ARID1A loss drives osimertinib resistance by epigenetically suppressing PTEN and activating the Akt pathway in lung cancer.

A microphysiological spheroid system for modeling glioblastoma structure and therapy response.

Prognostic significance and therapeutic implications of migrasome-related genes in Sorafenib treatment for primary liver cancer.

YY‑20394 (linperlisib), a highly specific PI3Kδ inhibitor, has demonstrated promising efficacy in a variety of hematological malignancies in clinical trials. ABT199 (venetoclax) as a monotherapy shows limited effects in acute myeloid leukemia (AML), underscoring the need for novel combinatorial therapeutic strategies. The drug sensitivity and potential synergistic effects of YY‑20394 and ABT199 were evaluated in three AML cell lines, MV‑4‑11, U937 and THP‑1, using a Cell Counting Kit‑8 assay. Apoptosis and cell cycle distribution were assessed using dual acridine orange/ethidium bromide staining and flow cytometry. Reverse transcription‑quantitative PCR and western blot analyses were employed to quantify the levels of Bcl‑2 apoptotic family members, c‑Myc, Akt and ERK. YY‑20394 inhibited the viability of MV‑4‑11, U937 and THP‑1 cells in a concentration‑dependent manner. In U937 cells, the highest IC50 value was observed, and YY‑20394 effectively suppressed their proliferation, induced apoptosis and caused cell cycle arrest. Furthermore, the combination of YY‑20394 and ABT199 demonstrated a synergistic effect in MV‑4‑11 cells, significantly enhancing apoptosis compared with either agent alone. Compared with the negative control group, the levels of c‑Myc and Akt phosphorylation were significantly reduced in the YY‑20394 group, and their inhibitory effects were retained in the combination group. ERK phosphorylation was significantly increased in the combination group. However, alterations in the Bcl‑2 pathways did not show a pattern consistent with the observed apoptotic phenotype. In summary, YY‑20394 is effective for inhibiting proliferation of AML cells, and its combination with ABT199 has synergistic pro‑apoptotic effects in MV‑4‑11 cells, which provides new insights and potential avenues for the treatment of AML and its subtypes. Further studies are warranted to explore the therapeutic efficacy and underlying molecular mechanisms of this combination in additional AML subtypes.

SFTPB: A signature gene for lung adenocarcinoma development.

Computational multi-omics modelling identifies TOP2A as a central prognostic biomarker and therapeutic target in renal cell carcinoma.

A palmitoylation-related prognostic risk scoring model and tumor microenvironment characterization in lung adenocarcinoma, using single-cell RNA sequencing data.

Vestibular schwannoma (VS) is a benign tumor originating from the vestibular nerve, and its complex tumor microenvironment presents significant challenges for research. This study employs single-cell transcriptome sequencing to comprehensively investigate the molecular characteristics of Schwann cells within VS and their potential immunoregulatory roles in the tumor microenvironment. We identified a novel subpopulation of Schwann cells, termed Schwann 4, which shows significantly expressed MHC class II molecules and co-enrichment of PI3K signaling, focal adhesion, and cell adhesion-related pathways, suggesting its potential involvement in tumor-immune modulation. Utilizing machine learning models, we pinpointed 179 genes significantly expressed in Schwann 4, with CTSZ emerging as a candidate gene. CTSZ expression is elevated in VS and is significantly correlated with the PI3K pathway. Comparative analysis revealed that CTSZ promotes proliferation in malignant CNS tumors, whereas its role in benign VS appears distinct. Experimental analysis revealed that CTSZ is correlated with regulatory T cells (Tregs) functionality markers via the PVR-TIGIT pathway, suggesting a potential mechanism for Schwann cell-mediated immune modulation. Functional assays further demonstrated that CTSZ knockdown impairs cell migration and focal adhesion kinase activity. Drug sensitivity analyses identified candidate agents such as YM201636 and AT7867, though their applicability to VS requires dedicated validation. This study contributes to understanding the molecular mechanisms of Schwann cells in benign nerve sheath tumors while providing preliminary evidence for future therapeutic investigation.

Model-supported patient stratification using multi-objective synergy optimization in combination therapy.

PYCR2 contributes to sunitinib resistance in hepatocellular carcinoma by activating the PPAR signaling pathway.

A palmitoylation signature for prognosis immune infiltration and drug sensitivity in esophageal carcinoma.

Although hyperthermic intraperitoneal chemotherapy (HIPEC) added to cytoreductive surgery shows promise for colorectal cancer with peritoneal metastases (CRC-PM), effectiveness remains variable. Given the predominance of consensus molecular subtype 4 (CMS4) in CRC-PM and resistance to standard agents, we hypothesized CMS4 exhibits distinct drug sensitivities. Drug sensitivity data from the DepMap PRISM Repurposing Dataset for 34 CRC cell lines were classified into the 4 CMS subtypes. Five intraperitoneal agents were analyzed: mitomycin-C, oxaliplatin, irinotecan, 5-fluorouracil, and cisplatin. Differential drug response among CMS subtypes was assessed using log2 fold change (log2FC) in cell viability. The 34 CRC cell lines were classified into 4 categories: CMS1 (29%), CMS2 (18%), CMS3 (26%), and CMS4 (26%). CMS4 cell lines demonstrated higher sensitivity than CMS2 lines to mitomycin-C (median log2FC = -2.35 versus -0.21, p = 0.019). CMS4 and CMS3 cell lines were significantly more sensitive to irinotecan than CMS1 and CMS2 cell lines (p = 0.004). Oxaliplatin, 5-fluorouracil, and cisplatin showed no differential sensitivity across subtypes. CMS4 cell lines demonstrated sensitivity (sensitivity threshold log2FC < -1.74) to mitomycin-C and irinotecan but showed lack of sensitivity to oxaliplatin, 5-fluorouracil, and cisplatin. CMS4 exhibits distinct drug sensitivity patterns that could guide personalized HIPEC agent selection. This may explain the success of mitomycin-C and the limited efficacy of oxaliplatin in HIPEC trials. Future clinical trials should consider genomic subtyping and drug sensitivity testing to guide personalized HIPEC strategies for patients with CRC-PM.

Ribosome biogenesis is involved in the progression of hepatocellular carcinoma (HCC), but the specific mechanisms and diagnostic values of ribosome biogenesis-related genes (RBRGs) in HCC remain unclear. We aimed to explore potential therapeutic targets in HCC from RBRGs. The differentially expressed RBRGs (DE-RBRGs) were explored using publicly available bulk RNA-sequencing data. Cox regression analysis was employed to evaluate the prognostic significance of the DE‑RBRGs. The optimal machine learning algorithm was selected to construct a prognostic model. The predictive performance of the model was assessed using Kaplan‑Meier analysis and receiver operating characteristic (ROC) curves. Single‑cell RNA‑sequencing data were subsequently utilized to identify key cell populations and the corresponding DE‑RBRGs. Bioinformatics analyses revealed 88 DE-RBRGs, predominantly enriched in ribosome biogenesis-related functions and pathways. The univariate Cox regression identified 12 DE-RBRGs with prognostic values. Following, the optimal machine learning algorithm (StepCox [forward] + SuperPC) was selected to construct a prognostic model. Survival analysis demonstrated that patients in the low-risk group exhibited markedly prolonged lifespan relative to their high-risk counterparts. ROC curves confirmed the predictive accuracy of this prognostic model in both training and validation cohorts. These 12 DE-RBRGs were significantly associated with immune cell infiltration, tumor immune evasion and drug sensitivity. Analysis of single-cell sequencing data identified hepatocytes as central mediators of HCC pathogenesis, which was associated with high expression of two DE-RBRGs: Nucleophosmin 1 (NPM1) and Ras-Related Nuclear Protein (RAN). NPM1 and RAN, which are highly expressed in hepatocytes, may serve as potential therapeutic targets in HCC. Their established roles in ribosome biogenesis could drive the development of novel therapies targeting this pathway.

Traditional Chinese medicine QingYiHuaJi formula (QYHJ) has anti-tumor effect in Pancreatic adenocarcinoma (PAAD). However, the potential mechanism and key targets of QYHJ have not been fully elucidated. The aim of this study was to explore the underlying mechanisms and key targets of QYHJ in PAAD treatment. The overlapping genes between the targets of QYHJ and the common differentially expressed genes (Co-DEGs) identified in PAAD were selected as potential QYHJ for PAAD-related genes. The protein-protein interaction (PPI) network analysis, functional enrichment and pathways analyses were performed. ROC curve and Cox regression model were used to evaluate the diagnostic and prognosis value. Correlation between hub genes and immune cell infiltration were further analyzed. A total of 9 hub genes (PTGS2, BCL2L1, ICAM1, MET, NQO1, MMP3, NFATC1, CCNB1, ERBB3) were identified. These hub genes were linked to inflammation, oxidative stress and apoptosis related signaling pathways. ROC analysis showed that 8 hub genes may serve as potential diagnostic markers. Survival analysis indicated that 6 genes (BCL2L1, CCNB1, ERBB3, MET, MMP3 and NFATC1) were closely related to prognosis of the PAAD patients. Cox regression analysis demonstrated that the model developed using the hub gene signature exhibited strong predictive capacity for clinical outcome. ICAM1, MET, NQO1 and ERBB3 were associated with infiltration of Th2 and Th17 immune cells. The low-risk group exhibited better drug sensitivity. These hub genes related to QYHJ have diagnostic value and may serve as potential prognostic and drug sensitivity biomarkers for PAAD.

Functional precision oncology platform of BRAFV600E-mutated colorectal cancer organoids predicts therapy response and reveals RNF43-mediated immunogenicity.

Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have substantially improved the clinical outcomes of patients with EGFR-mutated non-small cell lung cancer (NSCLC), most patients ultimately develop acquired resistance. MET amplification is a common resistance mechanism to EGFR-TKIs; however, its effects on receptor dimerization and the resulting dependence on EGFR or MET signaling have not been fully elucidated. We established a classical lung cancer cell line model with acquired resistance to osimertinib, a third-generation EGFR-TKI, through exposure to the drug (HCC827OR). Activation profiles of phospho-receptor tyrosine kinases and genomic alterations were investigated, and drug sensitivity to osimertinib and the MET-TKI savolitinib was evaluated. EGFR and MET signaling status and dimerization/interaction of EGFR, MET, and ERBB3 were analyzed. In addition, exogenous MET overexpression was introduced into parental HCC827 cells to assess its effects on drug sensitivity and receptor dimerization. HCC827OR cells exhibited MET amplification and showed sensitivity to savolitinib monotherapy. ERBB3 phosphorylation correlated with the efficacy of the TKIs. Consistently, we found reduced interaction between EGFR and ERBB3 and increased interaction between MET and ERBB3 in HCC827OR cells. MET homodimers and MET-EGFR interaction increased while EGFR homodimers decreased in those cells. Exogenous MET overexpression in the parental cells partially recapitulated the drug-resistant phenotype, showing partial sensitivity to savolitinib, increased MET homodimers, and decreased EGFR homodimers. MET amplification alters the balance of EGFR/MET/ERBB3 dimerization, leading to a shift in signaling dependence from EGFR to MET. These findings provide insight into therapeutic strategies for EGFR-mutated NSCLC.

Multidrug resistance (MDR) is a major determinant of relapse-associated mortality in pediatric acute lymphoblastic leukemia (pALL). Although miR-326 downregulation has been associated with poor prognosis, its role in chemoresistance remains undefined. This study investigated the mechanistic contribution of miR-326 to MDR in pALL. miR-326 expression was quantified by RT-qPCR in 58 fresh bone marrow samples and 14 paired diagnosis-relapse slides from pALL patients. A multidrug-resistant CD10-CD34- B-cell acute lymphoblastic leukemia (B-ALL) cell line was transfected with miR-326 mimic, and drug sensitivity was assessed by MTT assay. Bioinformatic analyses identified ABCA2 and YY1 as potential targets of miR-326, which were validated by RT-qPCR, Western blotting, and dual-luciferase reporter assays. Low miR-326 expression was associated with relapse and reduced 4-year disease-free survival. Restoration of miR-326 expression enhanced chemosensitivity and downregulated ABCA2 and YY1 at both mRNA and protein levels. Reporter assays confirmed direct targeting of both genes. miR-326 attenuates MDR in pALL through direct suppression of ABCA2 and YY1, highlighting its potential as a therapeutic target for overcoming chemoresistance in pediatric B-ALL.

Obesity contributes to worse outcomes in breast cancer, particularly in the luminal subtype, where cellular senescence could increase tumor aggressiveness. Parallelly, Estrogen Receptor Beta (ERβ) has emerged as an important mediator in the cellular response to obesity-associated inflammation that metformin could counteract. This study explores metformin's role in targeting senescence to mitigate obesity-induced tumor progression. Using the GSE189757 dataset, differentially expressed genes in obese versus lean luminal breast cancer patients were examined by in silico analysis. T47D, BT474, and MCF7 cell lines were treated with an obesity-related inflammatory cocktail (ELIT) and metformin. Protein levels, mRNA expression and functional assays assessed mitochondrial activity, oxidative stress, cell viability, and senescence-related markers. The role of ERβ was investigated through gene silencing, gene overexpression, and correlation studies using datasets. Experimental results show that ELIT exposure increased mitochondrial activity, oxidative stress, and senescence markers, particularly in T47D cells, effects that metformin mitigated. Metformin also reduced SASP-related gene expression, thereby limiting autocrine signaling effects on migration, mammosphere formation, and drug sensitivity. ERβ expression was observed as a potential modulator of ELIT-induced alterations, and metformin reduced its expression. Analysis of patient datasets revealed a positive correlation between ERβ gene (ESR2) expression and senescence-related markers in obese luminal breast cancer patients, particularly MCL1, BCL2L1, CCL2, and ICAM1. These findings indicate that ERβ exhibits a key role as mediator of obesity-induced tumor alterations by promoting senescence-related markers, and that metformin's ability to target ERβ offers a potential strategy to suppress senescence-driven malignancy and improve therapeutic outcomes of obese luminal breast cancer patients.

New insights into the ambivalent role and clinical implications of tripartite motif family proteins in colorectal cancer.

Acute myeloid leukemia (AML) remains difficult to cure, in part related to strong genetic and functional heterogeneity between and within individual patients. Metabolic reprogramming is emerging as an important feature of AML cells, allowing exploration of alternative treatment strategies. Here, we describe a novel DHODH inhibitor, JNJ-74856665, that showed strong efficacy in a subset of AML samples. In a multi-omics approach, by combining label-free quantitative proteome data with drug sensitivity data in bone marrow stromal co-cultures in a large cohort of primary AML patient samples we identified that sensitivity to DHODH inhibition (DHODHi) is linked to cholesterol and lipid metabolism. DHODHi resulted in an accumulation of cholesterol, mitochondrial reactive oxygen species (ROS) and lipid peroxidation. LC-MS/ MS-based lipidomics studies revealed that DHODHi resulted in a strong increase in polyunsaturated fatty acids and triglycerides, which are the primary lipid species stored in lipid droplets (LD). We hypothesized that this might be the consequence of increased ROS and lipid peroxidation levels, prompting the cell to detoxify such toxic lipid species by storing them in LD. Indeed, we could observe a marked increase in LD formation upon DHODHi. The transcriptional regulator SREBF2, known to control cholesterol and lipid metabolism, was up-regulated in DHODHi sensitive AML, and a strong synergy was observed between the combination of both DHODHi and the SREBP inhibitor dipyridamole. Our data indicate that it would be interesting to further explore combined DHODH and SREBP inhibition as a therapeutic target option in AML.