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PubMed2025

Clinical utility of comprehensive genomic profiling test for colorectal cancer: a single institution prospective observational study.

PURPOSE: Next-generation sequencing (NGS) has revolutionized cancer treatment by enabling comprehensive cancer genomic profiling (CGP) to guide genotype-directed therapies. While several prospective trials have demonstrated varying outcomes with CGP in patients with advanced solid tumors, its clinical utility in colorectal cancer (CRC) remains to be evaluated. METHODS: We conducted a prospective observational study of CGP in our hospital between September 2019 and March 2024. Overall survival (OS) of the patients who received CGP-based therapy and those did not was compared, and genomic variables associated with OS were evaluated. RESULTS: A total of 100 patients with CRC underwent CGP using four platforms. The median patient age was 67 years, and most had a good performance status. The most frequent genomic alterations were TP53 (82%), APC (82%), and KRAS (55%). Actionable mutations such as ERBB2 amplification and BRAF V600E were identified in some patients, and 9% received CGP-based therapy, including immune checkpoint inhibitors for tumor mutational burden-high or microsatellite instability-high tumors. Patients receiving CGP-based therapy had longer OS from expert panel discussion (16.0 vs. 10.8 months) compared to those who did not. Alterations in TP53, SMAD4, and NF1 were associated with worse OS. Interestingly, PTEN mutations were linked to improved survival. TP53 alterations were more common in left-sided CRC. CONCLUSION: Although some patients with CRC received CGP-guided therapy, a statistically significant survival benefit was not observed. However, TP53 and SMAD4 mutations were identified as negative prognostic markers, indicating their potential as targets for future drug development.

Humans↗

PubMed2026

OLFML2B promotes hepatocellular carcinoma malignancy via the PI3K/AKT-EMT axis and correlates with an immunosuppressive tumor microenvironment.

INTRODUCTION: Hepatocellular carcinoma (HCC) is a leading cause of global cancer-related mortality, highlighting the need for novel biomarkers and therapeutic targets. METHODS: The role of Olfactomedin-like 2B (OLFML2B) in HCC was investigated through multi-database analyses (The Cancer Genome Atlas, International Cancer Genome Consortium, Gene Expression Omnibus) and experimental validation. RESULTS: OLFML2B was significantly upregulated in HCC tissues, correlated with poor overall and disease-specific survival, clinicopathological features (tumor grade, stage, age, gender), and robust diagnostic performance (AUC > 0.7 across 14/15 datasets). Transcriptomic and single-cell analyses further revealed that high OLFML2B expression was associated with an immunosuppressive tumor microenvironment, characterized by increased infiltration of M2 macrophages, cancer-associated fibroblasts (CAFs), and regulatory T cells (Tregs), as well as reduced abundance of cytotoxic T cells and NK cells. Knockdown of OLFML2B suppressed malignant phenotypes, including cell proliferation, migration, invasion, and angiogenesis, attenuated PI3K/AKT-EMT signaling, and enhanced sensitivity to sorafenib, cabozantinib, and regorafenib in Huh7 and HepG2 cells. Additionally, OLFML2B knockdown suppressed tumor growth and metastasis in zebrafish xenografts. DISCUSSION: Collectively, these findings indicate that OLFML2B is required for HCC progression and represents a prognostic biomarker and potential therapeutic target.

Humans↗

PubMed2026

SCLC TumorMiner: A genomics platform for small cell lung cancer precision oncology.

Small cell lung cancer (SCLC) is among the most aggressive malignancies. Unlike many other cancers, it is not represented in The Cancer Genome Atlas, and available datasets are fragmented across institutions, disease stages, and treatment settings. RNA sequencing provides a powerful and cost-effective approach, but the high dimensionality of transcriptomic data and the heterogeneity of patient cohorts pose significant challenges. To address such challenges, we developed SCLC TumorMiner (https://discover.nci.nih.gov/SclcTumorMinerCDB/), which includes 50 tumor samples from relapsed patients at the National Cancer Institute (NCI) and 154 samples from untreated patients at the University of Cologne and Tongji University. SCLC TumorMiner enables molecular classification, genomic pathway analyses, risk stratification, identification of predictive cell-surface biomarkers such as DLL3 or TROP2, and drug-response biomarkers such as SLFN11. SCLC TumorMiner illustrates profound differences between untreated and relapsed patient samples. Additionally, "MyPatient", one of SCLC TumorMiner's modules, is presented as a medical assistant application prototype.

SCLC↗

PubMed2026

Kynurenine metabolism-related gene signature for prognostic stratification in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) remains a major global health burden with high mortality rates and limited therapeutic options. The identification of reliable biomarkers for early diagnosis and prognosis prediction is urgently needed. Kynurenine metabolism, a critical pathway in immune regulation and tumor progression, has been implicated in various cancers. However, its prognostic value in HCC has not been fully elucidated. This study aimed to develop a prognostic risk model based on kynurenine metabolism-related genes (KMRGs) for HCC patients. METHODS: Transcriptomic and clinical data of HCC patients were retrieved from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) databases. A prognostic risk model was established using least absolute shrinkage and selection operator (LASSO) and Cox regression analyses. Survival analysis and functional enrichment analysis were conducted to validate the predictive performance of the model and to investigate the underlying mechanisms. ALDH8A1 was ultimately identified as a target gene based on survival analysis, and its impact on tumor cell migration was assessed using the HCC cell line. RESULTS: A prognostic model based on seven KMRGs was established. The high-risk group exhibited significantly worse overall survival compared to the low-risk group. Functional enrichment analysis in high-risk patients highlighted significant enrichment in core biological processes, including spliceosome assembly and ribonucleoprotein complex biogenesis. Furthermore, a nomogram integrating the risk score and clinical pathological features was developed, demonstrating moderate predictive performance for HCC prognosis. CONCLUSIONS: This study successfully constructed a prognostic risk model based on seven KMRGs, providing a valuable tool for predicting clinical outcomes in HCC patients. These findings highlight the potential role of kynurenine metabolism in HCC progression and offer new insights for future therapeutic strategies.

ALDH8A1↗

PubMed2025

U2AF1 mutations rescue deleterious exon skipping induced by KRAS mutations.

The mechanisms by which somatic mutations of splicing factors, such as U2AF1S34F in lung adenocarcinoma, contribute to cancer pathogenesis are not well understood. Here, we used prime editing to modify the endogenous U2AF1 gene in lung adenocarcinoma cells and assessed the resulting impact on alternative splicing. These analyses identified KRAS as a key target modulated by U2AF1S34F. One specific KRAS mutation, G12S, generates a cryptic U2AF1 binding site that leads to skipping of KRAS exon 2 and generation of a non-functional KRAS transcript. Expression of the U2AF1S34F mutant reverts this exon skipping and restores KRAS function. Analysis of cancer genomes reveals that U2AF1S34F mutations are enriched in KRASG12S-mutant lung adenocarcinomas. A comprehensive analysis of splicing factor/oncogene mutation co-occurrence in cancer genomes also revealed significant co-enrichment of KRASQ61R and U2AF1I24T mutations. Experimentally, KRASQ61R mutation leads to KRAS exon 3 skipping, which in turn can be rescued by the expression of U2AF1I24T. Our findings provide evidence that splicing factor mutations can rescue splicing defects caused by oncogenic mutations. More broadly, they demonstrate a dynamic process of cascading selection where mutational events are positively selected in cancer genomes as a consequence of earlier mutations.

Journal Article↗

PubMed2026

Associations of neighborhood deprivation with breast cancer tumor genomics, targeted treatment use, and survival.

PURPOSE: Neighborhood environments appear to influence breast cancer biology and outcomes. This study evaluated somatic, treatment, and outcome differences by Area Deprivation Index in patients with metastatic breast cancer. METHODS: Retrospective, population-based cohort study using clinical and genomic data gathered between 2015 and 2024 at four academic institutions in the United States. The outcomes were differences in circulating tumor DNA mutation profiles, PI3K inhibitor use, and survival between patients with metastatic breast cancer living in high deprivation (Area Deprivation Index ≥ 60 by national rank) and low deprivation (< 60) neighborhoods. RESULTS: Among 1127 patients with metastatic breast cancer, 335 (29.7%) lived in high deprivation areas. These patients were more likely to have TP53 mutations (Odds ratio 1.49, 95% Confidence Interval 1.07-2.08, P = 0.018). Among hormone receptor-positive, HER2-negative patients eligible for PI3K inhibitors, those from high deprivation areas were less likely to receive them (17.4% vs. 36.7%, p = 0.02). Median survival from the time of circulating tumor DNA testing was significantly shorter in the high deprivation group (24 months versus 28 months, p = 0.04) and for Black patients in the high deprivation group versus Black patients in low deprivation group and all White patients (15 months versus 25-28 months, p = 0.02). CONCLUSIONS: We found that patients with metastatic breast cancer living in high deprivation neighborhoods were more likely to have TP53 mutations, an indicator of aggressive disease biology, less likely to receive PI3K inhibitors, and had shorter overall survival compared to patients living in low deprivation neighborhoods by Area Deprivation Index.

Humans↗

PubMed2026

Microplastics and nanoplastics-related genes signature predicts prognosis in pancreatic ductal adenocarcinoma and functional validation of interleukin 1 alpha.

BACKGROUND: Microplastics and nanoplastics (MNPs), as emerging environmental pollutants, have garnered significant attention from the global scientific community due to their potential threats to human health, particularly their association with the occurrence and development of cancer. The goal of our study is to create a predictive marker for pancreatic ductal adenocarcinoma (PAAD) based on MNPs-related genes, with the purposes of predicting survival outcomes and assessing the tumor immune microenvironment. METHODS: Using multi-cohort data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and International Cancer Genome Consortium (ICGC), we assessed the association between MNPs and PAAD prognosis through the Xiantao Academic (https://www.xiantao.love/). The development of a prognostic signature was followed by an assessment of its significance through the Kaplan-Meier method, time-dependent receiver operating characteristic (ROC), and decision curve analysis (DCA). The validity of the risk model was confirmed through the ICGC and GSE71729 cohorts. The model was then assessed for levels of tumor immune infiltration. To explore MNPs-related genes expression characteristics within immune cells in PAAD, we performed single-cell RNA sequencing and spatial transcriptomics analysis through the Sparkle Platform (https://grswsci.top/). Finally, in vitro experiments were conducted to investigate the biological function of interleukin 1 alpha (IL1A). RESULTS: A four-gene signature comprising XDH, IL1A, KIF20A, and ASPM, based on MNPs, was developed to stratify PAAD patients into two distinct risk groups. The high-risk group showed a significantly poorer prognosis. A similar trend was verified in the external cohorts ICGC and GSE71729. The signature risk score affected immune cell infiltration in the PAAD microenvironment. The infiltration of B cells, CD8+ T cells, cytotoxic cells, immature dendritic cells (iDCs), mast cells, plasmacytoid dendritic cell (pDC), T cells, Tem cells, T follicular helper (TFH) cells, and T helper 17 (Th17) cells had a positive correlation with the low-risk group. In contrast, high-risk patients tended to have increased number of T helper (Th2) cells and higher expression of SIGLEC15, CD274, IGSF8. Knockdown of IL1A in PAAD cells inhibited their tumor proliferation ability in vitro. CONCLUSIONS: Using MNPs-related genes, we built a prognostic model for PAAD, revealing that patients with high-risk scores are likely to have a worse prognosis. This model is designed to develop personalized treatment strategies tailored to the specific needs of each patient, thereby improving clinical outcomes for PAAD patients. Furthermore, IL1A could be a promising therapeutic candidate for PAAD.

Microplastics↗

PubMed2026

Alternative End Joining Dependency Imposed by miR-21-5p Defines Radiation Resistance and a Targetable Vulnerability in Oral Squamous Cell Carcinoma.

PURPOSE: Clinical control of oral squamous cell carcinoma (OSCC) is constrained by heterogeneous radiosensitivity driven by divergent DNA damage response programs. The architecture and functional contribution of alternative end joining (Alt-EJ), an error-prone DNA double-strand break (DSB) repair pathway frequently upregulated in cancer, to radiation resistance remains poorly defined. METHODS AND MATERIALS: We profiled microRNAs in radioresistant OSCC clones and performed multiomic integration across an institutional OSCC cohort, an external OSCC cohort from the Gene Expression Omnibus, The Cancer Genome Atlas pan-cancer tumors, and cell lines characterized by Sanger Genomics of Drug Sensitivity in Cancer to infer DNA damage response characteristics, genomic scar features, drug sensitivity, and radiation therapy outcomes. DSB repair capacity and pathway usage were validated using functional assays, including Alt-EJ reporters and droplet digital PCR quantification of microhomology-mediated repair events. Core Alt-EJ effectors such as PARP1 and POLQ were perturbed genetically and pharmacologically. Therapeutic efficacy of PARP or POLQ inhibition with or without irradiation was tested in a syngeneic OSCC model, followed by bulk tumor transcriptomics to assess pathway engagement. RESULTS: Upregulation of miR-21-5p was not only selectively detected in radioresistant OSCC, but also modulated radiosensitivity in vitro and in vivo, and was associated with inferior postradiation therapy survival. A calibrated miR-21-5p target-gene signature tracked Alt-EJ activity across patient and mouse tumors and cancer cell lines, correlated with microhomology-mediated indels and broader genomic scarring, and predicted sensitivity to clinically available PARP inhibitors. Functionally, enforced miR-21-5p expression increased Alt-EJ usage and accelerated DSB repair, whereas inhibition or depletion of key Alt-EJ effectors reduced repair efficiency and restored radiosensitivity. In vivo, Alt-EJ targeting with PARP or POLQ inhibitor abrogated miR-21-5p-driven radiation resistance; transcriptomic profiling supported suppression of Alt-EJ programs as the operative mechanism. CONCLUSIONS: These findings establish a mechanistic link between miR-21-5p activity and Alt-EJ dependence, provide a clinically deployable signature to identify Alt-EJ-dependent OSCC, and support rational combinations of Alt-EJ targeting agents with radiation therapy to overcome treatment failure and advance precision radiation oncology.

MicroRNAs↗

PubMed2026

Integrative Pan-Cancer Characterization of lncRNA UPK1A-AS1 and Its Role in Hypoxia-Associated Sorafenib Resistance in Hepatocellular Carcinoma.

Long noncoding RNAs (lncRNAs) are emerging as critical regulators of tumor initiation and progression through transcriptional and posttranscriptional mechanisms. UPK1A antisense RNA 1 (UPK1A-AS1), a cancer-associated lncRNA, has been reported to participate in oncogenic processes; however, its overall landscape across human malignancies and its biological role in therapy resistance remain poorly understood. Given the increasing importance of identifying functional lncRNAs with prognostic and therapeutic potential, this study presents a comprehensive multiomics characterization of UPK1A-AS1 and its experimental validation in hepatocellular carcinoma (HCC). We integrated datasets from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression Project (GTEx), the cancer immunology data engine (CIDE), and the cBioPortal for cancer genomics (cBioPortal) to systematically assess its expression pattern, genomic alterations, clinical significance, and immunological associations. Our analyses revealed that UPK1A-AS1 is significantly upregulated in multiple tumor types, with copy-number amplification as the predominant genomic alteration driving its overexpression. Elevated UPK1A-AS1 expression was correlated with advanced disease stage, poor differentiation, immune exclusion, and unfavorable prognosis, supporting its potential as a cancer type-dependent biomarker. In parallel, functional studies demonstrated that hypoxia transcriptionally induces UPK1A-AS1 in HCC, where it promotes sorafenib resistance by suppressing apoptosis. Silencing UPK1A-AS1 restored apoptotic and enhanced sorafenib efficacy both in vitro and in vivo. Collectively, our findings suggest that UPK1A-AS1 is a hypoxia-inducible oncogenic lncRNA that plays dual roles in cancer, with cancer type-dependent associations with progression and immune modulation across malignancies and mechanistically mediating hypoxia-associated drug resistance in HCC.

Humans↗

PubMed2025

Interconnected study of molecular pathways: miR-137 as a central element at the intersection of lipid metabolism and prostate carcinogenesis.

OBJECTIVE: To evaluate the roles of miR-137 and its target genes in lipid metabolism and prostate tumorigenesis. METHODS: We used a series of bioinformatic approaches to establish the relationship between miR-137 and its target genes. We mapped the metabolic pathways of interest in the Reactome database and identified the central target genes of miR-137 in this pathway using four platforms: Reactome, miRDB, miRmap, and TargetScan. To assess the expression and association with clinical parameters, we obtained information from the UALCAN, OncoDB, and GEPIA2 databases using a dataset of patients with prostate cancer from The Cancer Genome Atlas. For functional enrichment analysis and construction of the protein-protein interaction network, we used the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and STRING. RESULTS: Our in silico study of The Cancer Genome Atlas database revealed that miR-137 is underexpressed in tumor tissues, and its reduction is associated with poor prognosis. An intriguing set of eight genes within the PPARα pathway: PPARGC1A, PPARGC1B, NCOA1, NCOA2, NCOA3, MED1, MED27, and ESRRA displayed synergy, positive correlations, and synchronized expression patterns in adipose, hepatic, and prostatic tissues, all linked to the enigmatic processes of metabolic regulation. Among the highlighted genes, ESRRA was overexpressed in the malignant environment, whereas its counterparts remained underexpressed. The plot was thickened with associations between the expression of NCOA1, NCOA3, and MED27, lymph node involvement, and the overexpression of several genes linked to advanced prostate cancer stages. An intriguing pattern emerged, with patients exhibiting reduced disease-free survival overexpressing NCOA2, NCOA3, MED27, and ESRRA. CONCLUSION: This study elucidates the possibility that miR-137 subtly modulates metabolic genes in prostate cancer, suggesting its latent therapeutic potential as a biomarker for disease progression. BACKGROUND: ■ The reduction of miR-137 in tumor tissues is associated with a worse prognosis. BACKGROUND: ■ miR-137 has eight oncogenically relevant target genes acting in the PPARα lipid pathway. BACKGROUND: ■ NCOA1, NCOA3, MED27, and ESRRA are associated with advanced prostate cancer. BACKGROUND: ■ miR-137 exhibits significant clinical potential by repressing the activation of pathways that influence prostate tumorigenesis in hyperstimulated metabolic environments. BACKGROUND: Prostate cancer progression is sustained by the simultaneous activation of pathways involving lipid uptake and de novo synthesis. In this context, miR-137 inhibits adipogenic differentiation and may reduce lipid uptake by tumor cells by modulating the PPAR/ p160/ESRRA axis, considerably attenuating metabolic effects and suppressing prostate tumorigenesis.

Male↗

PubMed2024

Inverted triplications formed by iterative template switches generate structural variant diversity at genomic disorder loci.

The duplication-triplication/inverted-duplication (DUP-TRP/INV-DUP) structure is a complex genomic rearrangement (CGR). Although it has been identified as an important pathogenic DNA mutation signature in genomic disorders and cancer genomes, its architecture remains unresolved. Here, we studied the genomic architecture of DUP-TRP/INV-DUP by investigating the DNA of 24 patients identified by array comparative genomic hybridization (aCGH) on whom we found evidence for the existence of 4 out of 4 predicted structural variant (SV) haplotypes. Using a combination of short-read genome sequencing (GS), long-read GS, optical genome mapping, and single-cell DNA template strand sequencing (strand-seq), the haplotype structure was resolved in 18 samples. The point of template switching in 4 samples was shown to be a segment of ∼2.2-5.5 kb of 100% nucleotide similarity within inverted repeat pairs. These data provide experimental evidence that inverted low-copy repeats act as recombinant substrates. This type of CGR can result in multiple conformers generating diverse SV haplotypes in susceptible dosage-sensitive loci.

Humans↗

PubMed2023

Intratumor childhood vaccine-specific CD4+ T-cell recall coordinates antitumor CD8+ T cells and eosinophils.

BACKGROUND: Antitumor mechanisms of CD4+ T cells remain crudely defined, and means to effectively harness CD4+ T-cell help for cancer immunotherapy are lacking. Pre-existing memory CD4+ T cells hold potential to be leveraged for this purpose. Moreover, the role of pre-existing immunity in virotherapy, particularly recombinant poliovirus immunotherapy where childhood polio vaccine specific immunity is ubiquitous, remains unclear. Here we tested the hypothesis that childhood vaccine-specific memory T cells mediate antitumor immunotherapy and contribute to the antitumor efficacy of polio virotherapy. METHODS: The impact of polio immunization on polio virotherapy, and the antitumor effects of polio and tetanus recall were tested in syngeneic murine melanoma and breast cancer models. CD8+ T-cell and B-cell knockout, CD4+ T-cell depletion, CD4+ T-cell adoptive transfer, CD40L blockade, assessments of antitumor T-cell immunity, and eosinophil depletion defined antitumor mechanisms of recall antigens. Pan-cancer transcriptome data sets and polio virotherapy clinical trial correlates were used to assess the relevance of these findings in humans. RESULTS: Prior vaccination against poliovirus substantially bolstered the antitumor efficacy of polio virotherapy in mice, and intratumor recall of poliovirus or tetanus immunity delayed tumor growth. Intratumor recall antigens augmented antitumor T-cell function, caused marked tumor infiltration of type 2 innate lymphoid cells and eosinophils, and decreased proportions of regulatory T cells (Tregs). Antitumor effects of recall antigens were mediated by CD4+ T cells, limited by B cells, independent of CD40L, and dependent on eosinophils and CD8+ T cells. An inverse relationship between eosinophil and Treg signatures was observed across The Cancer Genome Atlas (TCGA) cancer types, and eosinophil depletion prevented Treg reductions after polio recall. Pretreatment polio neutralizing antibody titers were higher in patients living longer, and eosinophil levels increased in the majority of patients, after polio virotherapy. CONCLUSION: Pre-existing anti-polio immunity contributes to the antitumor efficacy of polio virotherapy. This work defines cancer immunotherapy potential of childhood vaccines, reveals their utility to engage CD4+ T-cell help for antitumor CD8+ T cells, and implicates eosinophils as antitumor effectors of CD4+ T cells.

Mice↗

PubMed2026

Senescent fibroblasts drive CD8+ T cell dysfunction in colorectal cancer via CD36-mediated lipid transfer and peroxidation.

BACKGROUND: Functional exhaustion of tumor-infiltrating CD8+ T cells represents a hallmark of colorectal cancer (CRC) immunosuppression, though its mechanistic drivers remain elusive. Given the established correlation between CRC progression and stromal senescence characterized by pathological lipid accumulation and impaired immunity, we investigated whether and how senescent fibroblasts actively regulate CD8+ T cell dysfunction. METHODS: Single-cell RNA sequencing (scRNA-seq) analysis was conducted to unveil the diverse fibroblast populations and the significant lipid metabolism changes between senescent fibroblasts and non-senescent fibroblasts in human CRC specimens and adjacent normal mucosa. Machine-learning identified senescent fibroblasts with a distinct gene signature. Cell-cell communication analysis was used to evaluate the interactions between senescent fibroblasts and CD8+ T cells in colorectal cancer. Co-culture experiments were conducted among senescent fibroblasts, CD8+ T cells and patient-derived organoids of CRC (CRC-PDOs), with the results evaluated with high-content imaging and propidium iodide/Hoechst 33,342 staining. Flow cytometry, ELISA and lipid pulse-chase with BODIPY FL C16 were performed to detect the alterations of CD8+ T cell cytotoxic function and metabolic status. AOM/DSS-induced CRC mouse model was used to conduct in vivo validation to evaluate whether senolytics could suppress CRC progression. Patients from the Cancer Genome Atlas colorectal cancer cohort were stratified into CD36-high and CD36-low groups by median expression, and drug sensitivity for GDSC2 compounds was predicted computationally using the oncoPredict R package. RESULTS: ScRNA-seq demonstrated the specific cell population presence and divergence of senescent fibroblasts between neoplastic and histologically normal adjacent cell clusters in CRC. Random Forest was employed for cell senescence classification. Feature importance analysis identified five genes as key contributors to the model’s decision process. Cell-cell communication analysis revealed enhanced interactions between senescent fibroblasts and CD8+ T cells in CRC. Co-culture of senescent fibroblasts significantly impaired the cytotoxic functions of CD8+ T cells on CRC-PDOs, which was reflected by the declined proportions of granzyme B (GZMB) + and interferon gamma (IFNγ) + CD8+ T cells and enhanced viability of CRC-PDOs. Mechanistically, the co-culture with senescent fibroblasts promoted the lipid shuttling into CD8+ T cells to induce lipid peroxidation and downstream impairment of cytotoxicity. Furthermore, the inhibition of CD36, the specific scavenger receptor for lipid uptake of CD8+ T cells, effectively suppressed lipid transfer and peroxidation thereby preserving the effector functions of CD8+ T cells and ultimately promoting tumor apoptosis. Complementarily, in vivo senolytic treatment significantly suppressed CRC progression in AOM-DSS CRC mouse models. Top 12 therapeutic agents were identified significantly enhanced predicted efficacy in CD36-high tumors. CONCLUSIONS: Our study identified a substantial population of senescent fibroblasts in human CRC through single cell transcriptomics, machine-learning and clinical biopsies. These senescent fibroblasts impair CD8+ T cell-mediated killing of CRC-PDOs via CD36-dependent lipid transfer, suggesting senolytic targeting of stromal cells as a promising immunotherapeutic strategy for CRC.

Colorectal Neoplasms↗

PubMed2026

NPLOC4 Constructs Tumor Immunosuppressive Microenvironment in Pan-cancer and Hepatocellular Carcinoma.

INTRODUCTION: NPLOC4 (nuclear protein localization 4 homolog) is mainly involved in DNA damage, cell cycle, and ubiquitination promotion. Nonetheless, the role of NPLOC4 in the tumor immune microenvironment (TIME) and its potential as a promising tumor therapeutic target remains unclear. METHODS: Therefore, analyses of NPLOC4 mRNA and protein expression, RNA subcellular localization, and patient prognosis associated with NPLOC4 expression were conducted across multiple tumor types. Additionally, the correlations between NPLOC4 and immune cells, non-immune cells, and immune molecules within the tumor immune microenvironment (TIME) were investigated. These analyses utilized data from various public resources, including the Genotype-Tissue Expression (GTEx) project, The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), The Human Protein Atlas (HPA), Clinical Proteomic Tumor Analysis Consortium (CPTAC), TIMER2.0, KM-Plotter, The University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN), and Tumor Immune Single-cell Hub 2 (TISCH2). Subsequently, we utilized hepatocellular carcinoma (HCC) patients' cancer and adjacent tissues plus tumor cell lines to verify the differential RNA and protein expression of NPLOC4 via qRT-PCR and immunohistochemistry (IHC). Then, the relationship of NPLOC4 expression level with immune infiltration score, infiltration of effector immune cells, suppressive immune cells, and several vital immune checkpoints was analyzed in HCC immune microenvironment. Furthermore, the distribution of expression of NPLOC4 in various cells in the HCC microenvironment was determined through single-cell sequencing analysis. RESULTS: We discovered that NPLOC4 was up-regulated in a variety of tumors and was correlated with poor prognosis. NPLOC4 not only had the potential as a tumor prognostic marker and therapeutic target but also was strongly linked to immune cells, immune checkpoints, and immune-related molecules and pathways in HCC immune microenvironment. CONCLUSION: In summary, NPLOC4 may serve as a promising target for immunotherapy.

Humans↗

PubMed2025

The landscape of structural variation in pediatric cancer.

Structural variants (SVs) account for over 60% of the driver variants in pediatric cancer, and in many cases act as the cancer initiating event. To study SVs from a pan-cancer perspective, we analyzed 1,616 pediatric cancer genomes in 16 major cancer types of hematological malignancies (n = 908), brain tumors (n = 183), and solid tumors (n = 525) and compared their profiles to those of 2,203 adult cancers. The SV burden varied ~100-fold across pediatric cancer types and demonstrated an 8- to 16-fold reduction compared to adult brain and solid tumors but was comparable in pediatric versus adult hematological malignancies. Recurrent SV hotspots occurred uniquely in pediatric acute lymphoblastic leukemias (ALLs) in proximity to RAG-mediated recombination signal sequences (RSS) and disrupted multiple immune-related loci as well as 69 genes, which often involved cryptic RSS sites. By contrast, such hotspots affected only immune-related loci but not driver genes in adult lymphoid cancers. Eight SV signatures extracted from the cohort had varying distributions across cancer types, with clustered translocations reflecting templated insertions in osteosarcoma, and medium-sized deletions (10 kb to 1 Mb) enriched in cancers with RAG-mediated deletions. Intra-patient evolutionary analysis in 13 patients with multiple spatiotemporally distinct samples revealed that RAG-mediated recombination in leukemia and complex rearrangements in solid tumors occurred both early in disease initiation and continuously during later diversification, contributing to clonal heterogeneity. Finally, we found that both driver genes and fragile sites were the two genomic regions most frequently disrupted by SVs. The unique and diverse SV landscapes that emerged from this comprehensive analysis expand the scope of RSS-mediated mutagenesis in pediatric ALL and will be a valuable resource for guiding future functional studies and the design of clinical genomic testing in pediatric cancer.

Journal Article↗

PubMed2026

Stromal Hedgehog Signaling Drives Segment-Specific Malignant Transformation of Gastrointestinal Stem Cells by Producing Bone Morphogenetic Protein Antagonists.

BACKGROUND & AIMS: Hedgehog signaling plays a complex role in epithelial-stromal interactions, but its effects on gastrointestinal stem cells mediated by heterogeneous stromal cell populations remain incompletely defined. Here, we investigate how stromal Hedgehog signaling regulates gastric stem cells and tumorigenesis in a segment-specific manner. METHODS: We genetically activated Hedgehog signaling in distinct stromal cell lineages using Col1a2-, Pdgfra-, Gli1-, Acta2-, and Prrx1-CreERT mouse lines, combined with lineage tracing, RNA sequencing, chromatin immunoprecipitation-quantitative polymerase chain reaction, and pharmacologic interventions. Human gastric cancer data from The Cancer Genome Atlas were also analyzed. RESULTS: We show that genetic activation of Hedgehog signaling in stromal cells marked by Col1a2, Pdgfra, or Gli1, but not by Acta2, induces tumorigenesis in the stomach and gastroesophageal junction, but not in the small or large intestine. Hedgehog signaling increases the expression of multiple bone morphogenetic protein antagonists in gastric but not colonic stromal cells, via Gli1-mediated transcription. These bone morphogenetic protein antagonists, in turn, activate Wnt/β-catenin signaling in gastric stem cells, driving their proliferation and initiating gastric cancer expressing CD44 and Sox9, but not Lgr5. Activating bone morphogenetic protein or inhibiting Wnt signaling blocks tumor initiation. Analysis of patient data from The Cancer Genome Atlas reveals elevated Hedgehog signaling in gastric cancers, which correlates with suppressed bone morphogenetic protein signaling. CONCLUSIONS: These findings uncover a gastrointestinal segment-specific oncogenic role for Hedgehog signaling in Col1a2+Acta2- stromal cells, mediated through the bone morphogenetic protein-Wnt-β-catenin axis.

BMP Antagonists↗

PubMed2026

Bioinformatic analysis reveals the potential association of ESRP1 with the splicing of cytoskeleton-associated genes in doxorubicin-resistant MCF7 breast cancer cells.

BACKGROUND: Breast cancer remains one of the most prevalent malignancies among women, with doxorubicin resistance posing a significant challenge that undermines treatment success and survival outcomes. Aberrant alternative splicing (AS), driven by dysregulation or mutations in splicing factors (SFs), is implicated in cancer initiation, progression, and drug resistance. This study aims to investigate the association of the epithelial cell-specific splicing factor ESRP1 with doxorubicin resistance in breast cancer, focusing on how ESRP1 deficiency correlates with AS changes that promote chemoresistance. METHODS: We analyzed RNA-sequencing (RNA-seq) data from doxorubicin-resistant (MCF7-DR) and parental (MCF7) breast cancer cell lines to identify enhanced alternative splicing events (ASEs) and changes in ESRP1 expression; we further leveraged The Cancer Genome Atlas (TCGA)-BRCA cohort to construct an SF-RASE correlation network for screening core SFs (including ESRP1). An integrative analysis combining crosslinking immunoprecipitation (CLIP-seq) data and The Cancer Genome Atlas (TCGA) database was performed to validate ESRP1 binding targets and assess the association between ESRP1-related splicing and cytoskeleton organization. RESULTS: We observed extensive AS changes and significantly downregulated ESRP1 expression in MCF7-DR cells. Integrative analysis identified 61 high-confidence ASEs that correlate with ESRP1 expression. Further bioinformatic integration suggests that ESRP1 expression is associated with the splicing patterns of SPTBN1, MAP2K7, FGFR3, and CYB561A3-four genes involved in cytoskeleton organization-though direct experimental verification to confirm a causal regulatory relationship between ESRP1 and the splicing of these genes is still pending. CONCLUSIONS: Our findings suggest that ESRP1 expression is closely associated with doxorubicin resistance in breast cancer cells, with concomitant alterations in key ASEs linked to cytoskeletal remodeling that correlate with ESRP1. Exploring the ESRP1-related splicing network may offer new strategies to overcome chemoresistance and improve patient outcomes. However, the small cell line sample size (n = 2 per group) constrains the robustness of ASE and SF-ASE correlation findings, and these results should be interpreted with caution and require further validation with larger sample cohorts.

Alternative splicing↗

PubMed2026

Yes-Associated Protein (YAP)1 and β-Catenin Immunohistochemistry as a Surrogate Marker for GTF2I-Mutant Type A/AB Thymomas.

Thymomas are rare thymic epithelial tumors classified by the World Health Organization into type A/AB thymomas, which commonly harbor GTF2I mutations and behave indolently, and type B thymomas and thymic carcinomas, in which these mutations are less common. Type A and AB thymomas are uniquely enriched for a recurrent somatic hotspot mutation in GTF2I p. L424H; yet, this gene is rarely included in clinical sequencing panels, limiting its diagnostic utility. Yes-associated protein (YAP)1, the principal effector of the Hippo signaling pathway, and β-catenin, the central transcriptional effector of the Wnt pathway, have emerging roles in thymoma biology; however, their relationship to GTF2I mutation status and histologic subtype has not been systematically characterized. We analyzed The Cancer Genome Atlas thymoma data set and an institutional cohort of 38 thymic epithelial tumors to evaluate YAP1 and β-catenin immunohistochemistry (IHC) as surrogate markers for GTF2I mutation status and histologic classification. In The Cancer Genome Atlas data set, YAP1 and CTNNB1 mRNA expression were markedly elevated in type A/AB thymomas relative to type B and carcinoma subtypes, and GTF2I-mutant tumors exhibited significantly higher YAP1 mRNA expression than GTF2I-wildtype tumors. Targeted next-generation sequencing of our institutional cohort confirmed enrichment of the canonical GTF2I p. L424H hotspot in indolent subtypes. By IHC, both nuclear YAP1 positivity and cytoplasmic β-catenin localization were significantly more frequent in indolent thymomas. Cytoplasmic β-catenin demonstrated high specificity (94%) for indolent histology, supporting its use in diagnostically challenging cases such as type A versus type B3 distinction on small biopsies. YAP1 IHC showed a high negative predictive value for GTF2I mutations, such that a YAP1-negative result reliably excludes a GTF2I-mutant tumor. These findings implicate crosstalk between Hippo and Wnt signaling in GTF2I-mutant thymomas and position YAP1 and β-catenin IHC as accessible, cost-effective surrogates for molecular subtyping in a tumor where standard sequencing panels have limited coverage.

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