搜索结果：Genes, chromosomes & cancer

Lung adenocarcinoma is the most common subtype of lung cancer and a significant contributor to cancer mortality globally. This has driven the development of targeted therapies, particularly those aimed at genetic alterations in certain genes, such as EGFR and ALK. ERBB2 (HER2) has also emerged as a potential oncogenic driver and therapeutic target in lung adenocarcinoma. Notably, ERBB2 is in close proximity on chromosome 17 to GRB7 and MIEN1, which are potential contributors to invasion and metastasis. Using TCGA-LUAD (The Cancer Genome Atlas Lung Adenocarcinoma) and CPTAC-3 (Phase III of the Clinical Proteomic Tumor Analysis Consortium) lung adenocarcinoma datasets, copy number variations (CNVs) for GRB7, ERBB2, and MIEN1 and their associations with various survival parameters were obtained. Results indicated that increased copy number (CN) of MIEN1 was significantly associated with worse disease-free survival (DFS) in both TCGA-LUAD and CPTAC-3 lung adenocarcinoma datasets and was significantly associated with worse progression-free survival (PFS) in the TCGA-LUAD dataset. There is also evidence showing a similar relationship in cervical cancer, which also has established links to ERBB2. CNV analyses in the TCGA-CESC and CGCI-HTMCP-CC (Cancer Genome Characterization Initiative-HIV+ Tumor Molecular Characterization Project-Cervical Cancer) cervical cancer datasets revealed that only increased CN of MIEN1 was statistically significantly associated with worse overall survival (OS) in both datasets. These CNV analyses suggest that MIEN1 should be further investigated as a potential contributor to oncogenesis.

The transcription process is controlled by non-coding regulatory elements, more than 70% of which are putative enhancers. These enhancers comprise over 600,000 regions and are marked by histone modifications. However, the mechanisms by which altered enhancers in cancer cooperate within the three-dimensional chromatin architecture to drive oncogenic programs remain poorly understood. By integrating 201 H3K27ac ChIP-seq datasets from prostate, we identify 3,216 high-confidence prostate cancer-specific putative enhancers. Ultra-high-resolution chromatin interaction profiling by Region Capture Micro-C at a representative chr6q24.1 locus reveals that these enhancers form cancer-specific, highly nested interactions with promoters that coalesce into a multi-connected hub absent in normal prostate cells. CRISPR/Cas9 perturbations of these enhancers, examined one by one, distinguish enhancer classes within the hub. Deletion of a central enhancer collapses hub-wide enhancer activities and architecture, leading to the downregulation of target genes, impaired proliferation, and reduced clonogenic growth. In contrast, deletion of a redundant enhancer results in minimal transcriptional changes, as neighboring enhancers rescue cancer signaling through compensatory architectural rewiring that strengthens alternative enhancer-promoter interactions. We also observe that FOXA1, a pioneer transcription factor activated in prostate cancer, directly binds to these enhancers and regulates distinct enhancer classes, leading to varying degrees of chromatin accessibility and gene expression changes. These findings suggest that enhancers function in a coordinated manner, forming multi-connected cancer-specific chromatin interaction hubs, with distinct enhancer classes contributing differently to gene regulation. This study advances our ability to modulate gene expression in a cell type-specific manner, opening new avenues for precision therapies.

Ovarian cancer is a heterogeneous solid tumor, whereas polycystic ovary syndrome (PCOS) is a distinct endocrine-metabolic ovarian disorder. Whether PCOS-associated ovarian dysregulation and ovarian cancer share convergent transcriptomic candidates remains unclear. This study aimed to identify shared transcriptomic candidates and define their cellular localization without implying a causal or clinical comorbidity relationship. Public bulk transcriptomic datasets from PCOS and ovarian cancer underwent platform-specific preprocessing, within-disease-arm harmonization, differential-expression analysis, robust rank aggregation, and machine-learning-based feature prioritization with SHapley Additive exPlanations. Single-cell RNA sequencing datasets were used to localize prioritized genes in PCOS-related ovarian cell populations and high-grade serous ovarian cancer (HGSOC)-derived compartments. Preliminary validation used DHEA-treated KGN cells and siRNA-mediated SIX4 knockdown in SKOV3 cells. Exploratory docking and molecular dynamics simulation assessed the structural tractability of a SIX4-centered axis. Integrated analysis identified shared molecular dysregulation enriched in cell-cycle regulation, chromosome segregation, epithelial remodeling, and Wnt-related pathways. Five candidate genes were prioritized: SIX4, CCNE1, MMP7, KIF2C, and GPX3. SIX4 was the highest-ranked contributor within the computational model. Single-cell analysis showed compartment-specific localization, with SIX4 enriched in HGSOC-derived epithelial populations. DHEA increased SIX4 expression in KGN cells, whereas SIX4 knockdown suppressed SKOV3 proliferation, migration, and colony formation. Molecular dynamics suggested stable predicted engagement between SIX4 and a Benzbromarone-related scaffold. This study identifies SIX4 as a candidate epithelial target in ovarian cancer within a shared, noncausal transcriptomic program associated with PCOS-related ovarian dysregulation.

Non-SMC condensin II complex subunit G2 (NCAPG2) is an important molecule in regulating chromosome segregation of mitosis and acts as an oncogene and biomarker in various tumors. This study aimed to explore the role of NCAPG2 in breast cancer (BC). The mRNA and protein expression of NCAPG2 was explored in the Gene Expression Profiling Interactive Analysis (GEPIA), Tumor Immune Estimation Resource (TIMER), Human Protein Atlas (HPA), and bc-GenExMiner databases. Survival analyses were performed using the Kaplan-Meier plotter and bc-GenExMiner databases. We used the COSMIC, CistromeDB, and cBioPortal databases to analyze the transcriptional regulation and genetic alteration. Function enrichment analyses were performed with CancerSEA and Metascape database. NCAPG2 expression was significantly higher in BC than normal samples. NCAPG2 expression was positively correlated with the Scarff-Bloom-Richardson (SBR) grade, HER2 status, lymph nodal status, TP53 and BRCA1/2 mutation, and Nottingham prognostic index (NPI), while negatively correlated with age, ER status, and PR status. Survival analyses indicated that overexpressed NCAPG2 was associated with the adverse prognosis of BC. Gene Set Enrichment Analysis (GSEA) and function enrichment analyses of single-cell and co-expressed genes of NCAPG2 consistently showed that NCAPG2 was involved in cell cycle, immune, DNA damage, cancer-related pathways, proliferation, and DNA repair. The result of TIMER showed that NCAPG2 was associated with infiltrating immune cells and the exhausted T cell phenotype, such as CD8+ T cells, PD-1, CTLA4, and TIM-3. We found that the mRNA and protein expression of NCAPG2 was upregulated in BC. Overexpressed NCAPG2 might act as an adverse prognosis biomarker in BRCA and had a distinct function in the cell cycle, proliferation, and immune infiltration.

Chromosome 17 Open Reading Frame 75 (C17orf75) encodes the protein Njmu-R1 (Protein Njmu-R1),, which is involved in intracellular vesicle trafficking; however, its role in tumor progression remains largely unclear. Public datasets from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and the Human Protein Atlas (HPA) were analyzed to evaluate the expression profile, mutation landscape, and diagnostic and prognostic value of C17orf75. Bioinformatics analyses were subsequently performed to explore its associations with immune infiltration. In addition, functional assays were conducted on Hep3B and MHCC-97H cells, and immunohistochemistry (IHC) was performed on clinical liver hepatocellular carcinoma (LIHC) samples. C17orf75 was significantly upregulated in multiple cancer types, particularly in LIHC. Elevated C17orf75 expression was associated with unfavorable prognosis and advanced clinicopathological features in LIHC. Functional enrichment analyses indicated that C17orf75-related genes were involved in cell cycle regulation, DNA replication, and epithelial-mesenchymal transition (EMT). Furthermore, C17orf75 expression was closely correlated with immune infiltration, ferroptosis-related genes, and m6A regulators. Knockdown of C17orf75 inhibited the proliferation, migration, and invasion of LIHC cells. C17orf75 knockdown induced G2-phase arrest without significantly affecting apoptosis. Moreover, knockdown of C17orf75 suppressed EMT. C17orf75 plays an important role in LIHC progression by regulating cell cycle progression and EMT, and it may serve as a potential therapeutic target for LIHC.

Colorectal cancer liver metastasis (CRLM) represents the leading cause of mortality in colorectal cancer (CRC). However, the molecular mechanisms enabling metastatic adaptation within the hepatic microenvironment remain unclear. We integrated single-cell RNA sequencing, spatial transcriptomics, and bulk transcriptomic data from CRC patients to characterize the immunometabolic landscape of CRLM. Machine learning models were used to identify key regulators, and functional assays were conducted to validate their biological roles. Nine major cell populations were delineated within CRLM, revealing enrichment of myeloid-derived suppressor cells and depletion of fibroblasts in metastatic lesions. Malignant cells displayed pronounced chromosomal instability and metabolic reprogramming. Among candidate regulators, PIGT emerged as a pivotal node linking metabolic adaptation and immune suppression. PIGT expression increased progressively from primary to metastatic states and was associated with immunosuppressive MIF, SPP1, and TGFβ signaling. Spatial transcriptomics demonstrated colocalization of PIGT-high tumor cells with ITGAM⁺ and CD163⁺ macrophages. Functionally, PIGT knockdown significantly suppressed cell invasion, migration, proliferation, and wound healing in vitro. Conversely, transcriptomic and qPCR analyses showed that PIGT-low tumors exhibited higher expression of inflammatory genes enriched in the IL-17 and TNF signaling pathways. Our integrative multi-omics and experimental analyses identify PIGT as a central regulator bridging tumor metabolism and immune modulation in CRLM. These findings highlight PIGT as a promising prognostic biomarker and potential therapeutic target for metastatic colorectal cancer.

Germline pathogenic variants (PVs) in POT1, one of the shelterin complex genes, correlate with tumor predisposition, primarily with melanoma, hematologic malignancies, sarcoma, papillary thyroid carcinoma and glioma. Breast cancer (BC) risk has not been shown to be elevated. We analyzed BC occurrence and features in a cohort of 29 female PV heterozygotes, of whom 13/29 (45%) were diagnosed with BC. Data regarding genetic, clinical, pathologic, treatment, and outcome characteristics were extracted. Patients in our cohort harbored three different POT1 PVs; The c.233T > C Ashkenazi founder PV occurred in 11/13 (84.6%). Median age at first BC diagnosis was 54 years (range 44-72); no patient was diagnosed before the age of 40. Pathological subtypes varied; invasive ductal carcinoma was the most common. All primary tumors were estrogen receptor positive; one was HER2-enriched; no triple-negative cancers were observed. Stage at diagnosis varied: 6 of 10 tumors with known staging were stage 0 or I, and one patient presented with metastatic disease. Treatment approaches were diverse as clinically appropriate. After a median follow-up of 110 months, three second BC events occurred, with no BC-related mortality. Personal and family history of other malignancies were frequent. This is the first dedicated report describing BC phenotypes in POT1 PV heterozygotes. Our findings suggest that enhanced BC surveillance may be warranted in this population. Larger cohorts are needed to further characterize the clinicopathological features of BC in POT1 carriers, to define lifetime BC risk and determine whether BC-specific screening recommendations should be established for this group.

SnoRNAs are regulatory RNAs that play indispensable roles in ribosomal RNA processing and translation. Their distinct structural conformations determine specific protein-binding partners, thereby mediating diverse epigenetic modifications. Most snoRNAs are transcribed from introns of snoRNA host genes (SNHGs). Processed snoRNAs can further yield piwi-interacting RNAs (piRNAs) and snoRNA-derived fragments (sdRNAs). These small RNA products are frequently dysregulated in tumors and exert significant oncogenic functions. In cancer, snoRNA dysregulation stems from DNA-level alterations such as chromosomal aberrations, base mutations, and gene silencing, as well as RNA-level disruptions including aberrant post-transcriptional modifications, degradation, and trafficking. Such dysregulated snoRNAs drive malignant hallmarks-sustained proliferation, invasion and metastasis, angiogenesis, metabolic reprogramming, immune evasion, senescence bypass, epigenetic remodeling, phenotypic plasticity, and microbiome-host crosstalk-through mechanisms spanning histone modifications, nucleic acid epitranscriptomics, and competitive endogenous RNA (ceRNA) networks. Consequently, tumor-associated snoRNAs detectable in body fluids represent promising non-invasive biomarkers for early cancer diagnosis and prognosis prediction. This review systematically summarizes snoRNA biogenesis pathways, elucidates mechanisms underlying their dysregulation in malignancies, summarizes the impact of aberrant snoRNAs on tumorigenesis and progression, and highlights clinically significant snoRNAs for diagnostic and therapeutic applications.

SWI/SNF chromatin remodelers are represented by three biochemically distinct subcomplexes, the abundant cBAF and the less abundant PBAF and GBAF. Genetics have identified important roles for PBAF in development and disease; however, relating PBAF-mediated phenotypes to biochemical function in chromatin regulation and gene activation has been challenging. Here, we show that the PBRM1 subunit of PBAF is critical for the completion of TGFβ1-mediated epithelial-mesenchymal transition (EMT) of mammary cells in vitro as well as the metastasis of murine breast cancers in vivo. Using epigenomics to profile different stages of EMT, we find that PBRM1 is necessary for targeting PBAF to inducible promoters marked by H3K14ac. We further find that PBRM1 facilitates DNA accessibility at sites bound by TGFβ1-inducible transcription factors, such as Atf3, for the induction of genes involved in migration, cell survival, and inflammation, providing evidence that PBAF is a vulnerability in late-stage metastatic cancers.

KIAA1143 is located within the 3p21.3 chromosomal region, which is frequently deleted in human cancers and enriched for tumor suppressor genes, and encodes an evolutionarily conserved protein; however, its biological functions and relevance to tumor biology remain largely uncharacterized. Here, we performed a comprehensive pan-cancer analysis of KIAA1143 through multi-omics data integration, optimized its prokaryotic expression and purification system, constructed its protein interactome by affinity purification coupled with mass spectrometry (AP-MS), and further predicted its three-dimensional structure by using AlphaFold 2. Our results demonstrate that KIAA1143 is widely expressed in multiple human tissues yet exhibits a marked discrepancy between mRNA and protein levels, suggesting stringent post-transcriptional regulation. Pan-cancer analysis further revealed that KIAA1143 is aberrantly expressed across diverse tumors and bears prominent cancer-specific prognostic relevance, exhibiting a bidirectional "prognostic paradox" in different tumor contexts. Interactome profiling identified 73 high-confidence interacting proteins, which were significantly enriched in key cancer-associated pathways, including oxidative phosphorylation, the ubiquitin-mediated proteolysis, mTOR, and MAPK signaling. Structural prediction indicated that KIAA1143 exhibits extensive intrinsic disorder throughout its full-length sequence. This study presents the first systematic multidimensional characterization of KIAA1143 by delineating its pan-cancer expression pattern, prognostic implication, interactome landscape and structural properties, and suggests that KIAA1143 acts as a novel context-dependent regulatory factor in cancer, providing a robust foundation for future mechanistic and functional investigations.

Ubiquitin‑like modifications, including ubiquitination, SUMOylation, and UFMylation, are essential post‑translational modifications that regulate diverse cellular processes. These modifications are dynamically reversed by their corresponding deconjugating enzymes, including deubiquitinases (DUBs), SUMO proteases, and UFM1‑specific proteases (UFSPs), which fine‑tune protein stability, localization, and signaling. Although these enzymes have been implicated in nucleolar function and DNA repair, their roles in mitotic regulation remain largely unclear. This study aimed to systematically explore the potential functions of deubiquitinase‑related proteases during mitosis in breast cancer. Transcriptome data from the TCGA‑BRCA cohort were analyzed to evaluate the expression patterns of 112 deubiquitinase‑related proteases. Gene set enrichment analysis (GSEA) identified 95 genes significantly associated with mitotic pathways. Among these candidates, UFSP2 ranked within the top 10% based on mitosis‑related enrichment scores, and its correlated gene set showed the strongest enrichment for mitotic pathways. This pattern was independently observed in the GEO dataset GSE96058. In MCF7 cells, UFSP2 knockdown was associated with increased pH3S10 levels and changes in the abundance of spindle assembly checkpoint (SAC) proteins, including TTK, BUB1, MAD1, and other SAC‑related components. Single‑cell RNA‑seq analysis further revealed that UFSP2 expression is lower in the early portion of the inferred tumor developmental trajectory and increases at later stages, accompanied by higher chromosomal instability scores estimated from CNV‑based analyses. Overall, these UFSP2‑associated transcriptional and phenotypic features may reflect its relevance to early tumor progression and the sustained proliferative capacity observed in later tumor states. Our study shows that UFSP2 expression exhibits an observable association with mitosis‑related processes in breast cancer cells, particularly with the abundance of spindle assembly checkpoint (SAC)-associated proteins, suggesting that UFSP2 may participate in maintaining mitotic stability. In addition, differences in UFSP2 expression may correspond to distinct biological features at different tumor stages, indicating that stage‑dependent changes in UFSP2 expression may align with the varying biological demands during tumor development. However, these findings are primarily based on correlative analyses and do not establish a direct causal role for UFSP2 in mitosis or tumor progression. Nevertheless, the consistent associations observed across multiple data layers highlight UFSP2 as a potentially important factor that warrants further investigation in future mechanistic studies.

The extracellular cyclic GMP-AMP (cGAMP)-ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) axis is an emerging pharmacological target that links tumor-intrinsic DNA stress to antitumor immunity. Tumor cells can generate cGAMP in response to chromosomal instability, micronuclear rupture, replication stress, and therapy-induced DNA damage. After export into the tumor microenvironment, extracellular cGAMP may be transferred to antigen-presenting cells and activate stimulator of interferon genes (STING)-dependent type I interferon and C-X-C motif chemokine ligand 10 (CXCL10) programs, thereby supporting dendritic-cell activation, immune priming, and cytotoxic T-cell recruitment. ENPP1 restricts this process by degrading extracellular cGAMP and by contributing to nucleotide catabolism associated with AMP- and adenosine-dependent immunosuppression. Accordingly, pharmacological ENPP1 inhibition differs from direct STING agonism by preserving endogenous tumor-derived cGAMP rather than imposing exogenous receptor activation. This Review summarizes the mechanistic basis, pharmacological rationale, and translational challenges of targeting the extracellular cGAMP-ENPP1 axis in cancer. We discuss ENPP1 inhibitors and cGAMP-stabilizing approaches, focusing on mechanism of action, pharmacokinetic/pharmacodynamic (PK/PD) relationships, target engagement, therapeutic window, and potential immunotoxicological constraints. We also propose a biomarker-guided framework incorporating cGAMP-generating capacity, ENPP1 expression and enzymatic activity, STING-response competence, and on-treatment pharmacodynamic conversion. Finally, we evaluate rational combinations with radiotherapy, chemotherapy, DNA damage response-targeted agents, immune checkpoint blockade, and immune-metabolic modulators. Clinical translation will require patient stratification, schedule-aware combination design, and robust pharmacodynamic validation in early-phase studies.

Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) represents a major clinical challenge in the management of non-small cell lung cancer (NSCLC). Chromosome 4q12 locus is an important gene locus associated with progression-free survival (PFS) in NSCLC patients receiving EGFR-TKIs therapy. However, it remains poorly characterized how genes at this locus function in NSCLC development and resistance to EGFR-TKIs. Here, we found that CLOCK at this locus is highly expressed in NSCLC tissues and correlates with unfavorable PFS of patients. CLOCK promotes malignant proliferation and metastasis of NSCLC in vitro and in vivo. CLOCK could attenuate treatment efficacies of gefitinib (one of the first-generation EGFR-TKIs) or osimertinib (one of the third-generation EGFR-TKIs). Mechanistically, CLOCK functions as a transcriptional factor to upregulate LAMC2 transcription and expression in NSCLC cells. There was significantly elevated LAMC2 expressed in NSCLC tissues and its high levels were associated with shortened survival of patients. Indeed, CLOCK could activate multiple kinase signaling pathways, such as the PI3K-Akt signaling and the MAPK signaling, by facilitating either the LAMC2-ITGB1 interaction and the LAMC2-EGFR interaction and thereby accelerating NSCLC proliferation and conferring EGFR-TKI resistance. Collectively, these findings for the first time identify CLOCK as a critical mediator of EGFR-TKIs resistance and a promising target to overcome EGFR-TKIs resistance in NSCLC.

Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options and poor prognosis. Understanding the underlying molecular mechanisms, particularly immune-related gene networks, is critical for identifying novel therapeutic targets. This study aimed to identify immune-related hub genes involved in TNBC progression by integrating microarray and RNA sequencing data. We integrated microarray and RNA sequencing datasets from five Gene Expression Omnibus (GEO) studies (GSE36295, GSE37751, GSE61724, GSE38959, and GSE58135) to identify differentially expressed genes (DEGs). Protein-protein interaction (PPI) networks were constructed using the STRING database. Key modules and hub genes were identified through network analysis. Functional enrichment was performed to elucidate biological pathways, while immune infiltration analysis assessed associations with the tumor microenvironment. Drug-gene interaction databases were queried for FDA-approved compounds targeting hub genes. The PPI network revealed 179 nodes and 781 edges, indicating high connectivity. Module analysis highlighted a significant cluster with the identified key genes such as CDK1, BUB1B, CCNA2, BUB1, CCNB1, KIF20A, CENPF, TOP2A, KIF11 and MELK validated at both mRNA and protein levels. Functional enrichment revealed pathways related to cell cycle control, chromosome segregation, and kinase activity. Immune infiltration analysis indicated involvement of B cells, macrophages, and neutrophils in the TNBC microenvironment. Drug-gene mapping revealed a lack of FDA-approved drugs targeting certain key hub genes. This integrative study identified key immune-related hub genes driving TNBC progression, with KIF20A emerging as a promising yet underexplored target. Drug repurposing strategies focusing on KIF20A and other identified hub genes may accelerate the development of effective treatments, offering valuable insights for future therapeutic and prognostic evaluations in TNBC.

Transposons, also known as jumping genes, are DNA sequences capable of relocating within or between chromosomes. Long interspersed element-1 (LINE-1), the only autonomously active retrotransposon in the human genome, plays a critical role in maintaining genomic stability through its dynamic regulation. Under normal physiological conditions, the host employs epigenetic and other mechanisms to maintain LINE-1 in a silenced state. However, when this precise regulatory control is disrupted, aberrant LINE-1 activation can lead to insertional mutations, resulting in genomic instability and the development of various genetic disorders and malignant tumors. Recent evidence has demonstrated elevated LINE-1 expression in multiple cancers, such as breast, esophageal, lung, and colorectal cancer, suggesting a close association between LINE-1 dysregulation and tumorigenesis. This review summarizes the multi-layered regulatory network governing LINE-1, encompassing epigenetic modifications, non-coding RNAs, and various host restriction factors. It also explores the molecular mechanisms underlying LINE-1 aberrant activation in the tumor microenvironment and outlines the diverse pathways through which LINE-1 influences tumor development, such as compromising genomic stability, triggering inflammation and immune responses, and participating in cellular immortalization. This review not only provides a theoretical foundation for utilizing LINE-1 as a molecular biomarker in cancer diagnosis but also offers new perspectives for developing novel anti-tumor therapeutic strategies based on LINE-1 regulation. 转座子又称跳跃基因，是一段能够在染色体内或不同染色体之间改变自身位置的DNA序列。长散在核元件-1 (long interspersed element 1，LINE-1)作为人类基因组中唯一具有自主逆转座活性的转座子，其动态调控对维持基因组稳定性具有重要的意义。在正常生理状态下，宿主通过表观遗传等机制使LINE-1处于沉默状态，但当这种精密调控被打破时，LINE-1异常激活介导的插入突变会引发基因组不稳定，进而诱发多种遗传性疾病和恶性肿瘤。近年来的研究证据表明，在乳腺癌、食管癌、肺癌以及结直肠癌等多种肿瘤中存在LINE-1的高表达，提示LINE-1的异常激活与肿瘤发生发展存在密切关联。本文综述了宿主对LINE-1多层次的调控网络，包括表观遗传修饰、非编码RNA以及多种宿主限制因子；探讨了LINE-1在肿瘤微环境中异常激活的分子机制，并总结了LINE-1影响肿瘤发生发展的多种途径，例如影响基因组稳定性、引发炎症和免疫反应以及参与细胞永生化过程。本文不仅为LINE-1作为肿瘤分子诊断标志物提供了理论依据，同时为基于LINE-1调控的新型抗肿瘤治疗策略提供了新的视角。.

Cancer recurrence and distant metastasis are major causes of cancer-related death, yet existing biomarkers and single-omics models have limited accuracy and interpretability across tumor types. We developed OMNIS (OMics Network Integration and Spatial representation), a convolutional deep-learning framework that embeds multi-omics profiles into a five-channel genomic image ordered by Hi-C-derived chromosomal proximity. Somatic mutation, copy-number alteration, DNA methylation and gene-expression data from 1,578 TCGA tumors across 33 cancer types were used to train classifiers for recurrence risk and for primary-versus-metastatic status. Performance was assessed by 10-fold cross-validation using AUROC, AUPR and threshold-based metrics. Integrated gradients yielded per-gene attribution scores; top-ranked genes were evaluated for prognostic value in two independent non-small cell lung cancer cohorts (GSE31210, n = 226; GSE135222, n = 27) using survival analyses. OMNIS achieved high discrimination for recurrence (AUROC/AUPR 0.970/0.937) and metastasis (0.980/0.883), with accuracies of 0.873-0.911 and negative predictive values ≥0.970 across tasks. Spatial genomic embedding accelerated convergence and outperformed non-spatial baselines. Attribution highlighted seven recurrence-associated genes (including IBA57, DNTTIP1, SLC20A2 and TMEM201) and ten metastasis-associated genes (including PLXNA1, POLR3D, TTLL4, SREBF2, TYMP and ZBTB7C). In external cohorts, expression of these genes showed independent, stage-dependent associations with progression-free and overall survival. OMNIS is a spatially informed multi-omics framework that couples accurate prediction with gene-level interpretability. By embedding three-dimensional genome organization into deep-learning models, OMNIS nominates biologically coherent, context-specific drivers of progression and may guide future biomarker development and personalized therapy in precision oncology.

Beyond its role in sex determination, the Y chromosome contains genes that regulate transcription, translation, and protein stability, thereby contributing to the pathogenesis of various male-specific diseases, including cancer. Although sex significantly influences cancer incidence and outcomes, the molecular mechanisms underlying these differences remain poorly understood. These disparities are particularly evident in colorectal cancer (CRC), where men experience higher incidence, metastasis, and mortality rates. Here, we provide the first evidence that the sexually dimorphic RNA helicase DDX3Y (DEAD-box helicase 3 Y-linked), but not its X-linked homolog DDX3X, is significantly downregulated in tumor tissues from male CRC patients (n&#x2009;=&#x2009;22). Overexpression of DDX3Y suppressed CRC cell proliferation, invasion, and colony formation while promoting apoptosis (p&#x2009;<&#x2009;0.01). Conversely, siRNA-mediated depletion of DDX3Y, but not DDX3X, enhanced proliferation, invasion, and colony formation in normal colorectal mucosal cells (p&#x2009;<&#x2009;0.01). Mechanistically, DDX3Y regulated the expression of key genes involved in cell growth and invasion, including KRAS, PIK3CA, PTEN, Snail, TCF7L1, and E-cadherin, whereas DDX3X had no significant effect on these targets. Collectively, these findings identify DDX3Y as a potential male-specific tumor suppressor in CRC and support further investigation of its prognostic and therapeutic potential in colorectal cancer.

A significant subset of tumors, including >50% of osteosarcomas-an aggressive bone malignancy affecting children, adolescents, and young adults-relies on alternative lengthening of telomeres (ALT), a telomerase-independent, DNA repair-based mechanism for telomere elongation. The overall 5 year survival rate for osteosarcoma patients is &#x223c;65%, underscoring the need to develop novel targeted therapies. Through the Cancer Dependency Map, we identified SMARCAL1, a DNA translocase previously shown to remodel stalled replication forks, as a top selective dependency factor in telomerase-negative tumors. Using a panel of ALT-positive and ALT-negative cancer cell lines, as well as osteosarcoma patient-derived xenograft cells, we confirmed that ALT-positive cells are uniquely sensitive to the loss of SMARCAL1, whose depletion exacerbates ALT-dependent phenotypes and telomeric DNA damage. Notably, we demonstrated that suppressing ALT abrogates their dependency on SMARCAL1. Mechanistically, we showed that SMARCAL1 loss leads to telomeric ssDNA accumulation in ALT-positive cells, dependent in part on DNA repriming mediated by the DNA primase/polymerase PRIMPOL. Moreover, SMARCAL1's ssDNA annealing activity counteracts DNA unwinding by the BLM helicase, limiting telomeric ssDNA accumulation and DNA damage in ALT-positive cells. Importantly, SMARCAL1 depletion induces senescence in ALT-positive cancer cells, rendering them susceptible to treatment with senolytic agents. Together, these findings establish SMARCAL1 as a key regulator of ALT metabolism and highlight SMARCAL1 as a promising therapeutic target for ALT-positive tumors.

Fibroblast growth factor receptor 2 gene (FGFR2) rearrangements are among the most common oncogenic drivers in intrahepatic cholangiocarcinoma (iCCA). While FGFR inhibitors are clinically approved, primary and secondary resistance remain major limitations. Preclinical investigation of resistance mechanisms, including cancer cell-extrinsic crosstalk, is hampered by current models that rely on human FGFR2-fusion transgenes in immunodeficient hosts. We therefore aimed to generate an entirely murine FGFR2-fusion driven iCCA (Ff-iCCA) model to study immunomodulatory mechanisms in the tumor microenvironment (TME). A syngeneic cholangiocyte organoid-based iCCA mouse model was engineered via endogenous chromosomal rearrangement of the Fgfr2 gene combined with Trp53 deletion (PFf) and other co-occurring genetic alterations. KrasG12D-mutated lines (PK) served as comparison. TME characterization was performed using 30-plex spatial proteomics on &#x223c;250,000 cells. Bulk RNA-sequencing was conducted on FGFR inhibitor-treated PFf and PK organoids. Pharmacodynamics of FGFR inhibition on Ff-iCCA were assessed by immunostaining and quantitative RT-PCR. Intrahepatic implantation produced well-differentiated Ff-iCCA with morphologic features resembling human small duct type iCCA. In immunocompetent hosts, additional co-alterations were required for tumor penetrance, with Pten deletion being most robust with 75%. Compared to KRAS-driven iCCA, Ff-iCCA showed a significantly increased infiltration by Ly-6C/G+ neutrophils (19-fold, p=0.004) and CD8+ T cells (8-fold, p<0.001). Transcriptome analysis revealed increased chemokine expression in PFf versus PK organoids, which was not reversed by FGFR inhibition. Ff-iCCA responded to FGFR inhibition with a 6.5-fold reduced proliferation in vivo (p=0.029), without observation of significant TME remodeling. Our syngeneic murine Ff-iCCA model recapitulates hallmarks of human FGFR2-fusion iCCA, providing a platform for functional investigation of cancer cell-TME crosstalk in this molecular subtype. This study introduces the first fully syngeneic, endogenously engineered murine model of FGFR2-fusion driven iCCA, overcoming the key limitation of prior models relying on human transgenes in immunodeficient hosts. The model faithfully recapitulates hallmarks of human FGFR2-fusion iCCA, including a small duct type morphology and a distinct neutrophil-enriched tumor immune microenvironment, validating its translational relevance. The finding that an upregulated chemotaxis signature in FGFR2-fusion persists despite FGFR inhibition, alongside upregulation of interferon-stimulated genes upon treatment, points to compensatory immunomodulatory mechanisms that remain to be mechanistically resolved. Overall, this work provides a physiologically relevant platform to interrogate cancer cell-tumor microenvironment crosstalk in FGFR2-fusion driven iCCA.