GSK3β as a key regulator of oncogenic programs in AML. This study provides a comprehensive pan-cancer atlas of GSK3 isoform-specific functionality, nominating GSK3β as a high-priority therapeutic target.

Many RNA viruses exhibit error-prone replication. Continuous generation of erroneous copies accelerates evolution. Avian leukosis virus subgroup J (ALV-J), an avian oncogenic virus, is a classical model virus for studying retroviruses. ALV-J's high mutation rates drive continuous evolution of its envelope and pathogenicity, posing significant challenges to the poultry industry. Here we employed deep mutational scanning to systematically assess envelope-wide mutation effects on ALV-J replication, integrating high-throughput sequencing with mutant libraries to identify critical envelope residues impacting viral fitness. Following 10 passages, the library virus exhibited enhanced replication capacity. Moreover, the library virus derived from SPF chickens displays screening results similar to those of the DF-1 cell-passaged virus. Most mutations were progressively eliminated during viral passaging, especially the first 80 amino acids of ALV-J envelope. Critical amino acid mutations, preferential deletion/insertion mutations and glycosylation patterns recapitulate evolutionary patterns observed in natural ALV-J isolates. Incorporation of all identified mutations into ALV-J J1 significantly increased in vivo replication efficiency and viral shedding of the recombinant virus. Functional study demonstrated that two key mutations independently promote viral replication: A64T enhancing entry via receptor-binding optimization, H304R promoting maturation through envelope cleavage efficiency. These insights enable targeted antiviral design by predicting evolutionary paths.

The actin-binding protein CAPG (Capping Actin Protein, Gelsolin Like) is implicated in oncogenesis, but its role in pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study combined bioinformatic analysis of TCGA/GEO datasets, immunohistochemistry on clinical samples, and functional in vitro assays to define CAPG's significance in PDAC. We found CAPG significantly overexpressed in PDAC tissues (n = 179 tumor vs. 171 normal, p < 0.05), with levels correlating with advanced tumor stage (T3 vs. T1) and predicting poorer overall (p = 0.0085) and disease-free (p = 0.015) survival. In vitro, siRNA-mediated CAPG knockdown in PANC-1 and AsPC-1 cells markedly inhibited proliferation (CCK-8 assay) and migration (wound healing assay), and significantly sensitized cells to gemcitabine-induced apoptosis. Mechanistically, CAPG knockdown was associated with reduced ERK1/2 phosphorylation and Cyclin D1 expression, and ERK1/2 inhibition phenocopied the anti-proliferative and chemosensitizing effects. Our results establish CAPG as a negative prognostic biomarker in PDAC, demonstrate its critical role in driving proliferation and migration-potentially via modulating ERK pathway activity-and highlight its promise as a therapeutic target whose inhibition can enhance chemotherapy efficacy.

Genes encoding subunits of the mitochondrial tricarboxylic acid cycle enzyme complex succinate dehydrogenase (SDH) are a leading cause of the neuroendocrine tumour syndrome hereditary paraganglioma-pheochromocytoma. Pathogenic variants of SDHD and SDHAF2 confer a remarkable parent-of-origin tumour risk, in which paternally inherited variants cause tumours but maternally inherited variants do not. Formulated to explain this observation, the Hensen hypothesis proposes that loss of an (unknown) imprinted gene(s), together with the remaining wildtype SDH gene, is a prerequisite for tumour formation; in effect a three-hit hypothesis. This study had three objectives, first, as a test of the Hensen model, second, as a potential model for a disease for which no mouse or cell model currently exists, and finally, as a test of chromosome (Ch.) configuration to interrogate large genomic regions carrying an unknown phenotypic modifier. We crossed a gene knockout line (Sdhc, mouse Ch.1) to a Robertsonian chromosome line, Rb(1:7), harbouring the homologous gene imprinting centre (human Ch.11p15, mouse Ch.7) implicated in human tumourigenesis, to create a metacentric chromosome with characteristics of human chromosome 11. We developed 7 cohorts combining Sdhc (mouse Ch.1) wildtype or knockout with distinct configurations of Rb(1:7), confirming both paternal and maternal inheritance of Sdhc. We noted significant weight gain, and in heterozygote Sdhc KO-Rb/wt mice high levels of immune activation. Thyroid abnormalities, including lesions with papillary thyroid carcinoma-like features, were common (30-50%) in Sdhc knockout mice with both heterozygous and homozygous Rb chromosomes, regardless of mode of inheritance. We also observed a single case of bilateral pheochromocytoma in which loss of Sdhc was not the driver. While our findings did not recapitulate features of the Hensen Model, this study does suggest that chromosomal structure, even in the form of a seemingly innocuous single Robertsonian configuration, can dramatically impact clinical phenotype.

Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subtype of breast cancer, with limited treatment options due to the absence of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 (HER2) expression. This characteristic renders TNBC resistant to hormone-based and HER2-targeted therapies, leaving cytotoxic chemotherapy as the predominant strategy and highlighting the urgency for novel interventions. In this study, we investigated the mechanism of action of GL24, a potent 4-(phenylsulfonyl)morpholine-based small molecule with selective tumor suppression effects on metastatic TNBC cells, while being ineffective against TNBC cells derived from the primary tumor site, using gene co-expression analysis. By considering the distinct phenotypic responses induced by GL24, we tailored our co-expression analysis approach, selecting gene pairs that exhibited differential co-expression in effective cells while excluding gene pairs that also showed differential patterns in non-effective cells. Constructing a co-expression network from these differential pairs, followed by enrichment analysis and functional annotation, revealed specific gene interactions and molecular pathways associated with GL24-mediated TNBC inhibition. These insights supported the previously established findings that showed convergence on apoptosis based on differentially expressed genes, while also providing complementary information by highlighting pathways involved in metabolic alterations, proliferation, and migration or invasion. This expanded understanding advances the knowledge of the mechanisms of GL24 in combating TNBC.

Premenopausal women at familial or hereditary risk of ovarian cancer must weigh the risks and benefits of risk-reducing surgery. How they navigate this decision is not well understood.