Esophageal squamous cell carcinoma (ESCC) is a prevalent malignancy, ranking eleventh in incidence and seventh in mortality globally. Remodeling and Spacing factor 1 (RSF1), a chromatin remodeling factor, is frequently overexpressed in various tumors and correlates with poor prognosis. This study, combining public database analysis and clinical sample validation, reveals significantly elevated RSF1 expression in ESCC tumor tissues, confirmed further in an ESCC orthotopic model. Functional assays show that RSF1 knockout (KO) significantly inhibits ESCC cell proliferation, migration, invasion, and in vivo tumor growth, while reintroducing RSF1 restores its oncogenic effects. Proteomic analysis highlights that RSF1 KO disrupts pathways associated with cell cycle control, apoptosis, and focal adhesion. Experimentally, RSF1 KO induces apoptosis and G2/M arrest, establishing its essential role in ESCC progression. Collectively, these findings establish RSF1 as an oncogenic driver and a promising therapeutic target in ESCC.

ELK1 is a Transcription factor (TF) belonging to the ETS-domain TF family, mainly activated via RAS-RAF-MEK-ERK signaling. As a nethermost pathway molecule, ELK1 binds to Serum-response elements (SREs) and directly regulates the transcription of Immediate early genes (IEGs) including FOS and EGR1. Due to ELK1's influence on key cellular processes such as proliferation, migration, apoptosis evasion, and Epithelial-to-mesenchymal transition (EMT), its role as a key contributor to tumorigenesis is emerging. In recent years, elevated expression and/or activation of ELK1 has been reported in various malignancies, including lung, breast, prostate, colorectal, blood, gastric, liver, cervical, thyroid and ovarian cancer. ELK1 acts primarily through direct DNA binding but also through interaction with other oncogenes, noncoding RNA molecules, TFs, and upstream kinases (other than ERK1/2), thus participating in diverse axes of transcriptional regulation. Its crucial role in IEG expression has been particularly implicated in cancer progression, metastasis, and drug resistance. Owing to its role in multiple cellular functions and its subsequent oncogenic potential, further elucidation of intracellular ELK1 interactions is of paramount importance. This review aims to summarize current evidence on ELK1's involvement in solid tumors, dissect reported mechanistic roles, and highlight recent insights that could fuel future ventures of high translational interest.

Tumor-initiating cells (TICs) constitute a subpopulation of cancer cells with stem-like properties contributing to tumorigenesis, progression, recurrence, and therapeutic resistance. Despite their biological importance, their molecular signatures that distinguish them from non-TICs remain incompletely characterized. This study aimed to comprehensively analyze transcriptomic differences between TICs and non-TICs, identify TIC-specific gene expression patterns, and construct a machine learning-based classifier that could accurately predict TIC status. RNA sequencing data were obtained from four human cell lines representing TIC (TS10 and TS32) and non-TIC (32A and Epi). Transcriptomic profiles were analyzed via principal component, hierarchical clustering, and differential expression analysis. Gene-Ontology and Kyoto-Encyclopedia of Genes and Genomes pathway enrichment analyses were conducted for functional interpretation. A logistic-regression model was trained on differentially expressed genes to predict TIC status. Model performance was validated using synthetic data and external projection. TICs exhibited distinct transcriptomic signatures, including enrichment of non-coding RNAs (e.g., MIR4737 and SNORD19) and selective upregulation of metabolic transporters (e.g., SLC25A1, SLC16A1, and FASN). Functional pathway analysis revealed TIC-specific activation of oxidative phosphorylation, PI3K-Akt signaling, and ribosome-related processes. The logistic-regression model achieved perfect classification (area under the curve of 1.00), and its key features indicated metabolic and translational reprogramming unique to TICs. Transcriptomic state-space embedding analysis suggested reversible transitions between TIC and non-TIC states driven by transcriptional and epigenetic regulators. This study reveals a unique transcriptomic landscape defining TICs and establishes a highly accurate machine learning-based TIC classifier. These findings enhance our understanding of TIC biology and show promising strategies for TIC-targeted diagnostics and therapeutic interventions.

Metabolic rewiring is a hallmark of both hepatic regeneration and malignant transformation, complicating the identification of cancer-specific traits. This study aimed to distinguish the metabolic profiles of proliferating hepatocytes and hepatocellular carcinoma (HCC) cells through integrated analyses of mRNA and protein expression, along with functional characterization. We compared non-malignant Upcyte® hepatocytes (HepaFH3) cultured under proliferative and confluent conditions with primary human hepatocytes, primary human hepatoma cells, and hepatoma cell lines. Proliferating HepaFH3 cells exhibited features of metabolic reprogramming, including elevated glycolysis, increased HIF1A expression, and ketone body accumulation, while maintaining low c-MYC expression and reduced BDH1 levels, distinguishing them from malignant models. In contrast, HCC cells showed upregulation of HK2, c-MYC, and BDH1, reflecting a shift toward aggressive glycolytic and ketolytic metabolism. Functional assays supported the transcript and protein expression data, demonstrating increased glucose uptake, elevated lactate secretion, and reduced glycogen storage in both proliferating and malignant cells. These findings reveal that cancer-like metabolic changes also occur during hepatic regeneration, limiting the diagnostic utility of individual metabolic markers. HepaFH3 cells thus provide a physiologically relevant in vitro model to study regeneration-associated metabolic adaptation and may offer insights that contribute to distinguishing regenerative from malignant processes. Our findings highlight the potential of integrated metabolic profiling in differentiating proliferation from tumorigenesis.

Autophagy is a crucial cellular process responsible for sustaining homeostasis through the degradation and recycling of proteins and organelles, providing energy during amino acid starvation and hypoxia. In cancer, autophagy can either inhibit tumor growth or support cancer cell survival. Our previous studies have shown that re-expression of the tumor suppressor gene DIRAS3 inhibits growth of ovarian cancer cells, promotes autophagic cell death in vitro, and induces tumor dormancy in vivo. Growth factors and extracellular matrix (ECM) components can, however, inhibit DIRAS3-induced autophagic cell death. This study explores whether fibronectin (FN) can counteract the growth inhibition induced by DIRAS3 in ovarian cancer cells. FN was found to inhibit DIRAS3-induced autophagy and to partially rescue ovarian cancer cells from DIRAS3-induced cell death while reducing DIRAS3-induced inhibition of p-FAK and p-AKT. Inhibiting FAK with defactinib in ovarian cancer cells enhanced DIRAS3-induced autophagy and cell death. Re-expression of DIRAS3 and treatment with defactinib produced tumor regression in xenograft models. Our findings suggest that ECM components in the tumor microenvironment like FN enhance the activities of β1 integrin, FAK, and AKT to inhibit DIRAS3-induced autophagic cell death, thereby promoting ovarian cancer cell survival.

Clonally established tumor cell lines often do not recapitulate the behavior of cells in tumors. The sequencing of a whole tumor tissue may not uncover transcriptome profiles induced by the interactions of all different cell types within a tumor. Interferons for instance have a vast number of binding sites in their target genes. Access to the DNA binding sites is determined by the epigenomic state of each different cell type within a tumor mass. To understand how genes such as interferons appear to have both tumor-promoting and tumor-inhibiting functions, single-cell transcript analysis was performed in the breast cancer tissue of HER2+ (epidermal growth factor receptor 2) patients. We identified that potential antagonistic oncogenic activities of cells can be due to diverse expression patterns of genes with pleiotropic functions. Molecular pathways both known and novel were identified and were similar with those previously identified for patients with rheumatoid arthritis. Our study demonstrates the efficacy in using single-cell transcript analysis to gain insight into genes with apparent contradictory or paradoxical roles in oncogenesis.

Basal-like breast cancer (BLBC) is associated with poor prognosis, high recurrence rates, and limited therapeutic options, largely due to its molecular heterogeneity and complexity, which include epigenetic alterations. This study investigated epigenetic regulatory networks in BLBC by analyzing DNA methylation in distal cis-regulatory regions and its impact on genes, transcription factors (TFs), and microRNAs (miRNAs) expression. Data from TCGA were processed using the ELMER and DESeq2 tools to identify differentially methylated regions and differentially expressed genes, TFs, and miRNAs. The FANMOD algorithm was used to identify the regulatory interactions uncovering the feed-forward loops (FFLs). The analysis identified 110 TF-mediated FFLs, 43 miRNA-mediated FFLs, and five composite FFLs, involving 18 hypermethylated and 32 hypomethylated genes, eight upregulated and nine downregulated TFs, and 21 upregulated and seven downregulated miRNAs. The TF-mediated FFLs major regulators involved the AR, EBF1, FOS, FOXM1, and TEAD4 TFs, while key miRNAs were miR-3662, miR-429, and miR-4434. Enriched pathways involved cAMP, ErbB, FoxO, p53, TGF-beta, Rap1, and Ras signaling. Differences in hallmark gene set categories reflected distinct methylation and miRNA expression profiles. Overall, this integrative analysis mapped the intricate epigenetic landscape of BLBC, emphasizing the role of FFLs as regulatory motifs that integrate DNA methylation, TFs, and miRNAs in orchestrating disease's development and progression and offering potential targets for future diagnostic and therapeutic strategies.

Epithelial-mesenchymal transition (EMT) is a key process in cancer progression and fibrogenesis. In this study, EMT was induced in Huh7 hepatocellular carcinoma cells via TGF-β1 treatment, and the resulting lipidomic and metabolomic alterations were characterized. Morphological changes and protein marker analyses confirmed the transition to a mesenchymal phenotype, with reduced E-cadherin and increased vimentin and N-cadherin expression. Lipidomic profiling revealed a dose-dependent reorganization of membrane lipids, with a pronounced increase in the levels of ceramides, cholesteryl esters, and lysophospholipids, consistent with alterations in membrane structure, potential cellular stress, and modulation of inflammatory pathways. Changes in the content of phospholipid classes, including phosphatidylethanolamines and phosphatidylserines, indicate possible variations in membrane dynamics and potentially point to modifications in mitochondrial function, cellular stress responses, and redox balance. Metabolomic analysis further indicates an alteration of choline and phosphatidylcholine metabolism, consistent with a shift from de novo membrane synthesis toward lipid turnover. Reduced glycolytic capacity and modified acylcarnitine levels indicated impaired metabolic flexibility and mitochondrial efficiency. The integration of phenotypic, lipidomic, and metabolomic data suggests that TGF-β1 induces EMT and drives a coordinated metabolic reprogramming. These findings highlight the involvement of lipid and energy metabolism in sustaining EMT and suggest that specific metabolic reprogramming events characterize the mesenchymal shift in hepatocellular carcinoma. By exploring this process in a tumor-specific context, we aim to deepen our understanding of EMT complexity and its implications for tumor progression and therapeutic vulnerability.

Major histocompatibility complex class I (MHC-I)-mediated antigen presentation plays a pivotal role in anti-tumor immunity by enabling CD8+ T cells to recognize and eliminate malignant cells. In melanoma, modulation of this pathway is critical for improving the efficacy of immunotherapies. Our study demonstrates that the natural compound Cepharanthine (CEP) exhibits notable antitumor activity by enhancing MHC-I-mediated antigen presentation. CEP treatment upregulated MHC-I expression (both membrane-bound and total levels) in melanoma cells in a concentration-dependent manner, thereby improving antigen-presenting capacity. Interestingly, when autophagy was pharmacologically blocked using Bafilomycin A1, co-treatment with CEP did not lead to further elevation of MHC-I expression, suggesting that CEP's effect is mediated through disruption of the autophagic pathway. Mechanistically, CEP induced autophagosome accumulation, as evidenced by an increase in GFP-LC3 puncta. Fluorescence imaging further confirmed that CEP selectively impaired lysosomal acidification without affecting autophagosome-lysosome fusion, thereby inhibiting late-stage autophagic flux. Furthermore, CEP treatment promoted CD8+ T cell infiltration into tumor tissues and enhanced the antitumor efficacy of anti-PD-1 therapy, resulting in greater tumor suppression compared to either treatment alone. The study elucidates how CEP's selective lysosomal inhibition creates a tumor microenvironment more susceptible to immune surveillance, primarily through preserved MHC-I surface expression and subsequent T cell recognition. This work highlights CEP as a promising immunomodulatory agent and provides a potential strategy for improving the outcomes of immune checkpoint blockade therapy.

Metastatic dissemination defines a complex phenomenon driven by genetic forces and, importantly, determined by interaction between cancer cells and the surrounding stroma. Although the biologic and immune reactions which characterize the process have been widely and extensively evaluated, fewer data are available regarding the mechanical and physical forces to which circulating neoplastic clones are exposed. It should be hypothesized that this interaction can be modified in case of concomitant pathologic conditions, such as chronic vasculopathy, which frequently occurs in lung cancer patients. We here aim at analyzing and discussing the complex interplay between lung malignant transformation and arteriopathy, mainly focusing on the immune-inflammatory systemic reaction. Notably-in most instances-smoking-related fixed airflow obstruction, including but not limited to COPD, frequently coexists and contributes to both tumor progression and vascular complications. Attention is paid mainly to the analysis of the role of immune checkpoint inhibitors and their interaction with triple bronchodilation and antiaggregants. Understanding the biomechanical and molecular dynamics of lung cancer progression in altered vascular territories has several translational implications in defining risk stratification and in surgical planning and therapeutic targeting. Moreover, computational modeling of the physical forces which regulate the transit and extravasation of metastatic clones in altered contexts could be of help in deciphering the whole process and in determining more effective blockade strategies.

This study aimed to identify factors influencing salivary gland uptake in fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT).

Negative pigment network (NPN) is a dermoscopic structure frequently associated with melanoma. Though commonly observed in Spitz naevi (SN) and Spitzoid melanoma (SM), its reflectance confocal microscopy (RCM) correlates have been primarily studied in non-Spitzoid melanocytic neoplasms. This study aimed to identify clinical, dermoscopic, and RCM features associated with dermoscopic NPN in Spitzoid neoplasms and explore its histopathological correlates. We retrospectively analysed clinical, dermoscopic, and RCM images from 128 histopathologically confirmed SN and SM cases diagnosed between 2014 and 2020. Lesions were grouped by presence or absence of dermoscopic NPN, and comparisons were made across clinical, dermoscopic, and RCM features. A subset of 20 cases underwent histopathologic correlation. Of the 128 cases, 96 (74%) were SN and 32 (26%) SM. NPN was present in 58 lesions (45%)-40 SN (42%) and 18 SM (56%). NPN was associated with lesion diameter ≥ 5 mm, presence of shiny white structures, dotted vessels, and inversely associated with diffuse blue-white veil. SMs showed higher frequencies of asymmetry, multicomponent patterns, and extensive NPN. RCM features previously linked to NPN-round or linear surface disruptions, bright suprabasal areas, and broadened interpapillary spaces-were seen in 87% of cases but did not correlate with diagnosis or dermoscopic NPN. Corresponding histologic features included keratin-filled dells, hypergranulosis, and broadened rete ridges or infundibula. RCM correlates of dermoscopic NPN are frequently observed in Spitzoid neoplasms, independent of visible dermoscopic NPN, suggesting perceptibility may depend on contrast within dermoscopic patterns.

The completeness of surgical resection is a key factor influencing outcomes in patients with papillary thyroid carcinoma (PTC) and regional lymph node metastases. However, the optimal extent of therapeutic lateral neck dissection remains a matter of debate This study aimed to assess the diagnostic accuracy of preoperative ultrasonography (US) in detecting lateral lymph node metastasis (LLNM) in patients with PTC and to identify clinical and pathological factors predictive of metastases at levels II and V.

Parathyroid carcinoma (PC) and atypical parathyroid tumors (APT), constituting rare endocrine malignancies, demonstrate overlapping clinical-radiological presentations with benign adenomas. This study aimed to investigate the predictive performance of three radiomics-based machine learning models for the identification of PC/APT from solitary parathyroid lesions using ultrasound.

The co-existence of medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC) is rare. The study analyzed the clinicopathological findings and prognosis of concomitant PTC in MTC patients.

An optimal surveillance plan of micro-nonfunctioning pituitary adenomas (micro-NFPAs) is not well established despite high prevalence and increasing incidence of these tumors. This study aims to characterize the natural history of conservatively treated micro-NFPAs and provide evidence for a management algorithm.

Exosomal molecules derived from cancer cells have been recognized as candidate biomarkers for cancer diagnosis and prognosis. This study aimed to evaluate the potential of the LDH-C4 expression level in cervical carcinoma.

The preservation of reproductive organs in females with muscle-invasive bladder cancer (MIBC) might improve reproductive and sexual function. This study aimed to identify potential clinical risk factors for reproductive organ involvement (ROI) using preoperative data from transurethral resection of tumor (TURT) reports and imaging findings.

Pancreatic cancer (PC) remains one of the most challenging cancers and has the worst prognosis. Tumor-associated MUC1 (tMUC1) is overexpressed and aberrantly glycosylated in over 80% of human pancreatic ductal adenocarcinoma (PDA). Chimeric antigen receptor (CAR) engineered T cells are an emerging cancer immunotherapy strategy and recently, we successfully engineered tMUC1-specific human and mouse CAR T cells and demonstrated their effectiveness as monotherapy against PDA in vitro and in vivo. In this study, we observed varying sensitivity among human PDA cell lines in response to tMUC1-targeted CAR T cell cytolysis. Notably, highly resistant HPAFII cells released greater amounts of interferon (IFN)-regulated ICAM-1, CXCL10, and CXCL11 compared to the more sensitive MiaPaCa-2 cells following CAR T cell challenge. Blocking IFN signaling using Ruxolitinib, a JAK1/2 inhibitor (JAKi), significantly reduced the upregulation of ICAM-1 and CXCL10. Western blot analysis revealed that both type I and type II IFN signaling pathways were elevated in PDA cells upon CAR T cell treatment. JAKi effectively suppressed this signaling response, with a more pronounced impact on the type I IFN pathway. Importantly, both IFN blockade and transient knockdown of IFN receptors significantly enhanced the sensitivity of PDA cells to CAR T cell-mediated cytolysis in vitro. Further mechanistic study revealed that CAR T cells partially lose their cytolytic potential after engaging with PDA cells. Treatment with CAR T cells triggered the up-regulation of immune checkpoint PD-L1 expression on PDA cells via tumor cell' own IFN signaling. Thus, blocking PD-L1 in HPAFII enhanced its response to CAR T cells. Similarly, neutralizing CXCL10 enhanced CAR T cell killing of HPAFII cells suggested CXCL10's involvement in resistance to CAR T cell cytolysis. RNA-seq data indicated higher expression of multiple genes along the IFN signaling pathway which were associated with poor prognosis in PDA patients. Taken together, tumor intrinsic IFN signaling may drive immune evasion in PDA cells against tMUC1-targeted T cell-mediated immunotherapy. This identifies tumor IFN signaling as a potential therapeutic target to improve CAR T cell efficacy in PDA treatment.

Lung adenocarcinoma (LUAD) represents a significant global health burden. The absence of reliable biomarkers and the heterogeneity in treatment responses continue to hinder improvements in patient prognosis. This study aimed to identify novel biomarkers capable of predicting patient outcomes and therapeutic responsiveness, while also assessing their potential as intervention targets for LUAD.