Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate below 10%. Cancer-associated fibroblasts (CAFs) promote epithelial-mesenchymal transition (EMT) and metastasis, yet the specific CAF subtypes and molecular axes driving PDAC progression remain incompletely understood. Here, using multi-omics data from PDAC samples, we identified a malignant ductal subpopulation, termed Ductal-T0, characterized by the highest EMT activity and prominent acquisition of myofibroblastic CAF (myCAF)-like transcriptional programs. Computationally, we predicted that myCAF-secreted THBS2 and FN1 engage the ITGA3/ITGB1/SDC1/SDC4 receptor axes in Ductal-T0 cells, which could activate TNF, NF-κB, TGF-β, and PI3K-AKT-signaling pathways to promote EMT. Pseudotime trajectory and velocity analyses suggested that Ductal-T0 cells exhibited the highest propensity to acquire myCAF-like features among all ductal subpopulations. Survival analysis revealed that an increased proportion of Ductal-T0 cells and elevated abundance of THBS2-ITGA3/ITGB1 and THBS2-SDC1 ligand-receptor pairs were significantly associated with poor prognosis. Spatial transcriptomics further revealed that myCAFs and Ductal-T0 cells co-localized at the tumor margin, which may contribute to reduced immune cell presence via dense extracellular matrix (ECM) barrier formation-a computationally inferred model of EMT-associated immune exclusion and metastatic progression-and identify THBS2 as a promising candidate for future therapeutic investigation to disrupt CAF-tumor crosstalk in PDAC.

Cancer stem cells (CSCs) drive therapeutic resistance, metastasis, and tumor recurrence through reversible transitions among stem-like, differentiated, epithelial, and mesenchymal states, which are sustained by interconnected epigenetic mechanisms. To our knowledge, this is the first review to integrate curcumin-mediated regulation of DNA methylation, chromatin remodeling, and non-coding RNAs within a single CSC plasticity framework and to propose the concept of an "epigenetic collapse of CSC plasticity" as a mechanistic explanation for how curcumin may weaken stemness, state switching, and adaptive treatment resistance. Evidence was critically evaluated through structured searches of PubMed/MEDLINE, Scopus, Web of Science Core Collection, Google Scholar, and citation tracking, while direct curcumin-epigenetic evidence was distinguished from independent CSC evidence and inferential mechanistic links. Curcumin has been reported to modulate DNMT1 and locus-specific DNA methylation; regulate HDACs, p300/CBP, EZH2, H3K27me3, and BMI1; and alter selected microRNA, long non-coding RNA, and circular RNA pathways, with comparatively stronger evidence involving the miR-34 family, miR-200c, miR-21, H19, and circHN1. However, current evidence is constrained by the predominance of bulk cancer-cell models, heterogeneous formulations and exposure conditions, and the scarcity of epigenetic rescue experiments combined with rigorous functional CSC assays. By unifying previously fragmented epigenetic evidence, this review advances a new evidence-weighted model in which curcumin may suppress CSC persistence not through a single molecular target, but by destabilizing the multilayer epigenetic circuitry that enables plasticity. Curcumin should therefore be regarded as a context-dependent, multilayer epigenetic modulator rather than an established CSC-eradicating therapy, and its translational relevance requires validation in prospectively defined CSC models with pharmacologically justified delivery and exposure conditions.

The human immune system executes immune defense against foreign antigens, immune surveillance against mutant cells, and immune homeostasis to maintain bodily physiological equilibrium. Transfer RNA (tRNA) is an important part of gene expression regulation. Recent studies have found that aberrant tRNA modifications can disturb the function of the immune system by altering translation efficiency, including regulating immune recognition and signal transduction, as well as influencing apoptosis and autophagy. tRNA modifications are also closely related to the development and occurrence of immune-related disorders such as infections, tumors, and autoimmune diseases. By integrating current research on immune-related tRNA modifications, this review systematically summarizes the mechanisms of tRNA modifications involved in three major immune functions and their relationship with related diseases, encompassing the direct regulation of immune cells and the indirect immune effects mediated through tissue or tumor cells. In addition, some tRNA modifications can also modulate immune responses by affecting tRNA cleavage and the consequent generation of tRNA-derived small RNAs (tsRNAs). Accordingly, this review outlines promising intervention targets and unresolved research bottlenecks, facilitating follow-up investigations into tRNA modification-dependent immune regulation and translational therapeutic research.

Esophageal squamous cell carcinoma (ESCC) is a highly prevalent malignancy worldwide. Moreover, ESCC remains poorly characterized at the molecular level, which contributes to limited therapeutic options and an overall poor prognosis. In this context, HMGA family members, which are overexpressed in tumors but almost absent in healthy adult tissues, seem to represent promising therapeutic targets. These proteins act by binding to AT-hook DNA-binding motifs and may regulate the expression of several genes associated with tumor progression. Therefore, integrating in silico, translational, and in vitro approaches, we investigated the functional consequences of blocking HMGA2-DNA interaction in ESCC tumor progression by using netropsin, a site-specific ligand for AT-rich DNA regions. Our results demonstrate that netropsin treatment significantly reduced cell viability, migration, and cell cycle progression, thereby promoting apoptosis. Furthermore, netropsin treatment was capable of partially reverting Epithelial-Mesenchymal Transition (EMT) activation associated with HMGA2 expression, by downregulating EMT activators, such as Slug and Twist. Finally, the netropsin treatment sensitizes ESCC cells to chemotherapeutic treatment with 5-Fluorouracil. Taken together, our findings highlight that AT binding-specific blockade could be correlated with the inhibition of HMGA2 and may reveal a promising approach to better understand ESCC progression.

Amplification of MDM2 is the molecular hallmark of atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL) and dedifferentiated liposarcoma (DDL). While fluorescence in situ hybridization (FISH) is widely used for diagnosis, the diagnostic and prognostic value of droplet digital PCR (ddPCR) remains poorly defined. We retrospectively analyzed 341 primary adipocytic tumors, including 85 liposarcomas (22 DDL), using ddPCR to quantify MDM2 copy number variation (CNV). Diagnostic performance was compared with FISH, and associations with clinicopathological variables and outcomes were evaluated using non-parametric tests, ROC analysis, survival analysis, and Firth's penalized Cox models. Comparison with FISH confirmed the diagnostic utility of ddPCR for detecting MDM2 amplification, while quantitative CNV assessment provided additional prognostic information. CNV values were significantly higher in deep-seated and dedifferentiated tumors and were strongly associated with local recurrence. ROC analysis identified a threshold of 16.85 copies predicting both dedifferentiation and recurrence (AUC 0.982 and 0.942, respectively). Patients with CNV ≥ 16.85 copies had significantly shorter recurrence-free and overall survival. In multivariable analysis, high CNV remained an independent predictor of recurrence (HR 36.6, 95% CI 4.0-4914.2). These findings support ddPCR as a robust method for MDM2 assessment and suggest that quantitative MDM2 copy number may improve both diagnosis and risk stratification in liposarcoma.

Next-generation sequencing (NGS) has become a cornerstone of precision oncology in colorectal cancer (CRC), although its role in routine patient stratification remains incompletely defined. This retrospective single-centre study characterised the molecular landscape of clinically selected CRC patients undergoing routine NGS and explored associations between genomic alterations and clinicopathological features. 97 eligible patients who underwent targeted NGS using two validated sequencing platforms were selected. Demographic, clinicopathological, and molecular data were integrated, and associations were evaluated using descriptive statistics, exploratory association testing, principal component analysis, and multiple correspondence analysis. At least one reportable genetic alteration was identified in 91 patients (93.8%), comprising 198 alteration events across multiple cancer-related genes. The most frequently altered genes with pathogenic or likely pathogenic variants were TP53 (55.7%), KRAS (40.2%), PIK3CA (18.6%), and BRAF (11.5%), while microsatellite instability was detected in 19.1% of evaluable tumours. Exploratory analyses identified associations between selected molecular alterations and clinicopathological characteristics. However, these were generally modest, frequently limited by small subgroup sizes, and none survived Benjamini-Hochberg correction. Principal component analysis demonstrated substantial molecular heterogeneity without defining distinct clinicopathological subgroups. Routine targeted NGS provides detailed molecular characterisation of CRC and generates information relevant to biomarker-informed clinical decision-making in real-world practice. However, targeted panels alone were insufficient to establish robust molecular subgroups in this retrospective cohort. These findings highlight the biological complexity of CRC and support larger prospective studies incorporating broader molecular profiling to improve precision patient stratification and optimise personalised therapeutic strategies.

Lung cancer ranks first in both incidence and mortality among all malignancies, and tumor microenvironment (TME)-induced CD8+ T cell exhaustion is a critical factor driving immune evasion and compromising the efficacy of immunotherapy. MicroRNAs (miRNAs), as key post-transcriptional regulators, shuttle between lung cancer cells and CD8+ T cells via extracellular vesicles (EVs), serving as critical communication hubs that reshape the TME. This review systematically synthesizes recent literature to summarize the regulatory patterns of miRNAs on functions of lung cancer cells and CD8+ T cells, and dissect the molecular mechanisms underlying miRNA-mediated bidirectional crosstalk between these two cell types. This review focuses on the dual-pronged immune evasion strategy employed by lung cancer cells to counteract CD8+ T cells. On the one hand, lung cancer cells aberrantly express endogenous miRNAs, such as miR-20a, miR-149-5p, and miR-326, to remodel their surface ligands and establish immune camouflage. On the other hand, they actively secrete EVs enriched in specific miRNAs, including miR-7108-3p, miR-651-5p, and miR-24-3p, which directly suppress CD8+ T cell function. Furthermore, lung cancer cells secrete additional miRNAs, notably miR-6794-5p, miR-708-5p, and miR-1234-3p, to reprogram other TME components, namely tumor-associated macrophages (TAMs), natural killer (NK) cells, and myeloid-derived suppressor cells (MDSCs). These reprogrammed cells, in turn, indirectly attenuate CD8+ T cells through a relay-like mechanism via immunosuppressive cytokines or surface checkpoint molecules produced by these cells. In addition, competing endogenous RNA (ceRNA) networks formed by long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) in lung cancer cells regulate miRNA activity at multiple levels, further impairing the immune effector functions of CD8+ T cells. Conversely, activated CD8+ T cells also secrete miRNA-containing EVs, which deliver these miRNAs to tumor cells, thereby inhibiting tumor progression. Elucidation of this miRNA-based bidirectional communication network will not only advance our understanding of immune evasion mechanisms in lung cancer but also provide novel insights into cell-free immunotherapeutic approaches based on CD8+ T cell-derived vesicles.

Gliomas are the most common group of primary brain tumors, among which glioblastoma multiforme (GBM) is characterized by a particularly poor prognosis and the limited effectiveness of available treatments. Ophiobolin A (OP-A), a natural sesterterpenoid, exhibits promising anticancer properties, including the ability to cross the blood-brain barrier and induce paraptosis-like cell death. However, the molecular mechanisms underlying its action, especially in the early phase of the cellular response, remain not fully understood. The aim of this study was to analyze early changes in the expression of genes associated with apoptosis, ferroptosis, and antioxidant mechanisms in T98G and U118MG glioma cells exposed to OP-A. Gene expression was assessed by RT-qPCR, apoptosis was evaluated using Annexin V/PI staining and flow cytometry, and treatment-induced morphological changes were documented by brightfield microscopy. Statistical analysis was performed using the Mann-Whitney U test. Descriptive Annexin V/PI analysis showed a lower proportion of viable cells and a higher proportion of early apoptotic cells in the analyzed OP-A-treated T98G and U118MG samples compared with the corresponding vehicle-control samples. These preliminary observations were based on technical replicates from a single biological experiment and require confirmation in independent biological replicates. Transcriptional profiling revealed a shift toward a pro-apoptotic phenotype, characterized by increased BAX and FAS expression together with a trend toward reduced BCL2 expression, whereas ferroptosis-associated genes remained largely unchanged. Notably, SLC7A11 upregulation suggested activation of compensatory antioxidant mechanisms in response to OP-A treatment. In T98G cells, OP-A induced a distinct and reproducible transcriptional signature that enabled accurate discrimination from control conditions (AUC = 0.833). Feature importance and SHAP analyses identified BAX as the most informative predictor, followed by SLC7A11 and FAS, with bootstrap validation confirming BAX as a stable marker. Pathway analysis demonstrated selective activation of apoptosis- and cysteine metabolism-related pathways, while hierarchical clustering revealed that OP-A generated a transcriptional profile distinct from oxidative stress-inducing agents. The predictive performance of this molecular signature was cell-line dependent, showing weaker discrimination in U118MG cells.Short-term OP-A exposure in T98G and U118MG cells was associated with exploratory trends in apoptosis- and redox-related gene expression and a higher proportion of Annexin V-positive cells. The machine-learning analyses identified candidate discriminatory features within this limited dataset but should be regarded as hypothesis-generating. Larger studies with independent biological replication, additional GBM models, different exposure conditions, and functional validation are required to confirm these observations and clarify the mechanism of OP-A action.

Inadequate supply of oxygen causing hypoxic cellular stress drives metabolic reprograming across diverse physiological conditions, including cancer. The activation of hypoxia-inducible factors (HIFs) to facilitate adaptation to low oxygen environments is well-characterized; however, post-transcriptional regulation by microRNAs (miRNAs) is poorly understood. Here, we investigated the mRNA and miRNA response in hypoxia-mediating reduced growth and cellular metabolism. Next-generation sequencing revealed the impact of hypoxia in cultured human hepatocellular carcinoma cells and identified over 400 mRNAs and 140 miRNAs that were differentially expressed. Hypoxia upregulated mRNA transcripts associated with glycolysis, DNA replication and the PI3K (phosphoinositide 3-kinase)-Akt pathway, which promote anaerobic metabolism for energy production, decreased cell proliferation and genomic instability, respectively. Upregulated miRNAs included miR-197-3p and miR-766-3p, targeting genes involved in lipid biosynthesis and metabolism. Downregulated miRNAs included miR-33a-5p and miR-15a-5p, targeting genes involved in glycolysis and lactate metabolism. Notably, miR-6834 emerged as a potential regulator of mechanistic target of rapamycin (mTOR) signaling and insulin-like growth factor binding protein-1 (IGFBP-1) signaling; miR-6834 overexpression altered 4E-BP1 phosphorylation levels and IGFBP-1 secretion. These findings provide critical insights into miRNA-mRNA regulation of metabolic adaptation and highlight miRNAs as potential targets for interventions with relevance to tumor biology and other hypoxia-associated conditions.

Mismatch repair deficiency (MMRd) is a critical biomarker in endometrial cancer (EC) for prognostication, Lynch syndrome screening, and immunotherapy eligibility. This study aimed to determine the prevalence of MMRd and its correlation with clinicopathological characteristics in EC. This prospective observational cohort included 93 patients with EC undergoing primary surgical treatment, managed as per the European Society of Gynaecological Oncology (ESGO) guidelines. MLH1, PMS2, MSH2, and MSH6 expression was assessed through immunohistochemistry (IHC) on formalin-fixed, paraffin-embedded hysterectomy specimens. Associations between mismatch repair (MMR) status and histology, grade, lymphovascular space invasion (LVSI), myometrial invasion, FIGO 2023 stage, nodal status, recurrence, and survival were analyzed. The median age was 66 years. Most tumors were endometrioid (86%), 29% were grade 3, 45.2% showed deep myometrial invasion, and 23.7% had substantial LVSI. MMRd was identified in 41.9% of cases, with MLH1 and PMS2 loss being most frequent, and was significantly associated with endometrioid histology (p = 0.027) and deep myometrial invasion (p = 0.011). No significant correlations were found with grade, LVSI, FIGO stage, nodal involvement, recurrence, or overall survival. Routine MMR assessment may refine risk stratification and guide individualized treatment decisions.

Castration-resistant prostate cancer (CRPC) is characterised by persistent androgen receptor (AR)-axis activity, therapy-driven resistance, and limited durability of available systemic treatments. Tumour-tropic mesenchymal stem/stromal cells (MSCs), including adipose-derived MSCs (ADSCs), have emerged as promising vehicles for targeted gene therapeutics. This review synthesises our three experimental studies examining stem cell-delivered gene-directed enzyme prodrug therapy (GDEPT) using cytosine deaminase (CD)/5-fluorocytosine (5-FC) and secreted TRAIL in CRPC xenograft models. We performed a comparative analysis of three studies in which hTERT-immortalised human ADSCs were engineered via lentiviral vectors to deliver CD alone, secreted TRAIL alone, or CD+TRAIL in combination, and were administered by intracardiac injection into male nude mice bearing PC3 xenografts. In vitro conversion efficiency, cell viability, apoptosis markers, and in vivo tumour volume endpoints were compared across studies. All three therapeutic platforms demonstrated measurable tumour growth inhibition relative to controls. The CD+TRAIL combination achieved the greatest in vivo efficacy (tumours approximately 26% of control at day 14), compared with CD alone (approximately 71%) or TRAIL paired with irinotecan. Enzymatic conversion of 5-FC to 5-FU exceeded 93% in conditioned medium. Primary translational risks include thrombotic events associated with systemic MSC dosing, tumourigenicity and genotoxicity of hTERT-immortalised, integrating-vector-engineered cells, immunogenicity of xenogeneic CD enzyme, and systemic 5-fluorouracil leakage from flucytosine metabolism. Stem cell-delivered CD/5-FC and TRAIL constitutes a biologically rational, modular strategy for local cytotoxicity and resistance circumvention in CRPC. Successful clinical translation will require resolution of delivery-route feasibility, thrombosis risk mitigation, and a rigorous investigational new drug (IND)-enabling safety package.

We explored the potential functions of differentially expressed miRNAs, mRNAs, lncRNAs, and circRNAs identified in the ovaries of gilts with normal estrus (NE) and follicular cyst-associated anestrus (AE), as well as their putative competing endogenous RNA (ceRNA) regulatory networks. Ovarian morphology was assessed via ultrasonography, and serum concentrations of Follicle-stimulating hormone (FSH), (Estradiol) E2, and Progesterone(P4) were measured. Ovarian tissues were harvested after slaughter for whole-transcriptome sequencing. Bioinformatic tools were used to screen differentially expressed RNAs(DERNAs) between NE and AE gilts. We further predicted target interactions among these transcripts, conducted functional enrichment analysis on target genes, and constructed candidate ceRNA regulatory networks potentially associated with gilt estrus. Phenotypic verification confirmed that ovarian ultrasonographic characteristics, histological morphology, and serum reproductive hormone levels were consistent with the physiological status of NE and AE gilts. Under the screening thresholds of p < 0.05 and |log2FC| ≥ 1, we identified 22 lncRNAs that may interact with 21 mRNAs via 50 miRNAs, alongside 39 circRNAs predicted to regulate 26 mRNAs through 72 miRNAs. Functional enrichment analysis indicated that target genes of these differentially expressed transcripts were predominantly enriched in the lysosome pathway, PPAR signaling pathway, chemokine signaling pathway, cholesterol metabolism and NOD-like receptor signaling pathway. Hub molecules including FGF1, GHR, TLR2, ssc-miR-370, and miR-21-5p were shared in lncRNA/circRNA-miRNA-mRNA regulatory networks; these molecules have been reported to participate in progesterone synthesis, estrus modulation, and endocrine homeostasis. Of particular interest, two non-coding RNAs, MSTRG.1285.1 and novel_circ_056113, were predicted to act as candidate ceRNAs that may sponge ssc-miR-370 and miR-21-5p, which could in turn modulate the expression of estrus-associated mRNAs including FGF1, GHR, and TLR2. The expression trends of MSTRG.1285.1, novel_circ_056113, miR-370, miR-21-5p, GHR, TLR2, and FGF1 were validated by qRT-PCR, and the quantification results agreed with transcriptome sequencing data. Collectively, this study constructed a predicted ceRNA regulatory network of ovarian transcripts comparing NE and AE gilts and uncovered multiple RNA molecules potentially involved in estrus regulation. These findings offer preliminary theoretical clues for exploring the onset of puberty in gilts.

Bladder cancer (BC) remains a major clinical challenge owing to limited therapeutic options and high recurrence rates. Oridonin (ORI), a natural diterpenoid derived from Rabdosia plants, exhibits promising anti-tumor activity, but its effects and mechanisms in BC remain poorly defined. We evaluated the anti-BC potential of ORI in vitro and in vivo using proliferation, migration, invasion, cell-cycle, and apoptosis assays, integrated transcriptomic and proteomic analyses, Western blotting, and a 5637 xenograft model. ORI dose- and time-dependently inhibited 5637 and T24 cell proliferation, induced S-phase arrest (from 23.37% to 42.12% in 5637 and from 31.87% to 50.28% in T24; p < 0.01), and reduced migration (from 53.39% to 13.77% and from 59.81% to 12.49%; p < 0.0001) and invasion (from 74.42% to 25.43% and from 67.03% to 30.12%; p < 0.001). Multi-omics analyses revealed widespread changes enriched in apoptosis- and cell-cycle-related pathways. Consistently, ORI promoted apoptosis and necrosis, up-regulating BAX, CASP3, BID, and CYCS and down-regulating BCL2, validating the omics findings. In vivo, ORI (20 mg/kg, daily gavage) significantly suppressed xenograft growth (p < 0.001) without obvious toxicity, indicating that ORI inhibits BC growth and metastasis by inducing S-phase arrest and apoptosis and is a promising candidate for BC therapy.

Bladder cancer (BC) is a common urological malignancy that lacks the non-invasive biomarkers that would make it suitable for early diagnosis. Human alpha-satellite DNA (hASAT) is a tandemly repeated centromeric/pericentromeric DNA family associated with chromosomal stability and cancer-related genomic instability. We quantified extracellular hASAT (ec-hASAT) in plasma circulating cell-free DNA by nanoplate-based digital PCR in a pilot cohort including 29 BC-negative samples, 10 patients with non-muscle-invasive BC (NMIBC), and 7 patients with muscle-invasive BC (MIBC). Plasma ec-hASAT copy number was higher in patients with BC than in the BC-negative group (Mann-Whitney U test, p = 6.61 × 10-7). BC-negative samples ranged from 225 to 11,864 copies/µL plasma, whereas BC samples ranged from 1138 to 16,097 copies/µL plasma. ROC analysis yielded an AUC of 0.944 for discriminating BC from BC-negative samples. At an exploratory threshold of 2000 copies/µL plasma, sensitivity was 94.1% (16/17; exact 95% CI, 71.3-99.9%) and specificity was 89.7% (26/29; exact 95% CI, 72.6-97.8%). These preliminary data support plasma ec-hASAT as a candidate minimally invasive biomarker for BC detection, including NMIBC, and justify validation in larger prospective cohorts.

Dynamic transcriptomic remodeling of epithelial cells represents a critical hallmark of lung adenocarcinoma (LUAD) progression, yet epithelial-cell progression signatures (ECPSs) linked to this process remain incompletely characterized, impeding our understanding of malignant LUAD transformation. Here, we performed a multi-resolution multi-omics study and identified two functionally opposing ECPSs: a Cancer-Promoting Signature (CPS) and a Cancer-Suppressing Signature (CSS). The CPS was progressively upregulated from normal to early- and advanced-stage lesions, while the CSS was gradually downregulated, and both were validated by multi-resolution transcriptomic data. Both the CPS and CSS demonstrated robust diagnostic value for LUAD, particularly in early-stage detection (median AUC > 0.95). In seven independent validation cohorts, the CPS and CSS served as robust prognostic risk and protective factors, respectively. Their combination could better stratify LUAD patients into distinct prognostic subgroups, with the CPShigh-CSSlow subgroup showing the worst prognosis, accompanied by high genomic instability, an immunosuppressive tumor microenvironment, and resistance to chemotherapy. Notably, the CPS and CSS exhibited broad translational value in other epithelium-derived cancers. HMGA1, a key CPS gene, showed epithelium- and advanced-stage-specific high expression, which was significantly associated with poor prognosis, genomic instability, and immune escape. Collectively, our study identifies the CPS and CSS as clinically reliable ECPSs, providing valuable biomarkers for clinical application to LUAD.

Bone metastasis is often treated clinically as a late complication of advanced cancer, yet accumulating evidence indicates that it is also a spatial evolutionary process shaped by clonal selection, niche adaptation, dormancy, and reseeding. This review examines BoM through a phylogeographic framework that links tumor ancestry with anatomical location and time. We discuss how heterogeneous primary tumors generate bone-tropic subclones, how circulating tumor cells pass through dissemination bottlenecks, and how disseminated tumor cells enter perivascular and endosteal niches that either maintain dormancy or support early micrometastatic outgrowth. We then compare clonal architectures across breast, prostate, lung, and renal cell carcinomas, emphasizing both lineage-specific programs and convergent bone-adaptive states, including osteomimicry, immune evasion, metabolic plasticity, and epigenetic remodeling. Methodological platforms such as multiregion sequencing, single-cell and spatial transcriptomics, lineage tracing, and liquid biopsy are evaluated with attention to the technical limitations imposed by mineralized tissue. Finally, we consider how bone lesions may function as reservoirs for secondary dissemination and how evolutionary thinking could improve biomarker development, dormancy prediction, trial design, and therapy selection. Viewing BoM as an evolving ecosystem may help shift the field from reactive skeletal management toward earlier, biology-informed intervention.

Estrogen receptor (ER)-positive breast cancer (BrCa) accounts for two-thirds of all BrCa cases worldwide. Therefore, ER-targeted endocrine therapy is the standard treatment for this disease. There has been a recent trend towards developing combination therapies using molecularly targeted drugs to improve outcomes. This study aimed to identify therapeutic targets demonstrating efficacy when combined with fulvestrant (a selective ER downregulator/degrader). We generated microRNA (miRNA) signatures from fulvestrant-treated MCF-7 cells by RNA sequencing. From the signature, we evaluated miR-374b-5p because its expression was elevated by fulvestrant treatment in MCF-7 cells. Also, in expression analysis by subtype of BrCa patients, miR-374b-5p expression was suppressed only in luminal BrCa. Ectopic expression assays revealed that miR-374b-5p attenuated the malignant phenotypes of MCF-7 cells. We searched for genes regulated by miR-374b-5p and discovered that 11 (NEK2, NUF2, HMMR, DEPDC1B, FOXM1, ELOVL6, KIF20A, NCAPH, CENPK, FAM83D, and KIAA0101) are closely involved in BrCa molecular pathogenesis. Among these target genes, we focused on forkhead box M1 (FOXM1), a transcription factor regulating cell cycle progression and division. Notably, combination therapy with fulvestrant and a FOXM1 inhibitor significantly suppressed MCF-7 cell proliferation. From the miRNA signature established in this study, we identified antitumor miR-374b-5p and its target genes and used these findings to explore candidate drugs with potential efficacy when combined with fulvestrant.

Small cell carcinoma of the cervix (SCCC) is a rare yet highly aggressive subtype of cervical cancer (CC), characterized by early invasion, high metastatic potential, frequent recurrence, and extremely poor prognosis, which severely impairs women's physical and mental health. Currently, high-risk human papillomavirus (hr-HPV, particularly HPV18) infection is recognized as one of the core drivers underlying the initiation and progression of SCCC. Malignant evolution is not triggered by a single infection event but is cooperatively regulated at multiple molecular levels, including HPV genome integration, critical gene mutations, and aberrant activation of multiple signaling pathways. In addition, SCCC exhibits an HPV-independent oncogenic pathway mainly mediated by somatic mutations in tumor protein 53 (TP53) and retinoblastoma 1 (RB1), thus forming a dual pathogenic mechanism. Based on current clinical understanding and molecular mechanisms, this paper reviews the molecular pathogenesis and subtypes of SCCC, reveals the associations between tumor heterogeneity, therapeutic resistance, and metastasis, and proposes potential novel targets for the treatment of SCCC. This study innovatively presents a closed-loop model of two-way empowerment between basic research and clinical application. It emphasizes that basic research should be oriented toward real clinical problems and highlights the reciprocal feedback of clinical practice on basic research, thereby achieving dynamic iteration and collaborative breakthroughs in both fields.

Liquid-liquid phase separation (LLPS) has attracted considerable attention in cell biology as a potentially widespread organizing principle in the cellular environment. LLPS involving proteins and nucleic acids participates in a wide range of cellular processes, including regulation of genome activity, modulation of enzymatic activity, and control of subcellular compartmentalization. Emerging evidence supports the idea that aberrant LLPS behavior is associated with various diseases, including cancer and infectious diseases. These findings suggest that LLPS provides a new framework for understanding complex regulatory phenomena in cells. In this review, we provide a comprehensive overview of LLPS, focusing on the biophysical mechanisms underlying condensate formation, the molecular composition of biomolecular condensates, and current experimental approaches used to study this process. In particular, we highlight the role of LLPS in aberrant transcriptional regulation, with a specific focus on its regulatory functions and underlying molecular mechanisms in tumor cells. Collectively, this review provides an updated perspective on the functional and mechanistic roles of LLPS in physiological and pathological contexts, particularly in tumor biology.

Colorectal cancer (CRC) remains a major cause of cancer mortality worldwide, highlighting the need for novel molecular targets and alternative therapeutic strategies. TYRO3, a member of the TAM receptor tyrosine kinase family, has been associated with tumor progression and poor prognosis in CRC. In this study, the effects of the natural compounds Meleagrin and Cucurbitacin B on TYRO3 expression and CRC cell behavior were investigated in HCT-116 and HT-29 cells. Cell proliferation, apoptosis, migration, and TYRO3 expression were evaluated using functional and expression-based analyses. Both compounds modulated TYRO3 expression and suppressed proliferation and wound closure dynamics in CRC cells. Cucurbitacin B exerted more pronounced antiproliferative and pro-apoptotic effects, whereas Meleagrin demonstrated antiproliferative activity with comparatively lower effects on normal colon epithelial cells (CCD 841 CoN), suggesting a potentially more favorable selectivity profile. Collectively, these findings support further mechanistic investigation of TYRO3-modulating natural compounds as potential therapeutic candidates for CRC.