About 40% of non-functioning (NF) Pancreatic Neuroendocrine Tumors (PanNETs) harbour mutations in MEN1, often co-occurring with DAXX/ATRX. While the ADM group (MEN1 and DAXX/ATRX co-mutated) exhibits homogeneous genetic and epigenetic features and a consistent risk of relapse, it shows considerable variability in treatment response, suggesting an underlying molecular diversity. In this study we aimed to elucidate the molecular mechanisms underlying this heterogeneity of ADM PanNETs by integrating transcriptomic (n = 36) and DNA methylation (n = 93) data. First, DNA methylation discriminates ADM-PanNET from PanNET mutated only in MEN1 (α-like), revealing enhancer, peri-centromeric, and telomeric methylation changes associated with alternative lengthening of telomeres and increased chromosomal instability. Transcriptomic analysis further revealed three distinct ADM subtypes: ADM hypoxic, ADM NST (No Special Type), and ADM immunosuppressive. The ADM hypoxic subtype is characterized by strong hypoxia signature, likely regulated epigenetically. The ADM NST subtype appears to be primarily driven by epigenetic changes that promote proliferation. Notably, the ADM immunosuppressive subtype, although significantly smaller (< 2.5 cm, p = 0.023), exhibits strong immune and metastasis-like signatures, suggesting a uniquely aggressive biology despite its reduced size. By defining these three novel ADM subtypes, our study provides a refined framework for understanding PanNET heterogeneity. This classification underscores potential diagnostic markers and highlights distinct biological vulnerabilities that may inform the development of subtype-tailored therapeutic strategies.

Salivary gland intraductal papillary mucinous neoplasm (SG IPMN) is a recently described entity arising predominately from intraoral minor salivary glands, characterised by a low-grade papillary cystic proliferation of mucinous columnar cells, so-named due to its resemblance to the pancreatic duct counterpart [1]. It is currently mentioned in the World Health Organization (WHO) Classification of Tumours (5th edition) salivary gland tumours introduction as a lesion with low-grade mucinous morphology that shares frequent AKT1 mutations with mucinous adenocarcinoma, hence it is thought to represent a low-grade salivary gland mucinous adenocarcinoma and is currently subsumed into this entity [1-3]. However, the classification of the neoplasm remains a controversial issue, with the WHO noting that it is still not established whether SG IPMN should be classified separately or within the mucinous adenocarcinoma spectrum as a potential precursor [2].

Lung cancer continues to be a significant health burden in the United States, with 2025 estimates indicating approximately 226,650 new cases and 124,730 deaths. NSCLC is the predominant histological subtype of lung cancer, representing approximately 80% to 85% of all diagnosed cases. Within the NSCLC cohort, the EGFR represents the most commonly altered tumor-initiating mutation, exhibiting the highest prevalence among actionable molecular aberrations. Ex20ins in the EGFR gene represent the third most common type of EGFR mutation, observed in approximately 0.3% to 2.9% of all NSCLC cases and 2% to 5% of EGFR-mutant NSCLC subtypes. In July 2025, the US FDA granted accelerated approval for sunvozertinib, an oral and irreversible EGFR tyrosine kinase inhibitor, for the treatment of NSCLC patients who have mutations in the EGFR Ex20ins. Sunvozertinib received conditional approval in China for the second-line NSCLC with mutations in the EGFR Ex20ins, based on safety and efficacy data derived from a Phase II clinical study. Before the approval of sunvozertinib, treatment approaches for EGFR Ex20ins-mutant patients with NSCLC were limited and largely suboptimal. Conventional EGFR-TKIs exhibited minimal clinical efficacy, primarily due to intrinsic structural resistance mechanisms conferred by these specific mutations. This manuscript focuses on the clinical studies that supported the USFDA accelerated approval of sunvozertinib, along with its ongoing and upcoming clinical trials, preclinical research, and other pharmacological aspects.

Rapid early progression (REP) is defined as MRI progression of glioblastoma after surgical resection before adjuvant therapy. REP occurs in approximately 50% of glioblastoma and is associated with worse overall survival. Despite the increasing trend towards molecular characterization of glioblastoma, no analysis has been performed between molecular alterations in glioblastoma and REP that may help define the urgency of adjuvant therapy.

Mesenchymal stem cell-derived exosomes (BM-MSC-Exos) have attracted increasing interest for their potential to modulate leukemic cell behavior in acute myeloid leukemia (AML). In this study, the effects of BM-MSC-Exos on the AML cell line THP-1 were evaluated. A dose-dependent reduction in cell viability was observed after 24 h of treatment, as determined by MTT assay. Flow-cytometric analysis revealed a significant increase in apoptotic activity following exposure to BM-MSC-Exos. Cell cycle analysis demonstrated an accumulation of cells in the G0/G1 phase, consistent with growth arrest. Gene-expression profiling by real-time PCR showed upregulation of pro-apoptotic genes (Caspase3, Caspase9, BID, and BAX) and downregulation of the anti-apoptotic gene BCL2. Likewise, expression of cell cycle regulators such as Cyclin D1 and CDK6 was reduced. Importantly, TUG1, an oncogenic long non-coding RNA implicated in leukemogenesis, was also significantly downregulated in exosome-treated cells. Taken together, these results may shed light on the possible role of BM-MSC-Exos in regulating apoptosis, cell-cycle progression, and TUG1 expression in leukemic cells. Further studies are warranted to elucidate the molecular mechanisms underlying these effects and to determine how BM-MSC-Exos-mediated modulation of TUG1 might contribute to leukemic cell regulation.

Germline pathogenic variants within the highly conserved exonuclease domain of the POLD1 gene predisposes to colorectal (CRC) and endometrial (EC) cancers. Tumours with POLD1-deficiency demonstrate unique genomic features including hypermutation and tumour mutational signatures (TMS) SBS10c, SBS10d and SBS20. The classification of variants within POLD1 remains challenging. The utility of incorporating tumour hypermutation status and TMS profiles into POLD1 gene-specific variant classification guidelines developed by ClinGen-InSiGHT remains to be established. We report a family with eight members heterozygous for the germline POLD1 c.1420C > A (p.Leu474Ile) variant. This variant resides within the exonuclease domain, is absent in gnomADv4.1 and is classified as a variant of uncertain clinical significance. Formalin-fixed paraffin embedded tissue and matched blood-derived DNA from person 001 (EC, 1 adenoma, 2 sessile serrated lesions), and two cousins, 009 (EC, 3 adenomas), and 010 (breast cancer, EC, CRC, 4 adenomas, 2 sessile serrated lesions and 1 traditional serrated adenoma) were tested using a custom multigene panel to determine tumour mutational burden (TMB) and TMS. All three ECs demonstrated characteristics of POLD1-deficiency namely hypermutated TMB and predominance of SBS10d. The CRC, 62.8% of the adenomas and 60% of the serrated polyps demonstrated SBS10c as the dominant TMS. EC, CRC, breast and multiple polyps from three family members heterozygous for the germline POLD1 c.1420C > A variant demonstrated hypermutation and SBS10c and SBS10d TMS, genomic features associated with defective POLD1. Somatic TMB and TMS profiling of multiple independent lesions demonstrated utility for identifying POLD1-deficiency suggesting this approach can support variant classification for POLD1.

Epigenetic dysregulation plays a critical role in colorectal cancer (CRC) progression. Our study investigated the role of FAM111B in tumorigenic phenotypes and ferroptosis in CRC and the mechanisms by which epigenetic alterations influence FAM111B expression. Bioinformatics analyses revealed FAM111B expression and predicted the association between IGF2BP2 and FAM111B or ELF1. The influence on cell phenotypes was determined by assessing cell proliferation, migration, apoptosis and ferroptosis. Mechanism analyses were performed using luciferase reporter and ChIP assays. Subcutaneous xenografts were used to evaluate the role in vivo. FAM111B, IGF2BP2 and ELF1 were upregulated in CRC tumours and cell lines. FAM111B downregulation inhibited cell proliferation and migration while inducing apoptosis and ferroptosis. IGF2BP2 increased FAM111B expression by stabilising its mRNA, and ELF1 transcriptionally upregulated IGF2BP2. Moreover, ELF1 modulated FAM111B expression through IGF2BP2. ELF1 knockdown suppressed cell proliferation and migration while triggering apoptosis and ferroptosis, which could be abolished by reintroduction of IGF2BP2 or FAM111B. Additionally, ELF1 depletion diminished the in vivo tumorigenicity of HCT116 cells. The ELF1/IGF2BP2/FAM111B cascade drives CRC progression and ferroptosis resistance. Targeting this cascade may provide a therapeutic avenue for CRC treatment.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly aggressive malignancy with a poor prognosis and limited effective treatment options. Our study comprehensively explores the complex role of programed cell death (PCD) mechanisms in PDAC development, examining 18 distinct PCD pathways and their genetic underpinnings. Using an advanced machine learning framework incorporating 429 algorithmic variations, we have developed an innovative PCD-based molecular signature that demonstrates robust prognostic capabilities. This signature exhibits superior performance across diverse patient cohorts, significantly outperforming traditional clinicopathological indicators. Through integrated pathway analysis, we revealed that high-risk patients show distinct activation of oncogenic pathways and significant alterations in the tumor immune microenvironment. These alterations include reduced infiltration of cytotoxic T lymphocytes and increased levels of immunosuppressive regulatory T cells (Tregs). Furthermore, leveraging the TISCH (Tumor Immune Single Cell Hub) database, we conducted detailed single-cell expression profiling of our signature genes across different cell populations within the tumor microenvironment (TME). This analysis uncovered cell-type-specific expression patterns of key PCD-related genes. Our results highlight the critical involvement of PCD in PDAC progression and introduce a promising tool for clinical risk stratification. The integration of bulk and single-cell transcriptomic analyses not only validates our molecular signature but also reveals potential cellular targets for therapeutic intervention. This PCD-focused approach may support the development of personalized therapeutic strategies and ultimately improve outcomes for PDAC patients.

Ovarian cancer is a lethal gynecological malignancy, largely due to late-stage diagnosis and poor prognosis. MicroRNA-597-3p (miR-597-3p) has been identified as a tumor suppressor in several cancers, while metastasis-associated colon cancer 1 (MACC1) functions as an oncogene that promotes metastasis. This study investigated the role of miR-597-3p and its regulation of MACC1 in ovarian cancer progression.

CD81 is a cell surface protein that plays an important part in tumor development. Several studies have shown that CD81 plays a role in cancer cell proliferation, invasion, and metastasis, particularly in leukemia. It has been reported that CD81 is overexpressed in non-Down syndrome acute megakaryoblastic leukemia (non-DS AMKL). In this article, we hypothesize that CD81 may play a vital role in acute megakaryoblastic leukemia (AMKL). We constructed the CD81 knockdown cell line using shRNA and found that CD81 knockout can inhibit the proliferation of AMKL and increase the apoptosis of AMKL in vitro. Therefore, CD81 may be a target of AMKL.

Oncolytic viruses (OVs) achieve selective cytolysis via tumor-specific entry receptor. However, the prevalence of OVs receptors in malignant tumors has not been fully determined yet. Here, we systematically identify and characterize critical cellular entry receptors for clinically relevant OVs, particularly focusing on SCARB2 expression and its potential therapeutic implications for oncolytic Enterovirus A71 (EV-A71) therapy in glioma.

Background & Aims: Pancreatic adenocarcinoma (PAAD) remains a highly lethal malignancy with limited therapeutic options, primarily due to the absence of reliable prognostic biomarkers. Immunogenic cell death (ICD) plays a pivotal role in anti-tumor immunity and has potential as both a prognostic marker and a predictor of immunotherapy response. This study aimed to identify ICD-related hub genes and establish a robust prognostic gene signature for PAAD using weighted gene co-expression network analysis (WGCNA). Methods & Results: Transcriptomic and clinical data of PAAD patients were obtained from the TCGA and GEO databases. ICD enrichment scores were calculated using single-sample gene set enrichment analysis (ssGSEA), and ICD-associated gene modules were identified through WGCNA. A prognostic ICD-related gene signature was then constructed, and patients were stratified into high- and low-score groups based on the median risk score. Functional enrichment analysis was performed using the Molecular Signatures Database (MsigDB). Correlations between the signature score, immune cell infiltration, and drug sensitivity (IC50 values from the GDSC2 database) were further assessed. Among the identified genes, AJM1 emerged as a key prognostic marker, validated in an independent PAAD cohort and through in vitro functional assays. Conclusion: This study developed and validated an ICD-related gene signature capable of predicting prognosis and immunotherapy responsiveness in PAAD. The identification and validation of AJM1 highlight its potential role as a prognostic biomarker and a novel contributor to the pathogenesis of PAAD.

Glioblastoma (GB) is a highly aggressive brain cancer with poor prognosis and a five-year survival rate of only 4-5%, largely due to challenges in surgical removal and radiotherapy limitations. Corosolic acid (CA), a natural pentacyclic triterpene, exhibits promising anti-cancer activity against GB. In this study, we founded that GBM8401-derived cancer stem cells (GBM8401-CSCs) display increased stemness, proliferation, migration, invasion, and elevated cancer stemness factors (Nestin, OCT4, CD133) compared to parental cells. CA treatment dose-dependently inhibited these malignant features and downregulated key cancer stemness genes. Combined with Temozolomide (TMZ), CA synergistically suppressed GBM8401-CSCs growth, colony formation, migration, invasion, and promoted apoptosis more effectively than either CA or TMZ alone and significantly reduced sphere formation and cancer stemness gene expression. Molecular docking results show a strong affinity of TMZ and CA for CD133 and OCT4 proteins, highlighting distinct molecular interactions. These results suggest that CA, especially in combination with TMZ, holds therapeutic potential for targeting human GB-CSCs.

Background: Dysregulation of N6-methyladenosine (m6A) RNA modification plays a critical role in the development and progression of non-small cell lung cancer (NSCLC). Methods: To explore the m6A modification landscape in NSCLC, we utilized direct RNA nanopore sequencing (dRNA-seq) to compare m6A patterns between NSCLC and adjacent normal tissues. Results: Our analysis revealed distinct m6A modification differences, with tumor tissues showing reduced m6A density compared to normal tissues. Aberrantly modified genes, such as SOX2 and TOP2A, exhibited hypomethylated m6A modifications and were upregulated in NSCLC tissues. We identified 14,419 differentially methylated m6A sites, with 49.5% hypermethylated and 50.5% hypomethylated. Functional enrichment analysis showed that hypermethylated genes were involved in DNA replication and transcription regulation, while hypomethylated genes were linked to cell migration and MAPK signaling. The expression patterns of m6A regulators, including METTL3, METTL16, CBLL1, FTO, ALKBH5, and ELAVL1, were consistent across NSCLC subtypes. Furthermore, correlation with clinical data from the TCGA database revealed that m6A-associated DEGs, such as HMGA1, ERO1A, LRFN4, SNTN, SLC2A1, DNASE2B, and VSIG2, were prognostically significant in NSCLC. Conclusions: This study underscores the pivotal role of m6A modifications in NSCLC and highlights the potential of dRNA-seq for identifying RNA epigenetic changes that may serve as novel therapeutic targets.

Thyroid cancer (TC) is the most common endocrine malignancy, with anaplastic thyroid cancer (ATC) being the most aggressive subtype. Evodiamine (EVO), a bioactive compound derived from Evodia rutaecarpa, possesses anti-inflammatory and anti-tumor properties, though its effects on ATC remain underexplored. This study investigated the anticancer potential of EVO using ARO and SW579 ATC cell lines in both in vitro and in vivo models. EVO significantly inhibited cell proliferation, induced G2/M phase arrest, and increased the sub-G1 population, indicating growth inhibition and cell death. Mechanistically, EVO activated the intrinsic caspase-dependent apoptotic pathway and triggered autophagy, as shown by autophagosome accumulation and elevated LC3-II levels. Importantly, blocking autophagy attenuated caspase activation, suggesting that autophagy contributes to EVO-induced apoptosis. Moreover, oral EVO administration markedly suppressed tumor growth in a nude mouse xenograft model without causing liver or kidney toxicity. TUNEL assay further confirmed enhanced tumor cell apoptosis in vivo. These results highlight EVO as a promising therapeutic candidate for ATC by simultaneously activating autophagy and apoptosis pathways.

Background: Neurofibromatosis type 2 (NF2), currently more accurately named NF2-related schwannomatosis (NF2-SWN), is classified as a multiple tumor syndrome, caused by impaired expression of the merlin protein. Approximately 50% of affected individuals inherit a germline mutation from their parents, while reports on the somatic mutation landscape of other genes are infrequent. Aim: To further explore the somatic mutations of NF2-SWN and provide a theoretical basis for the treatment of NF2-SWN. Design: A retrospective study was conducted to follow up on NF2-SWN patients who underwent surgical treatment in the Department of Neurosurgery of Xiangya Hospital. Whole-exome sequencing (WES) was performed on patients with a clear family history. Methods: This study compiled clinical data from 29 patients diagnosed with NF2-SWN, conducted WES on 7 patients with well-documented genetic histories, and subsequently analyzed their genetic mutations. Results: Whole-exome sequencing identified frequent somatic mutations in genes such as TTN, FLG, CR2, and FSIP2. Missense mutations and C>T transitions were the most common alteration types. Conclusion: TTN, CR2, FLG, and FSIP2 demonstrated elevated mutation frequencies in these familial NF2-SWN patients, indicating that these mutations may contribute to the development and progression of familial NF2-SWN.

Hericium erinaceus, renowned for its pharmaceutical potential, is particularly notable for its isolated diterpenoid derivative, erinacine S. Colorectal cancer (CRC) is one of the most prevalent cancers, characterized by CSC that contribute to chemoresistance and sustained tumor growth. While various drugs have been explored, the precise mechanism underlying multifaceted functions of erinacine S in inhibiting chemoresistant human CRC cells remains elusive. By using annexin-V/propidium iodide staining and a Fluo-3 fluorescence staining assay, the cell death and viability in cancer cells and an in vivo xenograft mouse model were measured by western blots and an immunohistochemical assay. This study unequivocally demonstrates that erinacine S treatment significantly induces apoptosis and suppresses the aggressiveness of chemoresistant human CRC cells. Erinacine S also exhibits remarkable inhibitory effects on tumor growth in an in vivo xenograft mouse model. Immunohistochemical analyses unveiled that erinacine S treatment significantly upregulates the expression of TRAIL, TNFR1, and DR5 proteins while downregulating p-AKT, p-ERK, HIF1α, PCNA, and NFκB levels in the xenograft mouse model of chemoresistant human CRC cells. Erinacine S treatment of HCT-116/FUR cells triggered the activation of extrinsic apoptosis pathways (TRAIL, TNFR1, DR5, and caspase-3) and exerted a time-dependent suppression on the expression of anti-apoptotic molecules like Bcl-2 in intrinsic pathway. The activation of the p-PAK/FAK/p300 pathways was intricately involved in erinacine S-induced transcriptional activation; this was evidenced by histone H3K9K14ac (Acetyl Lys9/Lys14) modifications in the promoters of TRAIL, TNFR1, and DR5. The inactivation of the CXCR4/PI3K/Akt/HIF-1 pathway played a pivotal role in mediating the capacity of erinacine S to inhibit chemoresistant CRC growth while enhancing tumor apoptosis. Thus, erinacine S demonstrates notable inhibitive effects, both in vitro and in vivo, through the inhibition of invasion, migration, and proliferation in human chemoresistant cell lines, and holds promise as a natural agent for clinical therapy of patients with CRC.

Background: Second primary malignancy (SPM) significantly impacts the survival of patients. This study endeavors to identify risk and prognostic factors of developing SPM after the first primary kidney cancer (FPKC), develop nomograms and explore potential mechanisms to optimize treatment strategies. Methods: Data of patients diagnosed with FPKC between 2000 and 2020 were obtained from the SEER database. The standardized incidence ratio (SIR) was calculated to assess the relative risk of developing SPM in FPKC patients. Competing risk model as well as Cox regression analyses were employed to identify independent risk and prognostic factors, and nomograms were constructed and evaluated. Finally, to understand how FPKC influences the risk of developing SPM, we carried out Mendelian randomization (MR) and transcriptome-wide association study (TWAS) analyses. Results: A total of 72408 and 5295 patients were included in stage I and II analysis, respectively. Risk distribution analysis revealed that FPKC patients exhibited a higher SPM risk than general population (SIR = 1.42, 95% CI: 1.40-1.44). Independent predictive factors were identified for model construction, and nomograms were developed. AUC of ROC, calibration curves and DCA illustrated excellent calibration and clinical applicability of the models. MR analyses indicated that kidney cancer might causally increase the risk of cancer in stomach, colon, rectum, lung, prostate, bladder, skin and eye. TWAS analysis identified 19 susceptibility genes associated with four types of cancers. Conclusion: This study successfully established nomograms, delving into the potential mechanisms of developing SPM after FPKC. All these findings will promote the optimization of treatment strategies.

Endoplasmic reticulum (ER) stress plays a pivotal role in tumor progression. As research in tumor biology advances, the relationship between ER stress and tumor initiation, development, and immune regulation has increasingly attracted attention. ER stress activates the unfolded protein response (UPR), thereby affecting key processes in tumor cells, including metabolism, proliferation, invasion, metastasis, and drug resistance. Moreover, it modulates tumor immune responses by regulating the functions of immune cells within the tumor microenvironment. This review consolidates the concept of ER stress as a central signaling hub that dictates cell fate and extensively remodels the tumor ecosystem. From a clinical perspective, this understanding provides a strong rationale for therapeutically targeting the UPR, suggesting that combining ER stress modulators with immunotherapy represents a promising strategy to overcome therapeutic resistance and improve patient outcomes.

Hepatocellular carcinoma (HCC), the most prevalent form of primary liver cancer, continues to pose significant clinical challenges globally. Enhancer of Zeste Homolog 2 (EZH2), a central component of the Polycomb Repressive Complex 2 (PRC2), possesses histone methyltransferase activity through its SET domain and is frequently overexpressed in various cancers. Nevertheless, the precise role and regulatory mechanisms of EZH2 in HCC remain inadequately defined. In this research, we evaluated the expression levels of EZH2 at the mRNA and protein stages in HCC samples and examined their correlation with clinical features and patient survival outcomes. Patients were categorized into early- and late-stage groups based on tumor grade. Our methylation analyses pinpointed two specific CpG sites within the EZH2 gene, cg08558971 and cg18416251, which exhibited inverse methylation patterns between tumor stages. One patient subgroup displayed high methylation at cg08558971 during early-stage disease and reduced methylation at cg18416251 during late-stage disease, while another subgroup demonstrated the reverse pattern. Further pathway enrichment analysis suggested these methylation variations might influence enhanced T-cell differentiation and suppress metabolic pathways. Additionally, correlation analyses consistently linked EZH2 expression to genes involved in these immune and metabolic pathways. Collectively, our data propose that EZH2 could serve as a meaningful independent prognostic biomarker for HCC, regulated by stage-dependent epigenetic changes that may drive tumor progression by modulating immune response and cellular metabolism.