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.

Cancer is a disease caused by genomic alterations, and identifying the profile of genetic changes in each cancer leads to the optimal choice of treatment, that is, precision medicine. In Japan, comprehensive genomic profiling tests were covered by insurance in June 2019, and cancer genomic medicine was fully implemented in clinical practice. In the field of urological malignancies, the approval of olaparib for metastatic castration-resistant prostate cancer with BRCA1/2 mutations has led to the practical application of cancer genomic medicine in many cases. However, various challenges exist in its implementation and clinical utilization. This review outlines cancer genomic medicine in urological malignancies, focusing on the types and characteristics of genetic tests performed in clinical settings, as well as the accessibility of treatments based on their results.

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.

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.

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.

Research in the 1970s showed that while retroviruses had been a key to identification of oncogenes, they were not actually a major cause of human cancer. Moreover, cells contained additional proto-oncogenes that did not necessarily have viral oncogene counterparts. In this excerpt from his forthcoming book, Joe Lipsick remembers the groundbreaking work on DNA transfection, chromosomal rearrangements, and gene amplification that identified the smoking guns responsible for activation of oncogenes such as RAS and revealed how translocations in immune cells produce cancer drivers like the Philadelphia chromosome.

Ewing sarcoma (ES) and its variants are rare and aggressive malignancies, occurring in paediatric and younger adult populations. Adamantinoma-like ES (ALES) is one of its variants, characterised by EWSR1::FLI1 fusions, and is exceptionally rare, especially in older adults. There are a few similar cases reported in the literature. We report a rare case of an older adult with a complicated medical history and reported a left neck mass on a follow-up visit; the mass developed over nine months. After evaluation, he was found to have a rare diagnosis of ALES in this age group, specifically with this Ewing Sarcoma RNA binding protein 1 and nuclear factor of activated T cells cytoplasmic 2 (EWSR1::NFATC2) gene fusion. This case highlights the challenges of diagnosing and the multidisciplinary management of rare variants of ES with uncommon gene fusions and raises awareness for the future potential of molecular diagnostics and treatment-specific applications for improved access to care and better outcomes for this population.

Osteosarcoma (OS) is a malignant tumor originating from osteoblasts. Methyltransferase-like 14 (METTL14) is an N6-methyladenosine (m6A) methyltransferase that has been reported to promote OS progression; however, its underlying mechanism remains unclear.

Macrocephaly, defined as a large head size, has a very broad differential and sometimes can be challenging to differentiate as benign versus indicative of pathology. In this review, we outline a stepwise approach to improving diagnosis of neurogenetic disorders versus other causes using the example of PTEN (phosphatase and TENsin homolog) Hamartoma Tumor Syndrome (PHTS). PHTS is a multiple hamartoma syndrome with medical management implications including the need for tumor surveillance, but often cases are not diagnosed until later in adulthood. Our review emphasizes the utility of using head circumference z scores in combination with other features as a triage tool for genetic identification of disorders such as PHTS.

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.