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Epithelial–mesenchymal transition (EMT) is an essential process in normal embryonic development and tissue regeneration. However, aberrant reactivation of EMT is associated with malignant properties of tumor cells during cancer progression and metastasis, including promoted migration and invasiveness, increased tumor stemness, and enhanced resistance to chemotherapy and immunotherapy. EMT is tightly regulated by a complex network which is orchestrated with several intrinsic and extrinsic factors, including multiple transcription factors, post-translational control, epigenetic modifications, and noncoding RNA-mediated regulation. In this review, we described the molecular mechanisms, signaling pathways, and the stages of tumorigenesis involved in the EMT process and discussed the dynamic non-binary process of EMT and its role in tumor metastasis. Finally, we summarized the challenges of chemotherapy and immunotherapy in EMT and proposed strategies for tumor therapy targeting EMT.

T-box transcription factor 20 (TBX20) serves a crucial regulatory role in the process of tumor occurrence. In lung cancer, the upregulation of TBX20 expression is positively associated with a poor prognosis; however, the specific underlying mechanism remains unclear. Therefore, in the present study, the expression of TBX20 in normal lung epithelial BEAS-2B and cancer cells A549 was detected by quantitative PCR and western blot. Lung cancer cell lines with overexpression and interference of TBX20 were constructed. Cell proliferation was detected by Cell Counting Kit-8, cell migration and invasion were detected by Transwell, and cell spheroid formation was assessed. The expression of EMT markers (E-cadherin, N-cadherin, vimentin), stemness markers (CD44, Sox2, Nanog), and immune factors (PD-L1, IL-6, CCL2) was detected by qPCR and WB. A subcutaneous lung cancer model in nude mice was established. After 4 weeks, the tumor volume was observed. The expression of E-cadherin, N-cadherin, vimentin, CD44, and PD-L1 in tumor tissues was detected by IHC. The infiltration of immune cells (CD8+T, CD4+T, M1/M2 macrophages) was detected by flow cytometry. In vitro experiments revealed that the expression levels of TBX20 were increased in the A549 lung cancer cells compared with those in BEAS-2B normal lung epithelial cells. In addition, cell viability, migration, invasion and spheroid formation capacity were greater in the A549 group than in the BEAS-2B group. Compared with in the negative control (NC) group, the TBX20 overexpression plasmid (oe-TBX20) group exhibited enhanced cell viability, migration, invasion and spheroid formation capacity. Furthermore, E-cadherin expression was reduced, whereas N-cadherin, vimentin, Sox2, CD44, Nanog, PD-L1, IL-6 and CCL2 expression levels were elevated. Notably, these changes were reversed in the TBX20 knockdown group. In vivo experiments revealed that compared with in the NC group, the oe-TBX20 group had significantly increased tumor volume, decreased E-cadherin levels, and elevated expression levels of TBX20, N-cadherin, vimentin, CD44 and PD-L1. Compared with NC group, the oe-TBX20 group exhibited significantly lower infiltration of CD4+ T and CD8+ T cells and M1-type macrophage, whereas that of M2-type macrophages and regulatory T cells increased. Conversely, these indicators were reversed in the short hairpin RNA-TBX20 group. In conclusion, TBX20 may induce epithelial-mesenchymal transition and stem cell characteristics, enhance the malignant behavior of lung cancer cells, and upregulate PD-L1 expression to promote immune escape.

Wilms tumor (WT) is the most common pediatric kidney cancer, which presents significant therapeutic challenges, particularly in high-risk cases, due to chemotherapy resistance and immunosuppressive tumor microenvironments (TMEs). Tumor stemness and immune evasion mechanisms are implicated in poor clinical outcomes, yet the molecular drivers underpinning these processes remain inadequately understood. We employed an integrative approach combining single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, bulk RNA-seq, and advanced machine learning techniques to uncover molecular regulators of tumor behavior in WT. A novel Cancer Stemness Prognostic Index (CSPI) was developed using machine learning algorithms to stratify WT patients by risk and histological subtype. Additionally, molecular docking simulations and in vitro functional assays were performed to validate the role of key regulators in tumor stemness and immune evasion, as well as to explore potential therapeutic strategies targeting these molecular drivers. Renin gene (REN) emerged as a central regulator of tumor stemness and immune evasion in WT. High-CSPI tumors exhibited enhanced tumor stemness phenotypes, metabolic reprogramming (ROS/oxidative phosphorylation), and suppressed immune activity. Spatial transcriptomics revealed distinct histological subtype-specific localization of stemness-related gene expression and physical proximity between REN-expressing tumor cells and natural killer (NK) cells. At spatial and single-cell resolution, REN-expressing tumor cells promoted NK cell exhaustion via PTN-NCL and COL4A1-CD44 ligand-receptor interactions, while showing limited impact on T cell dysfunction. Molecular docking identified estrogen-based compounds as potential REN inhibitors. Functional assays validated REN knockdown as significantly impairing tumor proliferation, migration, and survival . This study establishes REN as a pivotal driver of tumor stemness and immune evasion in WT, playing a dual role in promoting tumor aggressiveness and suppressing NK-mediated immune surveillance. Targeting REN offers promising therapeutic opportunities for high-risk WT cases by simultaneously inhibiting tumor progression and restoring immune function. These findings emphasize REN's potential as a transformative target for precision oncology and underscore the value of integrative transcriptomics in advancing personalized cancer treatment strategies.

Glioblastoma (GBM), the most malignant primary brain tumor in adults, has poor prognosis irrespective of therapeutic advances due to its radio-resistance and infiltrative growth into brain tissue. The present study assessed functions and putative druggability of BRCA1-associated ATM activator 1 (BRAT1) as a crucial factor driving key aspects of GBM, including enhanced DNA damage response and tumor migration. By a stable depletion of BRAT1 in GBM and glioma stem-like (GSC) cell lines, we observed a delay in DNA double-strand break repair and increased sensitivity to radiation treatment, corroborated by in vitro and in vivo studies demonstrating impaired tumor growth and invasion. Proteomic and phosphoproteomic analyses further emphasize the role of BRAT1’s cell migration and invasion capacity, with a notable proportion of downregulated proteins associated with these processes. In line with the genetic manipulation, we found that treatment with the BRAT1 inhibitor Curcusone D (CurD) significantly reduced GSC migration and invasion in an ex vivo slice culture model, particularly when combined with irradiation, resulting in a synergistic inhibition of tumor growth and infiltration. Our results reveal that BRAT1 contributes to GBM growth and invasion and suggest that therapeutic inhibition of BRAT1 with CurD or similar compounds might constitute a novel approach for anti-GBM directed treatments.

Background Development of distant metastases involves a complex multistep biological process termed the invasion-metastasis cascade , which includes dissemination of cancer cells from the primary tumor to secondary organs. NOTCH developmental signaling plays a critical role in promoting epithelial-to-mesenchymal transition, tumor stemness, and metastasis. Although all four NOTCH receptors show oncogenic properties, the unique role of each of these receptors in the sequential stepwise events that typify the invasion-metastasis cascade remains elusive. Methods We have established metastatic xenografts expressing high endogenous levels of NOTCH3 using estrogen receptor alpha-positive (ERα + ) MCF-7 breast cancer cells with constitutive active Raf-1/mitogen-associated protein kinase (MAPK) signaling (vMCF-7 Raf-1 ) and MDA-MB-231 triple-negative breast cancer (TNBC) cells. The critical role of NOTCH3 in inducing an invasive phenotype and poor outcome was corroborated in unique TNBC cells resulting from a patient-derived brain metastasis (TNBC-M25) and in publicly available claudin-low breast tumor specimens collected from participants in the Molecular Taxonomy of Breast Cancer International Consortium database. Results In this study, we identified an association between NOTCH3 expression and development of metastases in ERα + and TNBC models. ERα + breast tumor xenografts with a constitutive active Raf-1/MAPK signaling developed spontaneous lung metastases through the clonal expansion of cancer cells expressing a NOTCH3 reprogramming network. Abrogation of NOTCH3 expression significantly reduced the self-renewal and invasive capacity of ex vivo breast cancer cells, restoring a luminal CD44 low /CD24 high /ERα high phenotype. Forced expression of the mitotic Aurora kinase A (AURKA), which promotes breast cancer metastases, failed to restore the invasive capacity of NOTCH3-null cells, demonstrating that NOTCH3 expression is required for an invasive phenotype. Likewise, pharmacologic inhibition of NOTCH signaling also impaired TNBC cell seeding and metastatic growth. Significantly, the role of aberrant NOTCH3 expression in promoting tumor self-renewal, invasiveness, and poor outcome was corroborated in unique TNBC cells from a patient-derived brain metastasis and in publicly available claudin-low breast tumor specimens. Conclusions These findings demonstrate the key role of NOTCH3 oncogenic signaling in the genesis of breast cancer metastasis and provide a compelling preclinical rationale for the design of novel therapeutic strategies that will selectively target NOTCH3 to halt metastatic seeding and to improve the clinical outcomes of patients with breast cancer.

High mobility group box 3 (HMGB3) acts as an essential participator in fundamental biological processes, including transcriptional regulation, chromatin remodeling and DNA repair. HMGB3 is highly expressed and functionally essential during embryonic development, particularly in the hematopoietic and nervous systems, but it is significantly downregulated or silenced in most normal adult tissues. Its aberrant upregulation has been revealed in numerous human malignancies, such as leukemia, as well as breast, bladder, colorectal and gastric cancer, and its expression levels have been established to be closely associated with poor prognosis of specific patients. Accordingly, the present review systematically explores the central roles of HMGB3 in mediating resistance to cancer therapy. This review focuses on its multifaceted mechanisms of maintaining cancer stemness, enhancing DNA damage repair, modulating cell death pathways and remodeling the tumor microenvironment, thereby contributing to the resistance to chemotherapy, radiotherapy, targeted therapy and immunotherapy collectively. HMGB3 can be accepted as a key target in the development of highly promising therapeutic strategies, given its pivotal involvement in multidrug resistance, which may offer novel avenues for overcoming clinical treatment resistance and improving patient outcomes.

Chemotherapy resistance is a barrier to effective cancer prognoses. Cisplatin (CDDP) resistance is a major challenge for esophageal cancer (EC) therapy. A deeper understanding of the fundamental mechanisms of cisplatin resistance and improved targeting strategies are required in clinical settings. This study was performed to identify and characterize a marker of cisplatin resistance in EC cells. KYSE140 and Eca-109 cells were subjected to escalating concentrations of cisplatin, resulting in the development of cisplatin-resistant KYSE140/CDDP and Eca-109/CDDP cell lines, respectively. RNA Sequencing (RNA-seq) was utilized to screen for the genes exhibiting differential expression between cisplatin-resistant and parental cells. Reverse transcription quantitative PCR was conducted to assess gene expression, and western blotting was employed to analyze protein levels. A sphere-formation assay was performed to validate tumor cell stemness. Cell counting kit-8 (CCK-8) experiments were conducted to confirm the sensitivity of cells to cisplatin. We examined the relationship between target genes and the clinicopathological features of patients with EC. Furthermore, the expression of target genes in EC tissues was evaluated via western blotting and fluorescence probe hybridization (FISH). KYNU was upregulated in cisplatin-resistant EC cells (KYSE140/CDDP and Eca-109/CDDP cells) and in EC tissues compared to that in the respective parental cell lines (KYSE140 and Eca-109 cells) and non-carcinoma tissues. Downregulation of KYNU increased cell sensitivity to cisplatin and suppressed tumor stemness, whereas abnormal KYNU expression had the opposite effect. KYNU expression was correlated with the expression of tumor stemness-associated factors (SOX2, Nanog, and OCT4) and the tumor size. KYNU may promote drug resistance in EC by regulating cancer stemness, and could serve as a biomarker and therapeutic target for EC.

Background: Hepatocellular carcinoma (HCC) harbors a dynamic tumor microenvironment (TME) in which macrophages are highly abundant and plastic. Under physiological conditions, macrophages switch between inflammatory and resolution/tissue-repair programs to maintain homeostasis; however, during hepatocarcinogenesis these programs are reprogrammed into tumor-associated macrophage (TAM) states that foster immune suppression, angiogenesis, and tumor progression. Purpose: To summarize macrophage heterogeneity and polarization mechanisms in HCC, and to highlight omics-informed therapeutic opportunities for targeting TAMs and improving precision immunotherapy. Research Design: This review summarizes physiological macrophage polarization and the mechanistic basis of macrophage reprogramming in the hepatocellular carcinoma immune microenvironment, integrating evidence from recent advances in single-cell sequencing, multi-omics, and spatial transcriptomics, with a focus on macrophage subset diversity, key regulatory pathways governing polarization and function, and emerging macrophage-targeted interventions and biomarkers. Results: Recent single-cell and spatial multi-omics studies reveal substantial TAM heterogeneity and plasticity in HCC. Macrophage-targeted strategies—including TAM depletion, phenotypic reprogramming, and exosome-mediated drug delivery—show encouraging preclinical efficacy. Macrophage-associated prognostic models and biomarkers may support individualized immunotherapeutic approaches. Conclusions: Macrophage polarization in HCC represents a dynamic continuum that is essential for homeostasis but is co-opted by tumors to drive immunosuppression and tissue remodeling. Advances in single-cell and spatial multi-omics are redefining TAM subsets and actionable pathways, enabling more rational macrophage-targeted therapies. However, challenges remain in standardizing TAM definitions, identifying robust predictive biomarkers, minimizing off-target effects, and optimizing combinations with immunotherapy. Integrating longitudinal multi-omics with AI-based modeling may help predict macrophage state transitions, guide patient-specific regimens, and advance precision medicine in HCC. Plain language summary Hepatocellular carcinoma is a highly aggressive cancer. Studies have found that immune cells within tumors—particularly macrophages—play a crucial role in cancer development and therapeutic response. Macrophages have two main “personalities”: the M1 type, which can kill cancer cells, and the M2 type, which supports cancer growth. They shift between these states in response to signals from the tumor microenvironment. Both liver-resident Kupffer cells and infiltrating macrophages are involved in this process. Various molecules, such as cytokines, enzymes, and exosomes, influence their polarization. This polarized state of macrophages, in turn, affects key tumor processes such as stemness, proliferation, metastasis, and angiogenesis. In recent years, scientists have been exploring drugs that specifically target macrophage polarization to suppress liver cancer, offering new directions for future therapy. Graphical Abstract

Triple-negative breast cancer (TNBC) is an aggressive disease with a poor prognosis and lack of effective treatment. In this study, TNBCs were analyzed from the perspective of tumor stemness based on scRNA-seq data. The analysis showed that tumor cells of TNBC were divided into 4 subtypes, with subtype 2 having the highest stemness score. A prognostic model of 7 tumor stemness-related genes (AP2S1, CHML, FABP7, FADS2, PAXX, SDC1 and TOP2A) was developed based on marker genes of this subtype and TCGA data, and the predictive power of this feature was well validated in different clinical subgroups. TNBC patients in the low TS group had a better prognosis. In addition, drug sensitivity analysis showed that patients in the high TS (tumor stemness) score group were more sensitive to PD-L1 inhibitors and the chemotherapeutic agents. In conclusion, our study developed a prognostic model based on TNBC tumor stemness cell marker genes, which has a good ability to predict the prognosis of TNBC patients and the effect of response to drug therapy.

Tumor stemness represents a key biological process that drives tumor progression and therapeutic resistance across various cancer types. To systematically elucidate the regulatory roles of long non-coding RNAs (lncRNAs) in this process, we integrated bulk transcriptomic data from The Cancer Genome Atlas (TCGA) with publicly available pan-cancer single-cell transcriptomic atlases. Using machine-learning-based stemness metrics, we successfully quantified stemness features and identified unique lncRNA gene sets for each cancer type at the bulk data level. The high-stemness subtype exhibited enhanced proliferation, an immunosuppressive microenvironment, and profound metabolic reprogramming. Based on these findings, we constructed a robust prognostic model with remarkable predictive performance across multiple cancer types. At the single-cell resolution, we reconstructed the dynamic trajectory of stemness evolution, uncovering distinctive metabolic and cell-communication patterns within cancer stem cells (CSCs). This multi-scale analysis consistently nominated a core set of regulatory lncRNAs, including NEAT1 and MALAT1. Our work not only nominates potential targets for stemness-directed therapy but also provides a comprehensive framework for understanding lncRNA-driven mechanisms of cancer aggressiveness and resistance.