Lactate, as a critical byproduct of tumor metabolic reprogramming, plays an important role in DNA damage repair and tumor immune infiltration. This work aims to elucidate the molecular mechanisms by which lactate promotes tumor DNA damage repair (DDR) and subsequent immune evasion.

Cancer-associated fibroblasts (CAFs) play critical roles in tumor progression and immunosuppression; however, their contribution to the functional classification and personalized treatment of gastric cancer remains poorly defined. This study aimed to identify effective therapeutic targets to facilitate individualized treatment strategies for patients with gastric cancer.

Prostate cancer is the second most common fatal cancer in men. Identifying new biological therapeutic targets is crucial to effectively improve the prognosis of prostate cancer patients. Ovarian tumor family deubiquitinase 4 (OTUD4) is a member of the ovarian tumor-associated protease domain (OTUDs) family. Although previous studies have shown that the expression and function of OTUD4 vary across different tumors, its role in prostate cancer remains unknown. The aim of this study is to explore new therapeutic targets and diagnostic markers for prostate cancer and investigate their mechanisms of action.

An increasing number of studies have shown that ferroptosis is related to the initiation and development of small cell lung cancer (SCLC). The systematic review aimed to summarize the characteristics of ferroptosis from its pathogenetic role to translational therapeutic implications in SCLC.

Glioblastoma (GBM) remains the most prevalent and aggressive primary central nervous system (CNS) malignancy; however, the clinical efficacy of the preferred chemotherapeutic agent, Temozolomide (TMZ), is severely compromised by innate and acquired resistance. Sphingolipid metabolism acts as a pivotal regulator of GBM cell fate, and the imbalance of the "sphingolipid rheostat" is intimately linked to TMZ resistance. This provides potential targets for developing novel prognostic models to inform stratified treatment risk strategies, while offering a promising entry point for TMZ chemosensitization and stratified drug combinations.

Paraneoplastic pemphigus (PNP) is a highly fatal autoimmune blistering disease that commonly occurs in patients with underlying benign or malignant neoplasms. It poses significant challenges for diagnosis and treatment. To date, the cellular and molecular mechanisms underlying the pathogenesis of PNP remain largely unclear.

Active surveillance for low-risk papillary thyroid carcinoma (PTC) is hampered by the lack of reliable biomarkers to distinguish indolent from progressive tumors. While our previous single-cell analysis identified tumor-infiltrating B cells as key determinants of indolent PTC, their clinical utility remains constrained by low abundance and peripheral undetectability. We therefore employed Mendelian randomization (MR) to investigate this causal relationship and assess the potential of peripheral B-cell profiling as a non-invasive strategy for distinguishing indolent PTC.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a complex tumor ecosystem that contributes to its progression. Deubiquitinases (DUBs) are vital regulators in cancer. However, the overall activity of DUBs and their role in driving PDAC progression within immune microenvironment remain largely unknown.

Lung adenocarcinoma (LUAD) is usually detected late; sensitive, minimally invasive early-detection tools are urgently needed. Circular RNAs (circRNAs) in liquid biopsies are promising cancer biomarkers, yet it remains unclear which blood component-platelets or plasma exosomes-offers the richest and most informative circRNA source.

The lncRNA NEAT1 is overexpressed in multiple myeloma (MM) plasma cells and plays a key role in MM pathogenesis. NEAT1 is involved in ceRNA network in several cancers; however, data in MM are virtually absent. This study identified a NEAT1-driven ceRNA network involving 96 miRNAs and 40 target genes, selected as concurrently downregulated in NEAT1-KD AMO1 cells and upregulated in NEAT1-overexpressing AMO1 cells (AMO1-OVX). The co-expression of NEAT1 and the targets was validated in MM patients (GSE116294, GSE13591, GSE6477, CoMMpass), and in NEAT1-KD NCI-H929, LP1, and KMS27 cell lines, showing for all targets a consistent downregulation, resembling that of NEAT1. The functional implication of the ceRNA network was explored by functional enrichment analyses of the 40 targets, identifying 78 significant gene sets, 17 of which were found significantly enriched by GSEA analysis in at least one experimental condition among NEAT1-KD LP1, NCI-H929, and KMS27 cells, AMO1-OVX cells, or the extreme quartiles of NEAT1 expression in the CoMMpass dataset. Noteworthy, the cell cycle gene set was validated in 5 out of 6 conditions tested, suggesting that in MM the impact of NEAT1 upregulation on the cell cycle, experimentally demonstrated in our earlier publications, may be attributable, at least partially, to ceRNA mechanisms.

Protein arginine methyltransferases (PRMTs) catalyze the methylation of arginine residues on both histone and non-histone substrates, orchestrating cellular processes such as transcriptional regulation, RNA splicing, signal transduction, and DNA damage response. Because dysregulated methylation reprograms epigenetic and post-transcriptional landscapes to promote malignant transformation, aberrant PRMT activity is closely associated with tumorigenesis and cancer progression. Major family members, containing PRMT1, CARM1, PRMT5, and PRMT6, regulate gene expression through site-specific histone methylation, thereby contributing to the transcriptional activation or repression. PRMTs also methylate a wide range of non-histone proteins, including transcription factors, splicing regulators, and signaling intermediates, to coordinate cell cycle progression, DNA repair, and RNA metabolism. Collectively, PRMT-mediated methylation contributes to higher-order cancer phenotypes, including metabolic reprogramming-through modulation of glycolytic flux, lipid biosynthesis, and redox homeostasis-and immune evasion via altered immune signaling and checkpoint pathways within the tumor microenvironment. Recent advances in chemical biology have led to the development of selective PRMT inhibitors, several of which are currently under clinical evaluation. In this review, we provide a comprehensive and integrative overview of PRMT biology, systematically organizing current knowledge from multilayered regulatory mechanisms to downstream oncogenic effects and emerging therapeutic opportunities.

Pheochromocytomas and Paragangliomas (PPGL) are rare neuroendocrine tumors with favorable prognosis, although a significant subset (20-25%) progress to metastasis, worsening patient prognosis. For metastatic cases, pharmacological interventions become essential, yet most tumors show poor response to treatment. While clinical trials are ongoing, there is no established treatment for metastatic PPGL. Like other neuroendocrine tumors, PPGL exhibit high membrane expression of somatostatin receptors, and despite Peptide Receptor Radionuclide Therapy, PRRT, strategies have successfully been implemented, trials with cold somatostatin analogs were abandoned prematurely due to inconsistent results. To investigate this issue and identify potential therapeutic tools, we widely profiled somatostatin receptors expression in PPGL and conducted a comprehensive functional screening on wild-type and SDHB knockdown PPGL cell lines of native and synthetic somatostatin analogs. Results revealed that pheochromocytomas and paragangliomas similarly display a predominant SSTR2 and SSTR1 expression regardless of molecular cluster. Treatment with somatostatin, cortistatin, octreotide or pasireotide did not exert clear antitumoral effects on model cell lines. Notably, the selective SST2 agonist BIM-23120 significantly reduced cell proliferation and induced apoptosis in an SST2-dependent manner, but only in SDHB knocked-down PPGL cells. Indeed, only SDHB KD cells showed stronger membrane-enriched SST2 and clear receptor internalization upon BIM-23120 treatment. Molecular analysis revealed a generalized dephosphorylation affecting key proliferation, growth and cell survival pathways in response to BIM-23120 (unlike when treating with octreotide). Altogether, our results provide novel information on the status of the somatostatin system in PPGL and identify new potential therapeutic tools selectively targeting somatostatin receptors on this refractory tumor.

Precision cancer medicine (PCM), targeting cancer treatment to patients' individual genomic profiles, has the potential to improve diagnosis and outcomes substantially. Implementing PCM in healthcare systems requires that extended molecular diagnostics are accessible as part of routine practice. We conducted a mixed-methods study to identify and inform the infrastructure necessary for the implementation of extended molecular diagnostics as part of the health care system.

Hepatocellular carcinoma (HCC) represents a critical oncological challenge demanding innovative therapeutic interventions. miRNA has been known to play an important role in cancer inhibition to control HCC's development and progression by regulating cell proliferation and apoptosis. The major hurdle is to deliver the miRNA at the site of tumor. Metallic nanoparticles with modified surface can be used to solve this problem. In the current study, gold-nanoparticles (Au NPs) were prepared, and their surface was modified with PEG moiety to facilitate the attachment of miRNA. For the first time, the modified gold NPs were loaded with miR-199a. Our findings revealed that, when cells treated with gold bare (80 nM) for 24 h, a low cytotoxicity was obtained (11.11 ± 2.25%). When cells treated with nanocomplex miRNA- PEG -Au NPs (80 nM) for 24 h, a significantly increased cellular cytotoxicity was obtained (55.7 ± 4.55%). Also, the prepared nanocomplex exhibits a promising potential in suppressing tumor cell proliferation and significantly enhancing apoptosis in a concentration and time dependent manner. These results underscore the transformative potential of targeted nanomaterial-based miRNA delivery as a sophisticated therapeutic modality in cancer management. In conclusion, Au NPs are excellent carriers for miRNA where they increase the cellular uptake, exerting a promising anticancer effect on HCC cells, representing a new approach in developing precision therapeutics for hepatocellular carcinoma.

Osteosarcoma is a highly malignant bone tumor which primarily affects the juvenile population and is characterized by high rate of recurrence and metastasis. RNA editing has emerged as a key process in cancer progression. Herein, we investigated the role of RNA editing enzyme ADAR2 (Adenosine Deaminase Acting on RNA 2) in osteosarcoma. We demonstrated that ADAR2 expression increases during osteoblast differentiation and inversely correlates with the aggressiveness of osteosarcoma cells. Interestingly, the overexpression of ADAR2 in osteosarcoma cell lines reduces their tumoral properties and promotes their differentiation in osteoblast-like cells, as shown by gene expression analysis and mineralization assays. These results were also confirmed by in vivo experiments; indeed, intratibial injection of ADAR2-overexpressing osteosarcoma cells in NSG mice resulted in less aggressive tumors compared to mice injected with pEmpty or pInactive ADAR2 E/A vector-transfected cells. To elucidate the mechanisms by which ADAR2 overexpression induces osteogenic terminal differentiation of osteosarcoma cells, we performed RNA-seq analysis of Saos-2 cells and identified IGFBP7 (Insulin-like Growth Factor Binding Protein 7) as the most highly edited transcript in ADAR2-overexpressing cells. We showed that the editing activity of ADAR2 on IGFBP7 abolishes its proliferative effect on osteosarcoma cells and triggers terminal differentiation. Overall, our results indicate that ADAR2 acts as a tumor suppressor in osteosarcoma and may represent a novel therapeutic target for this aggressive pediatric tumor.

T-cell lymphoblastic lymphoma (T-LBL) and T-cell acute lymphoblastic leukemia (T-ALL) originate from thymic T-cell precursors, with ongoing debate on whether they are variants of the same disease or distinct entities. For 211 patients, including pediatric and adult T-ALL and T-LBL cases, targeted next-generation sequencing and SNP-arrays were performed, and single-nucleotide variants, indels and copy-number variants (CNVs) were analyzed. We aimed to assess genetic differences between T-ALL and T-LBL across age. Generally, mutational landscape analysis identified mutated PHF6 being associated with higher, NOTCH1 with lower age at diagnosis for both T-LBL and T-ALL. Association of CNVs with higher age was evident for T-ALL, but not T-LBL. Analysis of clonal evolution revealed that CNVs - especially deletions and LOH in chromosome 9 (LOH_in_9p) - were observed as first mutational event in both pediatric T-ALL and T-LBL. The sequence of genetic events, starting with LOH_in_9p followed by mutations in NOTCH1, was significantly more frequent in pediatric T-ALL and T-LBL. Detailed evaluation of the patients' individual clonal evolution indicated that the proportion of malignant cells without NOTCHMT determines the risk of relapse (hazard ratio 1.032, p = 4.65*10-5). In T-ALL, aside from MRD, validated molecular markers for risk-group stratification remain limited. Our data suggest that molecular metrics analogous to those in T-LBL may help refining risk stratification in T-ALL as well.

The RHO GTPase family regulates cytoskeleton-dependent processes, including proliferation and migration. Although their dysregulation is well described in solid tumors, little is known about their role in hematologic malignancies. We investigated the expression of ten RHO GTPase genes in bone marrow samples from patients with acute myeloid leukemia (AML) and myelodysplastic neoplasms (MDS) and analyzed TCGA AML data for prognostic associations. RHOBTB2, RND2, and RHOQ were differentially expressed compared with healthy controls. RHOBTB2 was elevated in both MDS and AML and associated with inferior overall and disease-free survival, including in intermediate-risk AML. Our findings reveal distinct dysregulation patterns of RHO GTPases in myeloid malignancies and confirm RHOBTB2 as a candidate prognostic marker in AML with a potential oncogenic role. These data support further investigation into the functional roles of RHO GTPases in leukemogenesis and their utility as emerging biomarkers in hematologic cancers.

Cancer predisposition due to constitutional (germline) genetic variants in high-risk or moderate-risk cancer predisposition genes presents clinical opportunities for risk mitigation. Focusing genetic testing only on patients who are most likely to be positive for germline variants might enhance the clinical utility of positive results, but this approach could fail to assess the rate and pattern of such variants in patients with cancer overall. We aimed to assess the frequency and nature of constitutional variants in cancer predisposition genes in patients with cancer in the UK health-care system.

Extrachromosomal circular DNA (eccDNA) are molecules that originate from chromosomal DNA but exist independently. While large eccDNA (ecDNA) contributes to tumorigenesis, the role of smaller eccDNA (<100,000 base pairs) in cancer remains unclear. Our analysis of 25 colorectal cancer (CRC) tumors and normal adjacent tissues revealed that eccDNA is significantly more abundant in tumor tissues, correlating strongly with chromosomal amplifications. The presence of whole intact genes on 1.29% of eccDNA was nonrandom. We identified 84 genes that recurred across tumors of multiple patients when present on eccDNA, with 19% of genes being cancer-associated. eccDNA-borne genes were often accompanied by increased expression, and their contribution to expression was much larger than that from linear amplifications and the larger ecDNA. The cytokine gene CXCL5 exemplified this phenomenon, showing substantial copy-number increase and upregulation when present on eccDNA. Functional validation in cell lines showed that CXCL5 eccDNA enhanced transcriptional output and immune cell recruitment function. The recurrence and overexpression of CRC-related genes on eccDNA indicate their selection in tumors, suggest that eccDNA can serve as an additional mechanism for dynamically influencing gene expression and is capable of conferring cancer phenotypes on cells. Analysis of chromatin landscapes revealed that eccDNA preferentially forms at sites of open chromatin and active transcription, with architectural boundaries marked by CTCF protein. Clinically, higher eccDNA levels correlated with poorer relapse-free survival in a small patient cohort. These findings suggest that circular DNA elements across the entire size spectrum participate in cancer evolution and warrant further investigation in larger cohorts.

Loss of DNA methylation is a hallmark of cancer that is proposed to promote carcinogenesis through gene expression alterations, retrotransposon activation and induction of genomic instability. Cancer-associated hypomethylation does not occur across the whole genome but leads to the formation of partially methylated domains (PMDs). However, the mechanisms underpinning PMD formation remain unclear. PMDs replicate late in S-phase leading to the hypothesis that they become hypomethylated due to incomplete re-methylation by the maintenance methyltransferase DNMT1 during cell division. Here we investigate the role of DNMT1 in shaping the cancer methylome by conducting whole genome bisulfite sequencing (WGBS), repli-seq and ChIP-seq on DNMT1 knockout HCT116 colorectal cancer cells (DNMT1 KO cells). We find that DNMT1 loss leads to preferential hypomethylation in late replicating, heterochromatic PMDs marked by the constitutive heterochromatic mark H3K9me3 or the facultative heterochromatic mark H3K27me3. However, we also observe that a subset of H3K9me3-marked PMDs gain methylation in DNMT1 KO cells. We find that, in DNMT1 KO cells, these hypermethylated PMDs remain late replicating but DNMT3A localises to them. This is accompanied by loss of heterochromatic H3K9me3, specific gain of euchromatic H3K36me2 and some gene upregulation. These same domains also have more variable DNA methylation than other PMDs in colorectal tumours in vivo. Our observations suggest that hypermethylated PMDs lose their heterochromatic state, enabling their methylation by DNMT3A and the establishment of a hypermethylated, non-PMD state, despite their late replication timing. More generally, our findings suggest that differential de novo DNMT activity plays a key role in establishing domain level DNA methylation patterns in cancer cells.