Over the past decades, survival outcomes for childhood acute lymphoblastic leukaemia (ALL) have significantly improved. However, adverse drug reactions (ADRs), particularly those related to 6-mercaptopurine (6-MP), remain a major concern. Myelosuppression associated with 6-MP administration can lead to infections or treatment interruptions. Excessive 6-thioguanine (6-TGN) levels worsen neutropenia, while elevated 6-methylmercaptopurine (6-MMP) levels contribute to hepatotoxicity. This study investigates genetic variants influencing 6-MP response in children with ALL. Seventeen tagSNPs in key enzymes involved in 6-MP metabolism, GMPS, IMPDH1, XO, and ITPA, were analysed. Genetic data were correlated with clinical and pharmacological parameters in 280 ALL patients treated under DFCI ALL 05-001, 11-001, and 16-001 protocols at CHU Sainte-Justine. Outcomes included 6-MP dose intensity, 6-TGN and 6-MMP metabolite levels, and hematologic and hepatic toxicities during consolidation II and maintenance phases. Results revealed that the rs6710015 variant allele in the XO gene is linked to lower 6-TGN and higher 6-MMP levels, while rs1884725 variant allele in the same gene is correlated with reduced neutropenia and higher cumulative 6-MP doses. In contrast, two variants in the IMPDH1 gene, rs2228075 and rs2278294, are correlated with more frequent neutropenia. These findings highlight novel genetic variants influencing 6-MP metabolism and toxicity in paediatric ALL patients.

p190A has been studied across various cancer types, and mutation rates of up to 20% were observed in some cancers, supporting the significance of p190A in carcinogenesis. Since the relevance of p190A in bladder cancer has not been addressed so far, we attempted to explore it. Evaluation of TCGA high-throughput sequencing datasets revealed p190A mutations in up to 8% of bladder cancer samples across several studies. Employing immunohistochemistry on tissue microarray that included 202 BC patient samples, we observed that lower p190A expression correlates with increased invasiveness and poorer survival outcomes. These findings suggested that p190A may have a tumor suppressor function in bladder tissue, consistent with its anticipated function in ploidy-control. p190A knockdown resulted in chromosomal instability in ureter-derived epithelial cells with otherwise normal karyotype, supporting its potential involvement in tumorigenesis. Loss-of-function studies in low-invasive bladder RT4 cell line and gain-of-function experiments in two highly invasive bladder cancer cell lines (T24 and BFTC) demonstrated that p190A influences cell migration and invasion in vitro, as determined by scratch assay and Boyden chamber approaches. This conclusion was further validated by ex vivo porcine bladder invasion approach, invadopodia formation, and gelatin degradation assays. Pathway analysis revealed that altered p190A expression influences both the Rho-ROCK-dependent LIMK1-cofilin pathway and the phosphorylation of cortactin by focal adhesion kinase, both of which regulate critical cellular processes such as actin network organization and polarization to facilitate efficient, coordinated cell migration and division. In summary, our results indicate that p190A has a genuine role in controlling cell-ploidy and regulates actin dynamics in the bladder urothelium, while loss of p190A results in genome instability and drives bladder cancer initiation and progression through deregulated actin dynamics.

Neuroblastoma (NB) is a devastating childhood cancer where most tumours have no clear oncogenic driver. We aimed to define whether HMMR, an oncogene-like protein in several cancers, harbors similar potential in neuroblastoma cells. HMMR is a hyaluronic acid (HA) receptor and a mitotic microtubule regulator. We show that high HMMR expression does not correlate well with MYCN driver expression and moreover statistically HMMR is an independent prognostic indicator of poor survival in NB patients. In cultured KELLY neuroblastoma cells, removal of the HMMR protein suppresses proliferation, motility and clonogenic capacity, while xenografts of HMMR-deficient cells imparted longer animal survival compared to wild type cells. Loss of motility in culture was compensated by addition of exogenous HA, suggesting that HMMR signaling is at least partly under HA control. Through an unbiased phosphoproteomic analysis, we also found that signaling downstream of MAPK1/2 was disrupted after loss of HMMR. In addition, RPS6 and p70S6 kinase were hypophosphorylated, while the DNA damage response (DDR) proteins such as CHK2 and TP53BP1 were significantly hyperphosphorylated. We thus provide, for the first time, evidence that HMMR does have oncoprotein-like properties in neuroblastoma cells and that HMMR expression has potential as a prognostic marker. Moreover, initial biochemical analyses highlight a potential influence for HMMR in MTOR and DDR pathway regulation.

Tumor-associated macrophages (TAMs) play a crucial role in fostering an immunosuppressive tumor microenvironment, promoting cancer progression, contributing to immune evasion and resistance to immunotherapy. However, the mechanisms by which TAMs exert these effects in gastric cancer (GC) remain unclear. Human TAMs were isolated from GC patients through magnetic sorting for RNA sequencing. THP-1 cell line and mice bone marrow-derived macrophages (BMDMs) induced TAMs were applied for functional assays. Two in-house tumor microarrays were utilized for validation: the Zhongshan Cohort, comprising 135 patients, and the Zhongshan Flow Cytometry (ZSFC) Cohort, which included 60 patients. In this study, we identified a significant accumulation of TREM2+ TAMs in GC tissues, correlating with poor prognosis. Functional assays revealed that targeting TREM2+ TAMs suppressed GC progression both in vitro and in vivo. Mechanistically, TREM2 stabilized signal transducer and activator of transcription 1 (STAT1) by preventing its ubiquitination mediated by Tripartite Motif Containing 21 (TRIM21), while simultaneously promoting STAT1 phosphorylation via spleen-associated tyrosine kinase (SYK), leading to upregulation of CCL8 and PD-L1, fostering an immunosuppressive tumor microenvironment. Furthermore, depletion of TREM2+ TAMs significantly enhanced the efficacy of anti-PD-L1 immunotherapy in GC allograft models. Collectively, our findings establish TREM2+ TAMs as key drivers of GC progression and immune evasion. Targeting TREM2+ TAMs represents a promising therapeutic strategy to overcome resistance to anti-PD-L1 therapy and reshape the tumor immune microenvironment.

Pituitary neuroendocrine tumors (PitNETs) are pathologically characterized by dysregulation of neuroendocrine function and systemic disruption of hormonal homeostasis, yet their regulatory effects on peripheral immune networks remain poorly characterized. Here, we systematically analyzed bulk RNA sequencing (RNA‑seq) from 883 PitNET tumors, 108 PitNET‑associated peripheral blood mononuclear cells (PBMC) samples, and 175 healthy PBMC controls, combined with 69 single‑cell RNA sequencing (scRNA-seq) samples covering tumors, normal pituitaries, as well as tumor‑derived and normal PBMCs. We identified a systemic immune disequilibrium in PitNET patients, characterized by increased circulating lymphocyte proportions, accompanied by upregulated cytokine-receptor interaction signatures. Notably, tumor resection reversed this imbalance, as supported by the normalization of monocyte and neutrophil counts, validated by flow cytometry and routine blood data from 600 samples (200 healthy controls and 200 PitNET patients with paired pre- and post-surgery follow‑up). Trajectory analysis identified terminally differentiated, secretory-specialized cell populations with lineage-specific hormone and cytokine hypersecretion. Ligand-receptor inference suggested these tumor-derived factors potentially engage circulating immune cell receptors. A random‑forest classifier based on PBMC transcriptomes distinguished PitNET subtypes, underscoring the diagnostic potential of peripheral immune signatures. Furthermore, in an estrogen-induced rat model, elevated PRL level coincided with the same peripheral immune skewing. Overall, our work provides a valuable resource and demonstrates PitNETs can be systemic immune modulators, where intrinsic hormone secretory activity and monocyte-lymphocyte imbalance collectively drive peripheral immune dysfunction.

Polycystic ovary syndrome (PCOS) is a frequent endocrine and metabolic imbalance that typically occurs in women of reproductive age. Its molecular pathophysiology is yet unknown, especially the ovarian cellular metabolic inefficiency that causes the transcriptional dysregulation of key genes linked to PCOS. Here, we discovered that one transcriptional-like regulator that causes PCOS is nuclear pyruvate kinase M2 (nPKM2). Using multiomics techniques, we show that enhanced lactylation of histone 3 on lysine residues 9 and 18 is linked to nPKM2 binding to the genome, changing the three-dimensional architecture of the genome. Genomic compartment switching, topologically associated domain fusion, and novel enhancer-promoter interactions subsequently enhance the expression of PCOS-related genes, including CYP17A1 and CYP11A1. In mice, ectopic expression of Pkm2 in female GCs consistently presented PCOS-like traits, such as interrupted estrous cycles, hyperandrogenism, and so on. Importantly, whole-organ tracing imaging directly unfolded the number of small follicles, which increased highly in Pkm2-tdtomato transgene mice compared with control. Furthermore, pharmacological inhibition of the nuclear accumulation of PKM2 mitigated PCOS-like symptoms in mice and restored a wild-type-like transcriptome. This study demonstrates the important function of PKM2-mediated histone lactylation in regulating the three-dimensional chromatin architecture and highlights PKM2 as a potential therapeutic target for PCOS treatment.

Objective To investigate the relationships of the expression of microRNA-487a-3p (miR-487a-3p) and A kinase-interacting protein 1 (AKIP1) mRNA in the endometrial cancer (EC) tissue with the patient survival within 5 years after surgery. Methods The EC tissue and adjacent normal tissue samples were collected from 130 EC patients who underwent surgical treatment at the Fourth Hospital of Shijiazhuang from September 2016 to April 2019.qRT-PCR was employed to determine the expression levels of miR-487a-3p and AKIP1 mRNA.The patients were followed up for 5 years after surgery to record the survival status.After removal of the patients who missed follow-up,78 surviving patients were recorded as the EC survival group,and 34 deceased patients were recorded as the EC death group.The dual luciferase reporter gene assay was conducted to verify the targeting relationship between miR-487a-3p and AKIP1 mRNA.Comparison was conducted for the expression levels of miR-487a-3p and AKIP1 mRNA between adjacent normal tissue and EC tissue,the expression levels of miR-487a-3p and AKIP1 mRNA in the EC tissue among patients with different clinical pathological parameters,and the clinical pathological parameters and the expression levels of miR-487a-3p and AKIP1 mRNA in the EC tissue between the EC survival group and the EC death group.The correlations of miR-487a-3p and AKIP1 mRNA levels in the EC tissue with the degree of tumor differentiation,International Federation of Gynecology and Obstetrics (FIGO) stage,lymph node metastasis,and depth of muscle invasion were analyzed.The relationships of miR-487a-3p and AKIP1 mRNA with patient prognosis and the risk factors affecting the survival of EC patients within 5 years after surgery were analyzed to evaluate the value of miR-487a-3p and AKIP1 mRNA levels in predicting the survival of EC patients within 5 years after survival. Results The EC tissue showed lower miR-487a-3p level (0.41±0.08 vs. 1.00±0.05;t=71.306,P<0.001) and higher AKIP1 mRNA level (2.35±0.37 vs. 1.00±0.03;t=41.465,P<0.001) than the adjacent normal tissue.The miR-487a-3p low expression group and AKIP1 mRNA high expression group had higher proportions of patients with low tumor differentiation,FIGO stage Ⅲ to Ⅳ,lymph node metastasis,and deep invasion of muscle layer than the miR-487a-3p high expression group and AKIP1 mRNA low expression group,respectively (all P<0.05).The results of dual luciferase reporter gene assay showed that the relative activity of luciferase in the miR-487a-3p small interfering RNA (siRNA)+AKIP1 mRNA-wild type (WT) group was higher than that in the miR-487a-3p empty vector+AKIP1 mRNA-WT group (2.85±0.19 vs. 1.00±0.04;t=23.339,P<0.001).There was no significant difference in the relative activity of luciferase between the miR-487a-3p empty vector+AKIP1 mRNA-mutant type (MUT) group and the miR-487a-3p siRNA+AKIP1 mRNA-MUT group (1.04±0.05 vs. 1.05±0.03;t=0.420,P=0.683).MiR-487a-3p in the EC tissue had negative correlations with AKIP1 mRNA,FIGO stage,lymph node metastasis,and depth of muscle invasion and a positive correlation with the degree of tumor differentiation (all P<0.001).AKIP1 mRNA had positive correlations with FIGO stage,lymph node metastasis,and depth of muscle invasion and a negative correlation with the degree of tumor differentiation (all P<0.001).The 5-year overall survival rates in the miR-487a-3p high expression group and AKIP1 mRNA low expression group (89.47% and 84.91%) were higher than those in the miR-487a-3p low expression group and AKIP1 mRNA high expression group (49.09% and 55.93%),respectively (both P<0.05).The EC death group had higher proportions of patients with low tumor differentiation,FIGO stage Ⅲ to Ⅳ,lymph node metastasis,and deep invasion of muscle layer,higher AKIP1 mRNA level in the EC tissue,and lower miR-487a-3p level than the EC survival group (all P<0.05).Low tumor differentiation,FIGO stage Ⅲ to Ⅳ,lymph node metastasis,deep invasion of muscle layer,low miR-487a-3p level,and high AKIP1 mRNA level were independent risk factors for the survival of EC patients within 5 years after surgery (all P<0.05).The area under curve (AUC) values of miR-487a-3p and AKIP1 mRNA alone (0.785 and 0.789,respectively) were lower than that of their combination (0.908) in predicting the survival of EC patients within 5 years after surgery (both P<0.05). Conclusion The EC tissue has a low miR-487a-3p level and a high AKIP1 mRNA level,both of which are correlated with clinicopathological parameters and prognosis and can be used to predict the survival of EC patients within 5 years after surgery.

Boosting the performance of chimeric antigen receptor T (CAR-T) cell therapy in solid tumors may provide a substantial advantage for patients with cancer. Recognizing the vital role of the nuclear factor of activated T cells (NFAT) in T cell function, we hypothesized the strategic regulation of NFAT activity by targeting c-Jun N-terminal kinases (JNK) can bolster the tumor-eradicating potential of CAR-T cells.

Only a subset of polymerase epsilon (POLE) mutations is associated with hypermutant phenotype; we hypothesized that only loss-of-proofreading (LOP) POLE mutations are associated with favorable immunotherapy response.

Leiomyomas are benign smooth muscle tumors that commonly present in the uterus, soft tissue, skin, and gastrointestinal tract but in rare cases can also arise within the eye. Notably, intraocular leiomyomas often show slightly different histopathologic and immunohistochemical features, referred to as mesectodermal morphology, given their presumed neural crest origin. Genetic and cytogenetic alterations of intraocular leiomyomas, as well as their association with various clinical and histopathologic features, have not been previously studied.

Gastric Signet Ring Cell Carcinoma (GSRCC) is an increasingly recognized subtype of gastric cancer, particularly prevalent in South Asian populations and regions within India. This carcinoma is distinguished by its abundant cytoplasmic mucinous cells and aggressive clinical behavior, often affecting younger individuals and leading to a poor prognosis due to its advanced-stage presentation and resistance to standard treatments. A critical factor in its progression is the tumor's uniquely immunosuppressive and stromal-rich microenvironment, characterized by dysfunctional immune infiltrates, activation of cancer-associated fibroblasts, extracellular matrix remodeling, and complement cascade dysfunction. Recent research has highlighted the significance of key biomarkers, including MSMB, AGR2, CLDN18.2, and notably GRIN2D, which play roles in tumor angiogenesis, immune evasion, and metabolic reprogramming. The interaction of these elements contributes to therapeutic resistance and immune escape, thereby reducing the effectiveness of chemotherapy and checkpoint inhibitor immunotherapies. Innovative strategies that integrate stromal-targeting agents, complement modulators, anti-CLDN18.2 antibodies, and novel GRIN2D-targeted therapies, along with precision molecular profiling, offer potential for enhancing patient outcomes. Tailored approaches that incorporate early detection and dynamic biomarker monitoring may ultimately transform GSRCC management toward personalized, evidence-based therapies and prevention.

Lysyl oxidase-like 3 (LOXL3) is a key member of the lysyl oxidase (LOX) family and belongs to the copper-dependent amine oxidase family. Its traditional core function is to catalyze the cross-linking of collagen and elastin in the extracellular matrix (ECM), thereby maintaining the structural integrity and normal physiological functions of the ECM. In recent years, studies on cancer molecular mechanisms have confirmed that LOXL3 exhibits abnormal expression in a variety of cancers: in common malignant tumors such as melanoma, liver cancer, gastric cancer, colorectal cancer, and breast cancer, its expression level is significantly higher than that in the corresponding normal tissues. Meanwhile, numerous prognostic analyses have demonstrated that high LOXL3 expression is an independent risk factor for poor prognosis in cancer patients. Such patients usually have shorter progression-free survival (PFS) and overall survival (OS), suggesting that LOXL3 may serve as a potential biomarker for evaluating cancer prognosis. At the functional and mechanistic level, the role of LOXL3 is not limited to ECM remodeling. It can directly affect key biological behaviors of cancer cells, including proliferation, invasion, metastatic potential, and sensitivity to chemotherapeutic drugs, by regulating a variety of intracellular signaling pathways. This article reviews the specific roles and potential molecular mechanisms of LOXL3 in cancer, covering its associations with key cancer pathological processes such as epithelial-mesenchymal transition, maintenance of genomic stability, and regulation of the tumor microenvironment. It focuses on clarifying the specific molecular pathways through which LOXL3 promotes pro-tumor activities in different tumors, as well as the regulatory effects of these pro-tumor activities on patients' relevant prognosis.

Meningiomas are the most common primary brain tumors in adults and have the potential for recurrence. Although most recurrent meningiomas retain their initial World Health Organization grade, a subset undergoes malignant transformation (MT). The molecular mechanisms underlying this transformation remain poorly understood. We aimed to characterize distinct recurrence subtypes-MT and grade 1-retained recurrence (GR)-using sequential multi-omic analyses. In this study, we reviewed meningioma patients with paired histological evaluations. Among these, 10 patients experienced MT and 25 showed GR. Patients with MT exhibited significantly higher Ki-67 proliferation indices and shorter overall survival. Comprehensive molecular profiling, including matched sequential recurrences, was performed on samples from six patients each with MT and GR meningiomas. Compared to GR tumors, MT tumors demonstrated a marked increase in tumor mutation burden and copy number alterations, with deletion of cyclin-dependent kinase inhibitor 2A emerging as a key acquired event. MT cases also showed selective upregulation of cell cycle-related genes, including Forkhead box M1, a feature absent in GR tumors. Notably, even prior to recurrence, MT tumors displayed distinct global DNA methylation patterns, particularly in regions targeted by the polycomb repressive complex 2 and H3K27me3 marks. Our findings suggest that molecular signatures evolve during MT and that certain intermediate aggressive meningiomas may progress toward malignancy. This study underscores the importance of DNA methylation and transcriptomic profiling in understanding tumor progression and recurrence. While molecular profiling holds promise for prognostication, further research is needed to identify key drivers of MT and clarify their roles in meningioma pathogenesis.

Esophageal squamous cell carcinoma (ESCC) is characterized by poor prognosis. tRNA-derived fragments (tRFs), a novel class of non-coding RNAs generated by tRNA cleavage, have emerged as key regulators of cancer development. However, the functional landscape of tRFs remains underexplored in ESCC. We here identified tRF-24-RPM8309M2S (tRF-24), a 5' tRF derived from mature tRNALeuAAG/TAG, which promotes the malignant progression of ESCC and offers a promising therapeutic target.

Ubiquitin-specific proteases (USPs) play a critical role in the development of various cancers. The study aimed to elucidated the pathogenic molecular mechanisms and analyze its clinical significance in esophageal squamous cell carcinoma (ESCC).

Chemotherapy incorporating the proteasome inhibitor bortezomib (BTZ) has improved outcomes for patients with multiple myeloma (MM); however, resistance to chemotherapy and disease relapse remain significant challenges, closely associated with cellular senescence. This study investigated the key drivers of myeloma cell senescence and its role in MM progression.

Perineural invasion (PNI) is an independent adverse prognostic marker for prostate cancer (PCa) metastasis. Gastrin releasing peptide receptor (GRPR) targeted imaging and therapeutics have entered clinical trials, while its role in PCa perineural invasion remains unclear. Here, we uncovered Family With Sequence Similarity 135 Member A ༈FAM135A༉a dominant PNI driver activated by GRPR in PCa. First, PNI-PCa tissue showed higher neuroactive ligand-receptor interaction activity, and with FAM135A being the most notable marker in PNI group. Then in-vitro experiments using a co-culture system of PCa cells (including AR-positive LNCaP and AR-negative DU145/PC3) showed that FAM135A silencing abrogated tumor malignancy and neural invasion. Moreover, in vivo PCa-Sciatic nerve invasion mouse model demonstrated FAM135A inhibition controls tumor growth and improves motor function. Interestingly, FAM135A is nucleus enriched and its nuclear translocation is mediated by protein cytoplasmic-nuclear transporter RAN. Mechanistically, RNA-Seq and ChIP-Seq analyses identified Teneurin Transmembrane Protein 3 (TENM3) as a transcriptional target of nFAM135A, and TENM3 plays an essential role in nFAM135A-induced cancer-nerve invasion. Notably, FAM135A is ultimately activated by Gastrin Releasing Peptide GRP and its receptor GRPR. Moreover, pharmacological GRPR inhibitor represses FAM135A expression via MED15 activation. Together, we unveil FAM135A as an oncodriver and biomarker of PCa perineural invasion, and provide a novel strategy for PCa innervation therapeutics.

The Wnt/β-catenin signaling pathway is a crucial regulator of colorectal cancer (CRC) development; however, its downstream targets and mechanistic contributions to tumorigenesis remain incompletely understood. Hepatocyte nuclear factor 4 alpha (HNF4α), a transcription factor primarily studied in liver function and hepatocarcinogenesis, has an unclear role in CRC. This study investigates the antagonistic and synergistic effects of HNF4α isoforms driven by the P1 and P2 promoters on Wnt/β-catenin signaling in colorectal cancer.

Pediatric acute myeloid leukemia (AML) is a clinically and genetically heterogeneous malignancy with variable outcomes. Accurate risk stratification based on cytogenetic and molecular markers is essential for guiding therapy. However, the prognostic impact of several key genomic alterations remains inconsistent across studies. This meta-analysis aims to evaluate the prognostic significance of cytogenetic and molecular abnormalities in pediatric AML and clarify their association with survival outcomes.

Ovarian cancer (OC) is a highly aggressive malignancy in women, and platinum resistance remains a major clinical obstacle. p53 mutations are prevalent in OC and exhibit functional heterogeneity that is associated with therapeutic response and disease progression. However, the roles and mechanisms underlying the functional heterogeneity of p53 mutations in platinum-resistant OC remain elusive. This investigation delineated that p53 mutations within the Loop 2, Loop 3, and β-strand S10 regions were closely linked to platinum resistance. In particular, functional assays unveiled that p53R175H and p53R175G mutations at Arg175 revealed distinct roles in tumor cell migration and drug resistance, with p53R175G conferring resistance to agents targeting p53R175H. Through multi-omics sequencing analysis, it was discerned that p53R175H and p53R175G promoted tumor progression through distinct cofactors and regulatory networks. p53R175H mediated upregulation of extracellular matrix-related genes, whereas p53R175G activated pathways associated with cytokine receptor interaction and membrane trafficking. Notably, the chromatin remodeling protein CHD1 selectively interacted with p53R175G, but not p53R175H, and regulated the transcriptional activity of p53R175G, including target genes such as IL7R. Moreover, CHD1 knockdown or pharmacological inhibition of IL7R synergistically enhanced platinum sensitivity, suggesting promising combination therapies specifically targeting the R175G mutation. The findings revealed that p53 mutations at the same residue exhibited distinct functional properties and relied on unique cofactors, offering valuable insights for precision therapy in OC.