Epithelial-to-mesenchymal transition (EMT) is a crucial cellular process for embryogenesis, wound healing, and cancer progression. It involves a shift in cell interactions, leading to the detachment of epithelial cells and activation of gene programs promoting a mesenchymal state. EMT plays a significant role in cancer metastasis triggering tumor initiation and stemness, and activates metastatic cascades resulting in resistance to therapy. Moreover, reversal of EMT contributes to the formation of metastatic lesions. Metastasis still needs to be better understood functionally in its major but complex steps of migration, invasion, intravasation, dissemination, which contributes to the establishment of minimal residual disease (MRD), extravasation, and successful seeding and growth of metastatic lesions at microenvironmentally heterogeneous sites. Therefore, the current review article intends to present, and discuss comprehensively, the status quo of experimental models able to investigate EMT and metastasis in vitro and in vivo, for researchers planning to enter the field. We emphasize various methods to understand EMT function and the major steps of metastasis, including diverse migration, invasion and matrix degradation assays, microfluidics, 3D co-culture models, spheroids, organoids, or latest spatial and imaging methods to analyze complex compartments. In vivo models such as the chorionallantoic membrane (CAM) assay, cell line-derived and patient-derived xenografts, syngeneic, genetically modified, and humanized mice, are presented as a promising arsenal of tools to analyze intravasation, site specific metastasis, and treatment response. Furthermore, we give a brief overview on methods detecting dissemination and MRD in carcinomas, highlighting its significance in tracking the course of disease and response to treatment. Enhanced lineage tracking tools, dynamic in vivo imaging, and therapeutically useful in vivo models as powerful preclinical tools may still better reveal functional interdependencies between metastasis and EMT. Future directions are discussed in light of emerging views on the biology, diagnosis, and treatment of EMT and metastasis.

Epithelial-mesenchymal transition (EMT) has been extensively studied for its roles in tumor metastasis, the generation and maintenance of cancer stem cells and treatment resistance. Epithelial mesenchymal plasticity allows cells to switch between various states within the epithelial-mesenchymal spectrum, resulting in a mixed epithelial/mesenchymal phenotypic profile. This plasticity underlies the acquisition of multiple malignant features during cancer progression and poses challenges for EMT in tumors. MicroRNAs (miRNAs) in the microenvironment affect numerous signaling processes through diverse mechanisms, influencing physiological activities. This paper reviews recent advances in EMT, the role of different hybrid states in tumor progression, and the important role of miRNAs in EMT. Furthermore, it explores the relationship between miRNA-based EMT therapies and their implications for clinical practice, discussing how ongoing developments may enhance therapeutic outcomes.

Oral squamous cell carcinoma (OSCC) is the most prevalent malignancy of the oral cavity and is characterized by a high propensity for invasion and a poor prognosis. Recent studies have highlighted the critical roles of cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) in tumor progression, particularly within the tumor microenvironment (TME).

This study aimed to investigate the correlation between CAFs, TAMs, and tumor budding in tongue squamous cell carcinoma (TSCC), and evaluate their impact on prognostic factors.

A total of 88 cases of surgically resected TSCC were analyzed. Immunohistochemical staining was performed using markers of CAFs (fibroblast activation protein, FAP) and TAMs (CD163). The correlation between CAF and TAM scores, tumor budding, and various clinicopathological factors was assessed. TAM scores were evaluated for the number of TAMs in the intratumoral areas (TAM-t) and the invasive front (TAM-fr). CAF scores were evaluated for cancer cells in the intratumoral area (cCAF-t), stromal cells in the intratumoral area (sCAF-t), stromal cells in the invasive front (sCAF-fr), and the infiltration pattern of CAF (IPC).

The IPC score was significantly associated with the tumor budding scores (p < 0.001) and poor DFS (p < 0.01). In the multivariate analysis, cCAF-t, sCAF-t, and IPC scores emerged as independent prognostic factors (p < 0.05) for early-stage TSCC. CAFs may play a pivotal role in tumor invasion.

These findings indicate that CAFs significantly influence the invasive characteristics of TSCC and are correlated with tumor budding and a poor prognosis. These results underscore the potential of targeting CAFs as a therapeutic strategy for improving OSCC outcome.

Gastric cancer (GC) is one of the primary contributors to cancer-related mortality on a global scale. It holds a position within the top five most prevalent malignancies both in terms of occurrence and fatality rates. Immunotherapy, as a breakthrough cancer treatment, brings new hope for GC patients. Various biomarkers, such as the expression of programmed death ligand-1 (PD-L1), the microsatellite instability (MSI) status, tumor mutational burden (TMB), and Epstein-Barr virus (EBV) infection, demonstrate potential to predict the effectiveness of immunotherapy in treating GC. Nevertheless, each biomarker has its own limitations, which leads to a significant portion of patients continue to be unresponsive to immunotherapy. With the understanding of the tumor immune microenvironment (TIME), genome sequencing technology, and recent advances in molecular biology, new molecular markers, such as POLE/POLD1mutations, circulating tumor DNA, intestinal flora, lymphocyte activation gene 3 (LAG-3), and lipid metabolism have emerged. This review aims to consolidate clinical evidence to offer a thorough comprehension of the existing and emerging biomarkers. We discuss the mechanisms, prospects of application, and limitations of each biomarker. We anticipate that this review will open avenues for fresh perspectives in the investigation of GC immunotherapy biomarkers and promote the precise choice of treatment modalities for gastric cancer patients, thereby advancing precision immuno-oncology endeavors.

Leukemic cells modulate the bone marrow microenvironment to enhance their survival. Lipolysis in bone marrow adipose tissue (BMAT) has emerged as a critical factor supporting leukemic cell survival, yet understanding its primary role in leukemia development remains limited. Fanconi anemia (FA), characterized by a predisposition to acute myeloid leukemia (AML) and hypersensitivity to environmental toxins, is a transitional model for studying leukemic transformation. İntegrated multi-omics analyses were conducted on BMAT-derived mesenchymal stem/stromal cells (MSCs) from healthy donors (HD), AML, and FA patients. These analyses revealed intricate interactions among genes, metabolites, and lipids. Particularly noteworthy were the effects observed following the inhibition of aryl hydrocarbon receptor (AhR) signaling by StemRegenin1 (SR1). BMAT-MSCs showed increased expression of epithelial-mesenchymal transition (EMT) genes in FA and AML, suggesting a potential shift towards cancer-associated fibroblasts in the dysregulated marrow microenvironment. Identification of potential circadian rhythm biomarkers (NPAS2, PER2, BHLHE40, PER3, CIART) in BMAT-MSCs indicates a link between related lipid metabolism genes (e.g., PTGS1, PIK3R1) and SR1 treatment, implicating them in lipolysis processes. Dysregulation of circadian rhythm-related genes (CIART, BHLHE40, NPAS2) in AML BMAT-MSCs, along with changes in circulating lipid metabolites like palmitate suggests their role in shaping the leukemia microenvironment. Upregulation of FABP5 and CD36 suggests a novel molecular mechanism involving FABP5 in AhR-mediated circadian regulation and identifies CD36 as a potential partner for FABP5 in BMAT-MSCs. Overall, this study unveils the interplay between AhR signaling, circadian rhythm, and the leukemia microenvironment in BMAT-MSCs, offering new insights into leukemia pathogenesis and therapeutic opportunities.

Osteosarcoma (OS) is a primary bone malignancy characterized by early metastasis and generally poor prognosis. ESPN is highly expressed and plays an important role in regulating the aggressive phenotypes of several cancer cell types. However, little is known about the molecular mechanisms underlying ESPN-mediated migration and invasion in OS cells.

In this study, we first analyzed the survival of osteosarcoma patients using Kaplan-Meier analysis to assess the prognostic relevance of ESPN. To further evaluate its clinical significance, we performed immunohistochemical analysis on osteosarcoma tissue samples and benign osteochondroma (OC) tissues. The biological function of ESPN in osteosarcoma was confirmed by a series of experiments conducted both in vitro and in vivo. Additionally, we explored the underlying molecular mechanisms through Western blotting, co-immunoprecipitation, immunofluorescence, and PCR, revealing key downstream signaling pathways.

In this study, we demonstrate that ESPN, acting as an oncogene, is highly expressed in OS cell lines and tissues, promoting OS cell proliferation and metastasis. Mechanistically, ESPN promoted the phosphorylation of PI3K by direct interaction with it and active the AKT/mTOR pathway, which enhanced the expression of the transcription factor ZEB1 and initiating the epithelial-mesenchymal transition (EMT) cascade. Furthermore, we validated that mTOR-mediated activation of p70 ribosomal protein S6 kinase (p70S6K) promotes the translation of ZEB1, thereby enhancing the growth and motility of OS cells.

Our findings reveal a previously unrecognized function of ESPN in OS, closely linked with EMT and cancer metastasis progression. Targeting ESPN may represent a potential therapeutic approach for patients with OS.

Brain metastasis (BM) is a significant factor contributing to the poor prognosis of patients with non-small cell lung cancer (NSCLC). Secreted phosphoprotein 1 (SPP1) is implicated in the progression and metastasis of several cancers. The role of SPP1 in NSCLC remains unclear, especially in NSCLC BM. This study aimed to identify genes associated with NSCLC BM and to investigate the involvement of SPP1 in NSCLC BM. Integrated genomic analysis was utilized to identify candidate genes in NSCLC. The expression levels of SPP1 were evaluated in NSCLC tissues and cell lines. In vitro and in vivo experiments were conducted to assess the effect of SPP1 on NSCLC cell behavior and BM. The potential mechanisms of SPP1 were demonstrated by CO-IP and liquid chromatography-mass spectrometry (LC-MS). The underlying mechanism involving the PI3K/AKT/mTOR pathway was explored. The results showed that SPP1 expression was upregulated in NSCLC tissues and cell lines. Depletion of SPP1 using shRNA inhibited cell proliferation, migration, and invasion in vitro and suppressed BM in vivo. Mechanistically, SPP1 facilitates the ubiquitination of P85α by interacting with the ubiquitin ligase RNF114, thus playing a role in regulating NSCLC BM through the PI3K/AKT/mTOR signaling pathway. Moreover, immunohistochemistry staining confirmed higher expression of SPP1 in NSCLC tissues with BM compared to those without BM. In summary, elevated SPP1 expression was associated with poor clinical outcomes in NSCLC patients. This study highlights the role of SPP1 as a regulator of cell metastasis and suggests its potential as a novel therapeutic target for BM in NSCLC.

Glioma, as one of the most complex and prognostically variable malignant tumors of the central nervous system, poses a significant challenge to clinical decision-making due to its molecular heterogeneity. This study aims to deepen our understanding of glioma molecular subtypes and explore key gene markers with prognostic and diagnostic value. We utilized an angiogenesis-related gene set and employed the Non-negative Matrix Factorization (NMF) algorithm to successfully identify two distinct prognostic subtypes, with subtype one exhibiting more unfavorable prognostic characteristics. To further elucidate the biological functional differences between these two subtypes, we conducted Gene Ontology (GO) functional annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and Gene Set Enrichment Analysis (GSEA). Building on this, we integrated differentially expressed genes between subtypes with core genes revealed by Weighted Gene Co-expression Network Analysis (WGCNA) through intersection analysis to pinpoint a series of key candidate genes. Subsequently, we constructed a Protein-Protein Interaction (PPI) network to identify genes occupying central nodes within the network. To screen markers with high specificity and sensitivity for prognosis and diagnosis, we adopted a dual-track strategy: on the one hand, we utilized machine learning algorithms such as Lasso regression, Support Vector Machine (SVM), and Random Forest (RF) to select core genes, identifying markers that can accurately predict the subtype with a poor prognosis; on the other hand, we employed a comprehensive evaluation system incorporating 101 machine learning ensemble algorithms to further validate and screen prognosis-related genes. Through cross-validation using these two strategies, we ultimately determined SERPINH1 and CTSZ as dual prognostic and diagnostic markers for glioma. This study not only provides a new perspective and tool for the molecular subclassification of glioma but also, through a rigorous multi-algorithm, multi-dimensional screening process, uncovers SERPINH1 and CTSZ as markers with potential clinical translational value. These findings are expected to offer more precise biomarker support for the early diagnosis and prognostic assessment of glioma, potentially paving new avenues for the development of personalized treatment strategies and improving patient outcomes. This has far-reaching implications for the clinical management of glioma in the field of neurosurgery.

Epithelial-mesenchymal transition (EMT) is a process in which epithelial cells, defined by apical-basal polarity and tight intercellular junctions, acquire migratory and invasive properties characteristic of mesenchymal cells. Under normal conditions, EMT directs essential morphogenetic events in embryogenesis and supports tissue repair. When dysregulated, EMT contributes to pathological processes such as organ fibrosis, chronic inflammation, and cancer progression and metastasis. Matrix metalloproteinases (MMPs)-a family of zinc-dependent proteases that degrade structural components of the extracellular matrix-sit at the nexus of this transition by dismantling basement membranes, activating pro-EMT signaling pathways, and cleaving adhesion molecules. When normally regulated, MMPs promote balanced ECM turnover and support the cyclical remodeling necessary for proper development, wound healing, and tissue homeostasis. When abnormally regulated, MMPs drive excessive ECM turnover, thereby promoting EMT-related pathologies, including tumor progression and fibrotic disease. This review provides an integrated overview of the molecular mechanisms by which MMPs both initiate and sustain EMT under physiological and disease conditions. It discusses how MMPs can potentiate EMT through TGF-β and Wnt/β-catenin signaling, disrupt cell-cell junction proteins, and potentiate the action of hypoxia-inducible factors in the tumor microenvironment. It discusses how these pathologic processes remodel tissues during fibrosis, and fuel cancer cell invasion, metastasis, and resistance to therapy. Finally, the review explores emerging therapeutic strategies that selectively target MMPs and EMT, ranging from CRISPR/Cas-mediated interventions to engineered tissue inhibitors of metalloproteinases (TIMPs), and demonstrates how such approaches may suppress pathological EMT without compromising its indispensable roles in normal biology.

Background: Aggressive forms of breast cancer, such as triple-negative breast cancer (TNBC), are associated with an increase in cancer cells that exhibit stem cell properties. The activation of the epithelial-mesenchymal transition (EMT) program, mediated by the transcription factor FOXC2, generates these stem-like cells. FOXC2 is linked to poor prognoses across various cancer types and is notably upregulated in TNBC, where it establishes and sustains these stem-like cells within the tumor population. Methods: Here, we decode the pathways regulating FOXC2 activation using EMT-enriched cell line models. Stemness was assessed using mammosphere assays and mesenchymal markers by western blot. Expression correlations with clinical data was examined using the EMTome. Results: We demonstrate that β-catenin serves as a critical mediator of mesenchymal and stemness characteristics through FOXC2 upregulation. By disrupting β-catenin, we find that FOXC2 expression, mesenchymal properties, and stemness are reduced; however, the introduction of exogenous FOXC2 expression in β-catenin deficient cells is enough to restore the mesenchymal and stemness phenotype. These findings support the idea that FOXC2 acts as the downstream regulator of β-catenin and influences both mesenchymal and stemness properties. Moreover, there is a positive correlation between the expression of β-catenin and FOXC2 in various cancer subtypes observed in clinical patient samples. Conclusions: Our study clarifies the role of the β-catenin/FOXC2 signaling axis in maintaining stemness properties, suggesting potential targets for TNBC and other cancers driven by EMT-related mesenchymal and stemness characteristics.

Cisplatin (CDDP) based chemotherapy has emerged as the predominant therapeutic regimen for patients with advanced gastric cancer (GC). However, its efficacy is dampened by the development of chemoresistance, which results in poor prognosis of patients. GLI2, a key transcription factor in the Hedgehog (Hh) signaling pathway, is regarded as a target for cancer therapy. However, the significance of GLI2 for CDDP resistance in GC has not been well established. Here, we show that GLI2 expression was upregulated in EMT-type GC and associated with poor prognosis. GLI2 promotes proliferation, migration, and CDDP resistance of GC cells by inducing EMT. In terms of mechanism, GLI2 binds to the promoter region of DEC1 and enhances its expression, thereby co-transcriptionally regulating ZEB1 expression. Animal experiments have demonstrated that both GLI2 knockdown and GLI2 inhibitor significantly enhance CDDP sensitivity in GC. Our data not only identify a novel GLI2/DEC1/ZEB1/EMT pathway in GC CDDP resistance but also provide novel strategies to treat GC in the future.

Hepatocellular carcinoma (HCC) is a difficult cancer to manage due to its highly invasive and metastatic nature.

To investigate the molecular function of transmembrane channel-like 5 (TMC5) in vitro and in vivo, with the objective of identifying novel diagnosis and treatment targets for HCC.

The expression of TMC in cancer and normal tissues, along with its correlation with HCC prognosis, was analyzed using the GENT2, GEPIA database, and Human Protein Atlas. COX analysis was conducted to assess the relationship between TMC5 expression and overall survival in TCGA-LIHC patients. Further experiments were conducted to investigate the effect of TMC5 in cancer progression through loss- and gain-of-function assays in vitro and in vivo.

Bioinformatics revealed that TMC5 expression was generally higher in tumors than in normal tissues, and its expression was associated with poorer patient survival outcomes. TMC5 expression in HCC tissues and cells was consistent with the results of the bioinformatics analysis. Suppression of TMC5 expression reduced migration, invasion, and proliferation, while also decreasing the expression of epithelial-mesenchymal transition (EMT)-associated molecules in MHCC97-LM3 cells. Conversely, higher TMC5 expression significantly increased cell migration, invasion, proliferation, and EMT in MHCC97 L cells. TMC5 knockdown significantly decreased both the formation and spread of nodules in liver tissue, whereas TMC5 overexpression promoted them.

Our study provides compelling evidence that TMC5 is highly expressed in HCC and drives cancer progression through the activation of EMT-mediated invasion. TMC5 could represent a valuable molecular target for the diagnosis and treatment of HCC.

Cellular senescence, defined as a state of permanent arrest in cell growth, is regarded as a crucial tumor suppression mechanism. However, accumulating scientific evidence suggests that senescent cells play a detrimental role in the progression of cancer. Unfortunately, the current lack of reliable markers that specifically reflect the level of senescence in cancer greatly hinders our in-depth understanding of this important biological foundation. Therefore, the search for more specific and reliable markers to reveal the specific role of senescent cells in cancer progression is particularly urgent and important. To uncover the role of senescence in gliomas, we collected senescence-related genes for integrated analysis. Consensus clustering was used to subtype gliomas based on the senescence gene set, and we identified two robust prognostic clusters of gliomas with distinct survival outcomes, multi-omics landscapes, immune characteristics, and differential drug responses. Multiple external datasets were used to validate the stability of our subtypes. Various computational and experimental methods, including WGCNA (Weighted Gene Co-expression Network Analysis), ssGSEA (single-sample Gene Set Enrichment Analysis), and machine learning algorithms (lasso regression, support vector machines, random forests), were employed for analysis. We found that CEBPB and LMNA are associated with poor prognosis in gliomas and may mediate immunosuppression and tumor proliferation. Drug prediction indicated that dasatinib is a potential therapeutic agent. Our findings provide insights into the role of the senescence gene set in patient stratification and precision medicine.

Fructose-1,6-bisphosphatase 1 (FBP1) is the enzyme that limits the process of gluconeogenesis as it facilitates the hydrolysis of fructose-1,6-bisphosphate(F-1,6-BP) to produce fructose-6-phosphate(F6P) and inorganic phosphate. Gluconeogenesis is the production of glucose from small carbohydrate substrates. The gluconeogenic process is typically suppressed in cancer because it inhibits glycolysis. Apart from its involvement in cellular glucose metabolism, FBP1 also plays a role in gene transcription, mRNA translation and stability regulation, and the immune microenvironment of tumors. Because of its multifaceted functions, the mechanisms by which FBP1 is involved in tumor development are complex. Moreover, FBP1 deficiency is associated with radiation and chemotherapy resistance and poor prognosis in cancer patients. Restoration of FBP1 expression in cancer cells is expected to hold promise for cancer therapy. However, up to now few reviews have systematically summarized the important functional mechanisms of FBP1 in tumorigenesis and the small molecule compounds that restore FBP1 expression. Therefore, this article addresses the question "How does FBP1 contribute to cancer progression, and can targeting FBP1 be a potential therapeutic approach?" by summarizing the effects of FBP1 on cancer development and progression as well as its mediated drug resistance and the future clinical applications of potential small molecule modulators targeting FBP1.

Current prognostic and predictive biomarkers for lung adenocarcinoma (LUAD) predominantly rely on unimodal approaches, limiting their characterization ability. There is an urgent need for a comprehensive and accurate biomarker to guide individualized adjuvant therapy decisions.

In this retrospective study, data from patients with resectable LUAD (stage I-III) were collected from two hospitals and a publicly available dataset, forming a training dataset (n=223), a validation dataset (n=95), a testing dataset (n=449), and the non-small cell lung cancer (NSCLC) Radiogenomics dataset (n=59). Tumor and peritumor scores were constructed from preoperative CT radiomics features (shape/intensity/texture). An immune score was derived from the density of tumor-infiltrating lymphocytes (TILs) within the cancer epithelium and stroma on hematoxylin and eosin-stained whole-slide images. A clinical score was constructed based on clinicopathological risk factors. A Cox regression model was employed to integrate these scores, thereby constructing a multimodal nomogram to predict disease-free survival (DFS). The adjuvant chemotherapy benefit rate was subsequently calculated based on this nomogram.

The multimodal nomogram outperformed each of the unimodal scores in predicting DFS, with a C-index of 0.769 (vs 0.634-0.731) in the training dataset, 0.730 (vs 0.548-0.713) in the validation dataset, and 0.751 (vs 0.660-0.692) in the testing dataset. It was independently associated with DFS after adjusting for other clinicopathological risk factors (training dataset: HR=3.02, p<0.001; validation dataset: HR=2.33, p<0.001; testing dataset: HR=2.03, p=0.001). The adjuvant chemotherapy benefit rate effectively distinguished between patients benefiting from adjuvant chemotherapy and those from observation alone (interaction p<0.001). Furthermore, the high-/low-risk groups defined by the multimodal nomogram provided refined stratification of candidates for adjuvant chemotherapy identified by current guidelines (p<0.001). Gene set enrichment analyses using the NSCLC Radiogenomics dataset revealed associations between tumor/peritumor scores and pathways involved in epithelial-mesenchymal transition, angiogenesis, IL6-JAK-STAT3 signaling, and reactive oxidative species.

The multimodal nomogram, which incorporates tumor and peritumor morphology with anti-tumor immune response, provides superior prognostic accuracy compared with unimodal scores. Its defined adjuvant chemotherapy benefit rates can inform individualized adjuvant therapy decisions.

Despite the significant potential of short hairpin RNA (shRNA)-mediated gene therapy for various diseases, the clinical success of cancer treatment remains poor, partly because of low selectivity and low efficiency. In this study, an mRNA-initiated autonomous multi-shRNA nanofactory (RNF@CM) is designed for in vivo amplification imaging and precise cancer treatment. The RNF@CM consists of a gold nanoparticle core, an interlayer of two types of three-stranded DNA/RNA hybrid probes, one of which is bound to aptamer-inhibited DNA polymerases, and an outer layer of the cancer cell membrane. After the specific delivery of RNF@CM into target cancer cells, an intracellular tumour-related mRNA target can initiate the RNF@CM with a circular strand-displacement polymerisation reaction, resulting in the release of significantly amplified fluorescence and continuous production of three types of shRNAs. The RNF@CM effectively distinguished cancer cells from normal cells, exclusively produced multiple shRNAs in response to a specific mRNA target in cancer cells, accurately diagnosed tumours in vivo, and significantly inhibited tumour growth with negligible toxicity, expanding the toolbox for on-demand gene delivery and precision theranostics.

Among patients with colorectal cancer (CRC), metastasis accounts for the majority of deaths, and epithelial-mesenchymal transition (EMT) is important in the metastatic process. However, the mechanism underlying the correlation between the two in CRC is unknown. Here, we verified that a receptor-independent protein, G-protein signaling modulator 1 (GPSM1), was increased in CRC and had a significant positive correlation with matrix metalloproteinase 19 (MMP19). GPSM1 and MMP19 knockdown or overexpression decreased and increased proliferation, migration and invasion of CRC cells, respectively. In addition, overexpression or knockdown of GPSM1 and MMP19 upregulated and inhibited EMT, respectively. Interfering with MMP19 reversed EMT activation via GPSM1 overexpression. Apoptosis was induced by GPSM1 and MMP19 knockdown and activated the caspase3/Bcl-2/Bax signaling pathway. In conclusion, these results support the role of GPSM1 and MMP19 in CRC progression.

Brain metastases (BMs) are the most common intracranial tumors in adults and the major cause of cancer-related morbidity and mortality. The occurrence of BMs varies according to the type of primary tumors with most frequence in lung cancer, melanoma and breast cancer. Among of them, lung cancer has been reported to have a higher risk of BMs than other types of cancers with 40 ~ 50% of such patients will develop BMs during the course of disease. BMs lead to many neurological complications and result in a poor quality of life and short life span. Although the treatment strategies were improved for brain tumors in the past decades, the prognosis of BMs patients is grim. Poorly understanding of the molecular and cellular characteristics of BMs and the complicated interaction with brain microenvironment are the major reasons for the dismal prognosis of BM patients. Recent studies have enhanced understanding of the mechanisms of BMs. The newly identified potential therapeutic targets and the advanced therapeutic strategies have brought light for a better cure of BMs. In this review, we summarized the mechanisms of BMs during the metastatic course, the molecular and cellular landscapes of BMs, and the advances of novel drug delivery systems for overcoming the obstruction of blood-brain barrier (BBB). We further discussed the challenges of the emerging therapeutic strategies, such as synergistic approach of combining targeted therapy with immunotherapy, which will provide vital clues for realizing the precise and personalized medicine for BM patients in the future.

Colorectal cancer (CRC) is a major cause of cancer-related mortality worldwide, with a significant impact on public health. Current treatment options include surgery, chemotherapy, radiotherapy, molecular-targeted therapy, and immunotherapy. Despite advancements in these therapeutic modalities, resistance remains a significant challenge, often leading to treatment failure, poor progression-free survival, and cancer recurrence. Mechanisms of resistance in CRC are multifaceted, involving genetic mutations, epigenetic alterations, tumor heterogeneity, and the tumor microenvironment. Understanding these mechanisms at the molecular level is crucial for identifying novel therapeutic targets and developing strategies to overcome resistance. This review provides an overview of the diverse mechanisms driving drug resistance in sporadic CRC and discusses strategies currently under investigation to counteract this resistance. Several promising strategies are being explored, including targeting drug transport, key signaling pathways, DNA damage response, cell death pathways, epigenetic modifications, cancer stem cells, and the tumor microenvironment. The integration of emerging therapeutic approaches that target resistance mechanisms aims to enhance the efficacy of current CRC treatments and improve patient outcomes.

The involvement of nerves in the development of breast cancer has emerged as a significant factor. Interaction between the nervous system and breast cancer can influence tumor initiation, growth, invasion, metastasis, reverse resistance to drugs, promote inflammation in tumors, and impair the immune system's ability to combat cancer. This review examined the intricate relationship linking the nervous system with breast cancer, emphasizing both central and peripheral aspects of the nervous system. Moreover, we reviewed neural cell factors and their impact on breast cancer progression, alongside the interactions between nerves and immunology, microbiota in breast cancer. Furthermore, the study discussed the potential of nerves as biomarkers for diagnosing and prognosticating breast cancer, and evaluated prospects for improving chemotherapy and immunotherapy therapeutic outcomes in breast cancer treatment. We hope to provide a deeper understanding of the neurobiological underpinnings of breast cancer and pave the way for the discovery of innovative therapeutic targets and prognostic markers.

Delving into cancer dormancy has been an inherent task that may drive the lethal recurrence of cancer after primary tumor relief. Cells in quiescence can survive for a short or long term in silence, may undergo genetic or epigenetic changes, and can initiate relapse through certain contextual cues. The state of dormancy can be induced by multiple conditions including cancer drug treatment, in turn, undergoes a life cycle that generally occurs through dissemination, invasion, intravasation, circulation, immune evasion, extravasation, and colonization. Throughout this cascade, a cellular machinery governs the fate of individual cells, largely affected by gene regulation. Despite its significance, a precise view of cancer dormancy is yet hampered. Revolutionizing advanced single cell and long read sequencing through analysis methodologies and artificial intelligence, the most recent stage in the research tool progress, is expected to provide a holistic view of the diverse aspects of cancer dormancy.

The aim of this study was to explore the functional role of LAMP3-mediated epithelial-mesenchymal transition (EMT) in fibroblast-like synoviocytes (FLSs) in rheumatoid arthritis (RA) patients and to evaluate its potential as a therapeutic target.

Changes in EMT and LAMP3 were investigated in the synovial tissue and FLSs of RA patients. In vitro experiments were performed using the EMT inhibitor C19, siRNA, and lentivirus to examine the impact of EMT and LAMP3 on RA-FLSs and the underlying mechanisms involved. Finally, C19 was administered to mice with collagen-induced arthritis (CIA) to validate the therapeutic efficacy of C19 in treating arthritis.

Compared with patients with osteoarthritis (OA), RA patients exhibited increased EMT and increased expression of LAMP3 in the synovium. The results from the in vitro experiments demonstrated that inhibiting EMT effectively reduced the excessive proliferation, anti-senescent properties, migration, and invasive behavior of RA-FLSs, as well as the secretion of MMP1, MMP3, and MMP13. Additionally, regulating the expression of LAMP3 not only affected the EMT pathway but also impacted the excessive proliferation and invasive behavior of RA-FLSs. In the CIA model, administration of the EMT inhibitor C19 significantly alleviated the progression of arthritis.

These findings demonstrate the inhibitory impact of EMT on arthritis and suggest that inhibiting EMT or LAMP3 may be a promising novel therapeutic approach for treating RA.

We have previously shown that general deletion of the gene encoding the p53-inducible Mir34a microRNA enhances the number and invasion of colitis-associated colorectal cancers (CACs) in mice. Since the p53-pathway has been implicated in tumor-suppression mediated by cells in the tumor microenvironment (TME) we deleted Mir34a in myeloid cells and characterized CACs in these with scRNA-Seq (single cell RNA sequencing). This revealed an increase in specific macrophage subtypes, such as Cdk8+ macrophages and Mrc1+, M2-like macrophages. The latter displayed elevated expression of 21 known Mir34a target mRNAs, including Csf1r, Axl, Foxp1, Ccr1, Nampt, and Tgfbr2, and 32 predicted Mir34a target mRNAs. Furthermore, Mir34a-deficient BMDMs showed enhanced migration, elevated expression of Csf1r and a shift towards M2-like polarization when compared to Mir34a-proficient BMDMs. Concomitant deletion of Csf1r or treatment with a Csf1r inhibitor reduced the CAC burden and invasion in these mice. Notably, loss of myeloid Mir34a function resulted in a prominent, inflammatory CAC cell subtype, which displayed epithelial and macrophage markers. These cells displayed high levels of the EMT transcription factor Zeb2 and may therefore enhance the invasiveness of CACs. Taken together, our results provide in vivo evidence for a tumor suppressive role of myeloid Mir34a in CACs which is, at least in part, mediated by maintaining macrophages in an M1-like state via repression of Mir34a targets, such as Csf1r. Collectively, these findings may serve to identify new therapeutic targets and approaches for treatment of CAC.

The cadherin superfamily of proteins is critical for cell-cell interactions and demonstrates tissue-specific expression profiles. In cancers, disruption of cell-cell adhesion is frequently associated with oncogenesis and metastasis. As such, these proteins have been the targets of multiple attempts to develop novel therapeutics in malignancy. This review article discusses prior and current clinical trials targeting the cadherin proteins.

Non-small-cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide, with epidermal growth factor receptor (EGFR) mutations present in a substantial proportion of patients. Third-generation EGFR tyrosine kinase inhibitors (EGFR TKI), exemplified by osimertinib, have dramatically improved outcomes by effectively targeting the T790M mutation-a primary driver of acquired resistance to earlier-generation EGFR TKI. Despite these successes, resistance to third-generation EGFR TKIs inevitably emerges. Mechanisms include on-target mutations such as C797S, activation of alternative pathways like MET amplification, histologic transformations, and intricate tumor microenvironment (TME) alterations. These resistance pathways are compounded by challenges in tolerability, adverse events, and tumor heterogeneity. In light of these hurdles, this review examines the evolving landscape of combination therapies designed to enhance or prolong the effectiveness of third-generation EGFR TKIs. We explore key strategies that pair osimertinib with radiotherapy, anti-angiogenic agents, immune checkpoint inhibitors, and other molecularly targeted drugs, and we discuss the biological rationale, preclinical evidence, and clinical trial data supporting these approaches. Emphasis is placed on how these combinations may circumvent diverse resistance mechanisms, improve survival, and maintain a favorable safety profile. By integrating the latest findings, this review aims to guide clinicians and researchers toward more individualized and durable treatment options, ultimately enhancing both survival and quality of life for patients with EGFR-mutated NSCLC.

MicroRNA-200c (miR-200c) is increasingly recognized as a crucial small RNA molecule that plays a significant and multifaceted role in the complex processes of tumor development, invasion, and metastasis across various types of cancers. Recent studies have compellingly demonstrated that miR-200c exerts its influence on tumor biology by meticulously regulating a range of critical processes, including cell proliferation, apoptosis, epithelial-mesenchymal transition (EMT), and cell migration, all of which are essential for the progression and aggressiveness of tumors. This comprehensive review aims to summarize the expression characteristics and functional implications of miR-200c across a diverse array of tumor types, delving into its potential utility as both a biomarker for early detection and a therapeutic target in the realm of cancer treatment. By synthesizing current research findings and insights, we aspire to provide valuable information that could significantly enhance early diagnostic capabilities and inform the strategic development of targeted therapy approaches in oncology.

The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, and signaling molecules that interact to promote tumor growth and therapeutic resistance. Elucidating the intricate interactions between cancer cells and the TME is crucial in understanding cancer progression and therapeutic challenges. A critical process induced by TME signaling is the epithelial-mesenchymal transition (EMT), wherein epithelial cells acquire mesenchymal traits, which enhance their motility and invasiveness and promote metastasis and cancer progression. By targeting various components of the TME, novel investigational strategies aim to disrupt the TME's contribution to the EMT, thereby improving treatment efficacy, addressing therapeutic resistance, and offering a nuanced approach to cancer therapy. This review scrutinizes the key players in the TME and the TME's contribution to the EMT, emphasizing avenues to therapeutically disrupt the interactions between the various TME components. Moreover, the article discusses the TME's implications for resistance mechanisms and highlights the current therapeutic strategies toward TME modulation along with potential caveats.

Triple-negative breast cancer (TNBC) is one of the most difficult subtypes of breast cancer to treat due to its distinct clinical and molecular characteristics. Patients with TNBC face a high recurrence rate, an increased risk of metastasis, and lower overall survival compared to other breast cancer subtypes. Despite advancements in targeted therapies, traditional chemotherapy (primarily using platinum compounds and taxanes) continues to be the standard treatment for TNBC, often with limited long-term efficacy. TNBC tumors are heterogeneous, displaying a diverse mutation profile and considerable chromosomal instability, which complicates therapeutic interventions. The development of chemoresistance in TNBC is frequently associated with the process of epithelial-mesenchymal transition (EMT), during which epithelial tumor cells acquire a mesenchymal-like phenotype. This shift enhances metastatic potential, while simultaneously reducing the effectiveness of standard chemotherapeutics. It has also been suggested that EMT plays a central role in the development of cancer stem cells. Hence, there is growing interest in exploring small-molecule inhibitors that target the EMT process as a future strategy for overcoming resistance and improving outcomes for patients with TNBC. This review focuses on the progression and drug resistance of TNBC with an emphasis on the role of EMT in these processes. We present TNBC-specific and EMT-related molecular features, key EMT protein markers, and various signaling pathways involved. We also discuss other important mechanisms and factors related to chemoresistance in TNBC within the context of EMT, highlighting treatment advancements to improve patients' outcomes.

Sophaline B (SPB), extracted from the seeds of Sophora alopecuroides L., is a natural bioactive compound that effectively exerts antiviral activities against the hepatitis B virus. This is the first study to demonstrate that SPB exerts anti-tumor effects on NSCLC by inducing pyroptosis and autophagy. SPB promotes NSCLC cell death by increasing the reactive oxygen species (ROS) production to induce pyroptosis via activating the NLRP3/Caspase-1/GSDMD signalling pathway. Meanwhile, SPB inhibits cancer cell proliferation by activating autophagy via blocking the PI3K/AKT/mTOR signalling pathway. Further investigation indicates that SPB inhibits NSCLC cell migration and invasion by increasing E-cadherin while decreasing N-cadherin, vimentin, and snail at the protein level. In addition, our results show that SPB inhibits cancer cell colony formation and human umbilical vein endothelial cell angiogenesis. Our study revealed the mechanisms of SPB triggering pyroptosis and autophagy in NSCLC, thus providing evidence and information on the SPB as an anti-cancer agent in NSCLC.

Colorectal cancer is one of the most common cancers worldwide and has a high mortality rate. In this study, we investigated the cytotoxic, proapoptotic, and anti-invasive effects of the synthetic indole phytoalexin MB-653. The antiproliferative effect was determined using an MTT assay, showing IC50 values of 5.8 ± 0.3 μmol/L for HCT116 cells and 6.1 ± 2.1 μmol/L for Caco2 cells. Flow cytometry and Western blot analysis were employed to investigate the molecular mechanisms underlying cytotoxicity, proapoptotic action, and anti-invasion effects. The proapoptotic activity was evidenced by the activation of caspases 3 and 7, mitochondrial dysfunction, and an increased number of apoptotic cells, confirmed by annexin V/PI and AO/PI staining. Additionally, MB-653 induces dose-dependent G2/M phase cell cycle arrest, the cause of which could be cyclin B1/CDC2 complex dysfunction and/or a decrease in α-tubulin protein expression. Another important observation was that MB-653 modulated several signalling pathways associated with various cellular activities, including survival, proliferation, tumour invasiveness, metastasis, and epithelial-mesenchymal transition (EMT). We further demonstrated its safety for topical and parenteral application. To sum up, our results indicate the real potential of MB-653 in treating colorectal cancer.

PFDN4, a subunit of the prefoldin complex, has been previously shown to be upregulated in breast and colorectal cancers, where its expression correlates with poor clinical outcomes. This study investigates PFDN4 expression across various cancer types, with a specific focus on its role in hepatocellular carcinoma (HCC) development and progression. Analysis of TCGA data revealed that PFDN4 is highly expressed in several cancers and is associated with poor prognosis. Further validation through multiple databases, tissue microarrays, and clinical samples confirmed that PFDN4 protein levels are significantly elevated in HCC tissues. Meanwhile, multiple database multivariate and univariate Cox regression analyses suggest that PFDN4 is an independent prognostic marker for HCC. To evaluate the functional effects of PFDN4, we established stable HCC cell lines with PFDN4 knockdown and overexpression. Using CCK-8, EdU, wound healing, and Transwell assays, we found that PFDN4 knockdown significantly suppressed cell proliferation, migration, and invasion, while its overexpression enhanced these behaviors. These findings were further validated in vivo. Mechanistically, transcriptome sequencing suggested that PFDN4 modulates HCC cell behavior through the MAPK/ERK signaling pathway, a result confirmed by Western blot and the use of the MAPK/ERK inhibitor SCH772984. Additionally, single-cell RNA sequencing data revealed that PFDN4 is primarily expressed in several immune cell types, including B cells, CD8 + Tex, DC, ILC, mast cells, macrophages, Tprolif, and Treg. In conclusion, our study demonstrates that PFDN4 is upregulated in HCC and drives tumor progression via the MAPK/ERK pathway, highlighting its potential as both a prognostic marker and therapeutic target for HCC.

Recent evidence has revealed that cancer is not solely driven by genetic abnormalities but also by significant metabolic dysregulation. Cancer cells exhibit altered metabolic demands and rewiring of cellular metabolism to sustain their malignant characteristics. Metabolic reprogramming has emerged as a hallmark of cancer, playing a complex role in breast cancer initiation, progression, and metastasis. The different molecular subtypes of breast cancer exhibit distinct metabolic genotypes and phenotypes, offering opportunities for subtype-specific therapeutic approaches. Cancer-associated metabolic phenotypes encompass dysregulated nutrient uptake, opportunistic nutrient acquisition strategies, altered utilization of glycolysis and TCA cycle intermediates, increased nitrogen demand, metabolite-driven gene regulation, and metabolic interactions with the microenvironment. The tumor microenvironment, consisting of stromal cells, immune cells, blood vessels, and extracellular matrix components, influences metabolic adaptations through modulating nutrient availability, oxygen levels, and signaling pathways. Metastasis, the process of cancer spread, involves intricate steps that present unique metabolic challenges at each stage. Successful metastasis requires cancer cells to navigate varying nutrient and oxygen availability, endure oxidative stress, and adapt their metabolic processes accordingly. The metabolic reprogramming observed in breast cancer is regulated by oncogenes, tumor suppressor genes, and signaling pathways that integrate cellular signaling with metabolic processes. Understanding the metabolic adaptations associated with metastasis holds promise for identifying therapeutic targets to disrupt the metastatic process and improve patient outcomes. This chapter explores the metabolic alterations linked to breast cancer metastasis and highlights the potential for targeted interventions in this context.

Changes in mitochondrial metabolism produce a malignant transformation from normal cells to tumor cells. Mitochondrial metabolism, comprising bioenergetic metabolism, biosynthetic process, biomolecular decomposition, and metabolic signal conversion, obviously forms a unique sign in the process of tumorigenesis. Several oncometabolites produced by mitochondrial metabolism maintain tumor phenotype, which are recognized as tumor indicators. The mitochondrial metabolism synchronizes the metabolic and genetic outcome to the potent tumor microenvironmental signals, thereby further promoting tumor initiation. Moreover, the bioenergetic and biosynthetic metabolism within tumor mitochondria orchestrates dynamic contributions toward cancer progression and invasion. In this review, we describe the contribution of mitochondrial metabolism in tumorigenesis through shaping several hallmarks such as microenvironment modulation, plasticity, mitochondrial calcium, mitochondrial dynamics, and epithelial-mesenchymal transition. The review will provide a new insight into the abnormal mitochondrial metabolism in tumorigenesis, which will be conducive to tumor prevention and therapy through targeting tumor mitochondria.

Bladder cancer exhibits substantial heterogeneity encompassing genetic expressions and histological features. This heterogeneity is predominantly attributed to alternative splicing (AS) and AS-regulated splicing factors (SFs), which, in turn, influence bladder cancer development, progression, and response to treatment.

This study aimed to explore the immune landscape of aberrant AS in bladder cancer and establish the prognostic signatures for survival prediction.

Bladder cancer-related RNA-Seq, transcriptome, and corresponding clinical information were downloaded from The Cancer Genome Atlas (TCGA). Gene set enrichment analysis (GSEA) was used to identify significantly enriched pathways of cancer-related AS events. The underlying interactions among differentially expressed genes (DEGs) and cancer-related AS events were assessed by a protein-protein interaction network. Univariate and multivariate Cox regression analyses were performed to identify crucial prognostic DEGs that co-occurred with cancer-related AS events (DEGAS) for overall survival. The area under the curve (AUC) of receiver operating characteristic (ROC) curves was used to assess the efficiency of the prognostic signatures. The CIBERSORT algorithm was used to explore the abundance of immune infiltrating cells.

A total of 3755 cancer-related AS events and 3110 DEGs in bladder cancer were identified. Among them, 379 DEGs co-occurred with cancer-related AS events (DEGAS), of which 102 DEGAS were associated with 14 dysregulated SFs. GSEA and KEGG analysis showed that cancer-related AS events were predominantly enriched in pathways related to immunity, tumorigenesis, and treatment difficulties of bladder cancer. Multivariate Cox regression analysis identified 8 DEGAS (CABP1, KCNN2, TNFRSF13B, PCDH7, SNRPA1, APOLD1, CX3CL1, and DENND5A) significantly associated with OS, and they were further integrated into the prediction model with good AUCs at 3-year, 5-year and 7-year ROC curves (all>0.7). Immune infiltration analysis revealed the significant enrichment of three immune cell types (B cells naïve, dendritic cells resting, and dendritic cell activated) in high-risk bladder cancer patients.

This study not only unveiled comprehensive prognostic signatures of AS events in bladder cancer but also established a robust prognostic model based on survival-related DEGAS. These aberrant AS events, dysregulated SFs, and the identified 8 DEGAS may have significant clinical potential as therapeutic targets for bladder cancer.

Quinoa saponins can inhibit the survival of specific cancer cells. However, there is still a lack of systematic research on the effects of quinoa saponins on colon cancer cells. This experiment confirmed that quinoa saponins prevented human colon cancer HT-29 cells from growing in vitro. The MTT experiment revealed that quinoa saponins significantly decreased the proliferative vitality of HT-29 cells. In comparison to the control group, the proportion of cell number in the G0/G1 phase increased by 22.97% and the rate of apoptosis increased by 22.55% after treating cells with quinoa saponins (40 μg/mL). By regulating the expression of Cyclin D1 and p21, it caused the cell cycle to be blocked in the G0/G1 phase. It also promoted the expression of Caspase3 and Bax while suppressing the expression of Bcl-2, which led to the apoptosis of HT-29 cells. In addition, quinoa saponins caused cells to undergo autophagy by upregulating the expression of LC-3II and Beclin1, while the addition of autophagy inhibitors significantly reduced the inhibitory effect on cell proliferation. Finally, the migration of HT-29 cells was also inhibited by quinoa saponins. After treating cells with quinoa saponins (40 μg/mL), compared with that in the control group, the wound healing rate of cells decreased by 38.21% and the migration ability decreased by 69.48%. The potential mechanism could be connected to increasing E-cadherin expression while decreasing N-cadherin expression. Importantly, all of these changes induced by quinoa saponins were dose dependent. Overall, these findings give a scientific basis for the anticancer mechanism of quinoa saponins.

GBM is one of the most malignant tumor in central nervous system. The resistance to temozolomide (TMZ) is inevitable in GBM and the characterization of TMZ resistance seriously hinders clinical treatment. It is worthwhile exploring the underlying mechanism of aggressive invasion and TMZ resistance in GBM treatment. Bioinformatic analysis was used to analyze the association between RND1 and a series of EMT-related genes. Colony formation assay and cell viability assay were used to assess the growth of U87 and U251 cells. The cell invasion status was evaluated based on transwell and wound-healing assays. Western blot was used to detect the protein expression in GBM cells. Treatment targeted RND1 combined with TMZ therapy was conducted in nude mice to evaluate the potential application of RND1 as a clinical target for GBM. The overexpression of RND1 suppressed the progression and migration of U87 and U251 cells. RND1 knockdown facilitated the growth and invasion of GBM cells. RND1 regulated the EMT of GBM cells via inhibiting the phosphorylation of AKT and GSK3-β. The promoted effects of RND1 on TMZ sensitivity was identified both in vitro and in vivo. This research demonstrated that the overexpression of RND1 suppressed the migration and EMT status by downregulating AKT/GSK3-β pathway in GBM. RND1 enhanced the TMZ sensitivity of GBM cells both in vitro and in vivo. Our findings may contribute to the targeted therapy for GBM and the understanding of mechanisms of TMZ resistance in GBM.

Tripartite motif-containing protein 50 (TRIM50) is a recently discovered E3 ubiquitin ligase that participates in tumor progression. TRIM50 is overexpressed in many cancers, although few studies focused on TRIM50's role in breast cancer.

We overexpressed TRIM50 in triple-negative breast cancer cell lines using plasmid and found that TRIM50 upregulation markedly reduced breast cancer cell proliferation, clone formation, and migration, as well as promoted breast cancer cell apoptosis. Western blotting revealed that accumulated TRIM50 resulted in both mRNA and protein depletion of SNAI1, and partially attenuated the epithelial-mesenchymal transition (EMT) induced by SNAI1.