Search Results (254)

Background: Melanoma metastasis, driven by tumor microenvironment (TME)-mediated crosstalk facilitated by extracellular vesicles (EVs), remains a major therapeutic challenge. A critical barrier to clinical translation is the overlap in protein cargo between tumor-derived and healthy cell EVs. Objective: To address this, we developed Scaffold-free Functional Deconvolution (SFD), a novel computational approach that leverages a comprehensive healthy cell EV protein database to deconvolute non-oncogenic background signals. Methods: Beginning with 1915 proteins (identified by MS/MS analysis on an Orbitrap Fusion Lumos Mass Spectrometer using the IonStar workflow) from melanoma EVs isolated using REIUS, SFD applies four sequential filters: exclusion of normal melanocyte EV proteins, prioritization of metastasis-linked entries (HCMDB), refinement via melanocyte-specific databases, and validation against TCGA survival data. Results: This workflow identified 21 high-confidence targets implicated in metabolic-associated acidification, immune modulation, and oncogenesis, and were analyzed for reduced disease-free and overall survival. SFD’s versatility was further demonstrated by surfaceome profiling, confirming enrichment of H7-B3 (CD276), ICAM1, and MIC-1 (GDF-15) in metastatic melanoma EV via Western blot and flow cytometry. Meta-analysis using Vesiclepedia and STRING categorized these targets into metabolic, immune, and oncogenic drivers, revealing a dense interaction network. Conclusions: Our results highlight SFD as a powerful tool for identifying clinically relevant biomarkers and therapeutic targets within melanoma EVs, with potential applications in drug development and personalized medicine. Full article

Some pancreatic ductal-type (PDADK) and lung adenocarcinomas (LADK) lacking other molecular drivers are reported to harbor NRG1 fusions as potential novel therapeutic targets. We investigated the feasibility of a fluorescent in situ hybridization (FISH)-based diagnosis of NRG1 fusions in a case series of PDADK and LADK lacking other identified oncogenic drivers. First, among a case series of PDADK, KRAS analyses (PCR followed in PCR-negative cases by RNA sequencing—RNAseq) found 27/162 (16.7%) KRAS wild-type cases, among which 1/162 (0.6%) NRG1 fusion was diagnosed using FISH. Secondly, among a case series of LDAK, 191/446 (42.8%) cases had no molecular alterations in EGFR, KRAS, BRAF, HER2, MET, ALK, ROS1 and RET according to NGS and FISH analyses and, among them, 4/446 (0.9%) cases had NRG1 fusions using FISH. Finally, four additional cases out of the two previously mentioned cases series (1 PDADK and 3 LADK) with NRG1 fusions diagnosed by first-line RNAseq were also concluded as NRG1 FISH-positive. The NRG1 FISH tests for the nine NRG1 FISH-positive cases resulted in 50% to 80% of positive tumor nuclei, all with single 3′-NRG1 FISH signals. In our series, of the 22 cases analyzed with both NRG1 FISH (positivity criterion of at least 15% of tumor nuclei with a split between the 5′- and the 3′- parts of the probes and/or isolated single 3′-NRG1 signal) and RNAseq, 17 cases were FISH– RNAseq– and 5 cases were FISH+ RNAseq+ (no FISH+ RNAseq– or FISH– RNAseq+ cases in our study) resulting in 100% sensibility and specificity for the NRG1 FISH test. In the case of no access to RNAseq, NRG1 FISH consists of a valuable tool searching for NRG1 fusions in patients with advanced cancers. Full article

In addition to their well-known role in ATP production, mitochondria are vital to cancer cell metabolism due to their involvement in redox regulation, apoptosis, calcium signaling, and biosynthesis. This review explores how cancer cells drive the extensive reprogramming of mitochondrial structure and function, enabling malignant cells to survive hostile microenvironments, evade therapy, and proliferate rapidly. While glycolysis (the Warburg effect) was once thought to be the dominant force behind cancer metabolism, recent updates underscore the pivotal contribution of mitochondrial oxidative phosphorylation (OXPHOS) to tumor development. Cancer cells often exhibit enhanced mitochondrial ATP production, metabolic flexibility, and the ability to switch between energy sources such as glucose, glutamine, and pyruvate. Equally important are changes in mitochondrial morphology and dynamics. Due to disruptions in fusion and fission processes, regulated by proteins like Drp1 and MFN1/2, cancer cells often display fragmented mitochondria, which are linked to increased motility, metastasis, and tumor progression. Moreover, structural mitochondrial alterations not only contribute to drug resistance but may also serve as biomarkers for therapeutic response. Emerging evidence also points to the influence of oncometabolites and retrograde signaling in reshaping mitochondrial behavior under oncogenic stress. Collectively, these insights position mitochondria as central regulators of cancer biology and attractive targets for therapy. By unraveling the molecular mechanisms underlying mitochondrial reprogramming—from energy production to structural remodeling—researchers can identify new approaches to disrupt cancer metabolism and enhance treatment efficacy. Full article

Horizontal trafficking of subcellular components, such as nucleic acids, proteins, and membrane fragments, is utilized by tumor cells to facilitate tumor cell proliferation and survival. Conventionally, tumor cells have been known to undergo long-range transfer through the import and export of extracellular vesicles and exosomes. However, other means of intercellular transfer are also employed by tumor cells. These trafficking methods can facilitate changes in anti-tumor immunity and distribute oncogenic protein variants to nearby cells to provide a hospitable tumor microenvironment. The molecular mechanisms that drive many of these cell trafficking mechanisms are conserved, relying on de novo synthesis of filamentous actin. However, the delineation between these processes is not yet known. This review will highlight four recently characterized and underappreciated contact-dependent intercellular trafficking mechanisms: (i) trogocytosis, (ii) entosis, (iii) cell fusion, and (iv) tunneling nanotubes/microtubes utilized by tumor cells to promote a hospitable microenvironment. Full article

Background/Objectives: The neurotrophic tropomyosin receptor kinase (NTRK) genes NTRK1, NTRK2, and NTRK3 encode tyrosine kinase receptors, and their fusion genes are known as the oncogenic driver genes for cancer. This study aimed to compare the diagnostic ability of NTRK fusion among five types of multi-cancer genome profiling tests (multi-CGP tests) and determine a useful multi-CGP test for NTRK fusion, recorded in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database in Japan. This study aimed to compare the diagnostic results for NTRK fusions among the five different CGP tests. Methods: A total of 88,688 tumor cases were enrolled in the C-CAT profiling database from 2019 to 2024. The detection frequency of NTRK fusion genes was compared to the results for five multi-CGP tests: NCC Oncopanel, FoundationOne CDx (F1), FoundationOne Liquid (F1L), GenMineTOP (GMT), and Guardant360. Results: NTRK fusion genes were detected in 175 (0.20%) of the 88,688 total cases. GMT, which is equipped with RNA sequencing function, frequently detected NTRK fusion genes (20 of 2926 cases; 0.68%) in comparison with the other four multi-CGP tests that do not have RNA sequencing analysis. GMT showed significantly (p < 0.05) higher diagnostic ability for NTRK fusions compared with the other four multi-CGP tests. Especially, NTRK2 fusion was significantly (p < 0.001) more highly determined by GMT than it was by the other four multi-CGP tests. The detection rates for FGFR1 and FGFR3 were significantly higher in GMT than in other multi-CGP tests. In contrast, the detection rates of the ALK and RET fusion genes were significantly higher in F1L. Conclusions: GMT, which is equipped with RNA sequencing analysis, might show a useful diagnostic ability for NTRK fusions, especially for NTRK2 fusion genes. Full article

Background/Objectives: ALK+ Anaplastic Large Cell Lymphoma (ALCL) is an aggressive T-cell lymphoma that is characterized by expression of the Anaplastic Lymphoma Kinase (ALK), which is induced by the t(2;5) chromosomal rearrangement, leading to the expression of the NPM-ALK fusion oncogene. Most previous preclinical models of ALK+ ALCL were based on overexpression of the NPM-ALK cDNA from heterologous promoters. Due to the enforced expression, this approach is prone to artifacts arising from synthetic overexpression, promoter competition and insertional variation. Methods: To improve the existing ALCL models and more closely recapitulate the oncogenic events in ALK+ ALCL, we employed CRISPR/Cas-based chromosomal engineering to selectively introduce translocations between the Npm1 and Alk gene loci in murine cells. Results: By inducing precise DNA cleavage at the syntenic loci on chromosome 11 and 17 in a murine IL-3-dependent Ba/F3 reporter cell line, we generated de novo Npm-Alk translocations in vivo, leading to IL-3-independent cell growth. To verify efficient recombination, we analyzed the expression of the NPM-ALK fusion protein in the recombined cells and could also show the t(11;17) in the IL-3 independent Ba/F3 cells. Subsequent functional testing of these cells using an Alk-inhibitor showed exquisite responsiveness towards Crizotinib, demonstrating strong dependence on the newly generated ALK fusion oncoprotein. Furthermore, a comparison of the gene expression pattern between Ba/F3 cells overexpressing the Npm-Alk cDNA with Ba/F3 cells transformed by CRISPR-mediated Npm-Alk translocation indicated that, while broadly overlapping, a set of pathways including the unfolded protein response pathway was increased in the Npm-Alk overexpression model, suggesting increased reactive changes induced by exogenous overexpression of Npm-Alk. Furthermore, we observed clustered expression changes in genes located in chromosomal regions close to the breakpoint in the new CRISPR-based model, indicating positional effects on gene expression mediated by the translocation event, which are not part of the older models. Conclusions: Thus, CRISPR-mediated recombination provides a novel and more faithful approach to model oncogenic translocations, which may lead to an improved understanding of the molecular pathogenesis of ALCL and enable more accurate therapeutic models of malignancies driven by oncogenic fusion proteins. Full article

Anaplastic Large Cell Lymphoma (ALCL) represents a diverse group of mature T-Cell Lymphomas unified by strong CD30 expression but with different molecular and clinical subtypes. This review summarizes recent molecular advances in ALCL, highlighting key discoveries that have refined its classification, diagnosis, and therapeutic strategies. ALCL comprises four major entities: systemic ALK-positive ALCL, systemic ALK-negative ALCL, Breast Implant-Associated ALCL (BIA-ALCL), and primary cutaneous ALCL. Each subtype exhibits unique phenotypes, along with cytogenetic and molecular alterations that affect clinical outcomes. Nevertheless, different oncogenic mechanisms mediate STAT3 activation. In ALK-positive ALCL, ALK fusion proteins drive oncogenesis via constitutive activation of STAT3 and other signaling pathways. ALK-negative ALCL comprises heterogeneous genetic subtypes, in which JAK/STAT3 pathway alterations and novel gene fusions are gaining recognition as potential therapeutic targets. This review emphasizes the need for integrative molecular diagnostics to improve stratification of ALCL subtypes and targeted treatment approaches. Future research should focus on elucidating the biological mechanisms underlying these alterations and on translating molecular insights into clinical practice. Full article

PAX genes, known as master regulators, encode paired box (PAX) proteins that govern key processes in organ development and are widely expressed in normal tissues. Notably, PAX proteins also play a pivotal role in both promoting and suppressing tumorigenesis. They influence essential cellular functions such as survival, proliferation, fate determination, differentiation, invasion, metastasis, and the formation of oncogenic fusion proteins. In this review, we summarize the current understanding of these transcription factors. First, we provide a brief overview of their molecular structure, which underlies their classification into four subgroups. Then, we examine the expression patterns of each PAX gene across organ systems and explore their biological roles in the most relevant malignant neoplasms affecting human health. Additionally, we highlight their diagnostic, prognostic, and predictive significance in the context of cancer. Full article

Myeloproliferative neoplasms (MPNs) are a group of rare blood cancers characterized by the excessive production of blood cells in the bone marrow. These disorders arise from acquired genetic driver mutations, with or without underlying genetic predispositions, resulting in the uncontrolled production of red blood cells, white blood cells, or platelets. The excessive cell production and abnormal signaling from driver mutations cause chronic inflammation and a higher risk of blood clots and vascular complications. The primary goals of MPN treatment are to induce remission, improve quality of life and survival, as well as to reduce the risk of complications such as thrombosis, vascular events, and leukemic transformation. This review provides a comprehensive update on the diagnosis and therapeutic advancements in major MPN subtypes, including chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, and primary myelofibrosis. It examines these complex diseases from a molecular and evolutionary perspective, highlighting key clinical trials’ long-term follow-up and therapies targeting driver mutations that have transformed treatment strategies. Additionally, several important advancements in addressing challenges such as anemia in myelofibrosis, along with promising emerging therapies, are also discussed. Full article

Alveolar rhabdomyosarcoma (ARMS) is a highly aggressive pediatric soft-tissue sarcoma driven by PAX3/7-FOXO1 fusion proteins. Despite intensive multimodal therapy, outcomes remain poor for patients with fusion-positive ARMS. This review integrates recent advances in the molecular pathogenesis of ARMS, highlighting key diagnostic and therapeutic targets. We discuss the central role of fusion proteins in transcriptional reprogramming, impaired myogenic differentiation, and super-enhancer activation. Emerging biomarkers (YAP, TFAP2B, P-cadherin) and oncogenic kinases (Aurora A, CDK4, PLK1) are evaluated alongside receptor tyrosine kinases (FGFR, MET) and transcription factors involved in metabolic rewiring (FOXF1, ETS1). Additionally, we examine immunotherapeutic strategies, epigenetic modifiers, and noncoding RNAs as potential therapeutic avenues. Together, these insights provide a comprehensive framework for developing biomarker-guided, multi-targeted therapies to improve outcomes in ARMS. Full article

Chromosomal rearrangements are implicated in the pathogenesis of several human malignancies, but, concurrently, they also represent targetable opportunities, as exemplified by imatinib (Gleevec), which targets the BCR-ABL gene fusion in myeloid leukemia. In prostate cancer, several chromosomal rearrangements have been identified, most of them involving ETS genes, which encode key transcription factors. In this review, we explore the discovery of 5′ partners that classify ETS gene fusions into distinct groups based on the prostate specificity and androgen responsiveness. Furthermore, we try to address the relationship between gene fusion status and patient outcomes and discuss the possibility of using prostate-specific targeting of ETS gene fusions in cancer detection, stratification, and treatment. Full article

Background: Recent research has increasingly highlighted alterations in the proto-oncogene MET, whose abnormal activation has been implicated in multiple cancers. MET encodes c-MET, a receptor tyrosine kinase critical for cellular growth, survival, and migration. Aberrant c-MET signaling, driven by mutations or gene amplification, promotes proliferation and invasion, contributing to tumorigenesis. Scope of the Review: While MET mutations are most often observed in non-small cell lung cancer (NSCLC), they also occur in other malignancies, including breast and gastric cancers. This review highlights key MET alterations, such as gene amplification, gene fusions, and exon 14 skipping deletions, and examines their prevalence across various tumor types. Major Conclusions: We discuss the clinical significance of c-MET as a therapeutic target and identify gaps in knowledge that could inform the development of alternative treatment strategies. Full article

Non-small cell lung cancer (NSCLC) is operated commonly by diverse genetic alterations, and oncogenic fusions represent a significant therapeutic role. Common fusions include ALK, ROS1, RET, and NTRK, signaling pathways in tumorigenesis. Recent advances in investigating tumor molecular biology include underlying fusions, including chromosomal rearrangements, highlighting their role as oncogenic drivers. The development of targeted therapies, such as tyrosine kinase inhibitors (TKIs), has impacted most patients’ NSCLC treatment. Despite the greater profiles, such as remarkable efficiency and tolerable side effects compared to traditional chemotherapy, challenges, such as acquired mutations, lead to more ongoing research-optimized future NSCLC therapies. Full article

In the tumor context, platelets play a significant role in primary tumor progression, dissemination and metastasis. Analysis of this interaction in various cancers, such as non-small cell lung cancer (NSCLC), demonstrate that platelets can both transfer and receive biomolecules (e.g. RNA and proteins) to and from the tumor at different stages, becoming tumor-educated platelets. To investigate how platelets are able to transfer oncogenic material, we developed in vitro platelet-like particles (PLPs), from a differentiated MEG-01 cell line, that stably carry RNA and protein of the KRAS^G12D oncogene in fusion with GFP. We co-cultured these PLPs with NSCLC H1975 tumor cells to assess their ability to transfer this material. We observed that the generated platelets were capable of stably expressing the oncogene and transferring both its RNA and protein forms to tumor cells using qPCR and imaging techniques. Additionally, we found that coculturing PLPs loaded with GFP-KRAS^G12D with tumor cells increased their proliferative capacity at specific PLP concentrations. In conclusion, our study successfully engineered an MEG-01 cell line to produce PLPs carrying oncogenic GFP-KRAS^G12D simulating the tumor microenvironment, demonstrating the efficient transfer of this oncogene to tumor cells and its significant impact on enhancing proliferation. Full article

Since epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors were introduced in 2004, various driver gene mutations have been identified in non-small cell lung cancer, particularly adenocarcinoma, where mutations are typically mutually exclusive. EGFR and Kirsten rat sarcoma viral oncogene (KRAS) mutations are most prevalent in Japan, with routine testing now standard. However, hematoxylin and eosin staining often fails to detect mutations, except in cases such as ALK fusion lung cancer. We report a 76-year-old non-smoking Japanese woman diagnosed with adenocarcinoma confirmed as KRAS G12D/S-positive. Histological features, including thanatosomes (hyaline globules), nuclear pleomorphism, and cytoplasmic clearing, may aid in identifying mutations. Numerous thanatosomes were identified, some containing nuclear dust. Thanatosomes revealed periodic acid–Schiff reactivity with diastase resistance, fuchsinophilia with Masson’s trichrome stain, and dark blue-black color with Mallory’s PTAH stain. This is the first report linking thanatosomes in KRAS-mutant pulmonary adenocarcinoma to apoptosis via cleaved caspase-3 staining. Full article