Increasing evidence indicates that cancer stem cells (CSCs) and cancer stem-like cells form a special subpopulation of cells that are ubiquitous in tumors. These cells exhibit similar characteristics to those of normal stem cells in tissues; moreover, they are capable of self-renewal and differentiation, as well as high tumorigenicity and drug resistance. In prostate cancer (PCa), it is difficult to kill these cells using androgen signaling inhibitors and chemotherapy drugs. Consequently, the residual prostate cancer stem cells (PCSCs) mediate tumor recurrence and progression.

This review aims to provide a comprehensive and up-to-date overview of PCSCs, with a particular emphasis on potential therapeutic strategies targeting these cells.

After searching in PubMed and Embase databases using 'prostate cancer' and 'cancer stem cells' as keywords, studies related were compiled and examined.

In this review, we detail the origin and characteristics of PCSCs, introduce the regulatory pathways closely related to CSC survival and stemness maintenance, and discuss the link between epithelial-mesenchymal transition, tumor microenvironment and tumor stemness. Furthermore, we introduce the currently available therapeutic strategies targeting CSCs, including signaling pathway inhibitors, anti-apoptotic protein inhibitors, microRNAs, nanomedicine, and immunotherapy. Lastly, we summarize the limitations of current CSC research and mention future research directions.

A deeper understanding of the regulatory network and molecular markers of PCSCs could facilitate the development of novel therapeutic strategies targeting these cells. Previous preclinical studies have demonstrated the potential of this treatment approach. In the future, this may offer alternative treatment options for PCa patients.

Cancer, influenced by genetics and the environment, involves anoikis, a cell death mechanism upon extracellular matrix detachment crucial for metastasis. Understanding this relationship is key for therapy. We analyze cancer and anoikis trends using bibliometrics.

A search was conducted from Web of Science Core, PubMed, Scopus and non-English databases such as the CNKI (inception- 21 December 2024). Data analysis employed Microsoft Excel, VOSviewer, CiteSpace, R software, and the online platform (https://bibliometric.com/).

2510 publications were retrieved, with a significant increase in the last decade. China led, the University of Texas system was productive, and the Oncogene Journal was popular. Breast, and colorectal cancers were frequently studied. Among them, representative tumor-related mechanisms were identified, commonalities such as (EMT, ECM, autophagy) and respective specific mechanisms were summarized.

This bibliometric analysis highlights rapid advances in anoikis research in cancer, emphasizing EMT and FAK pathways' translational potential, guiding targeted therapies, and improving cancer treatment outcomes.

The dissemination of tumor cells with ensuing metastasis is responsible for most cancer-related deaths. Cancer vaccines may, by inducing tumor-specific effector T cells, offer a strategy to eliminate metastasizing tumor cells. However, several obstacles remain in the development of effective cancer vaccines, including the identification of adjuvants that enhance the evolvement and efficacy of tumor-specific T cells. Cholera toxin-based adjuvants have shown efficacy in vaccines for infectious diseases, but their role in cancer vaccine therapies remains to be elucidated. Here, we explored the potential of cholera toxin A1 (CTA1)-based adjuvants to boost anti-tumor T cell responses and protect against metastasis. We report that an adjuvant where CTA1 was fused to a dimer from Staphylococcus aureus protein A (DD) enhanced immune responses against the tumor-associated antigens TRP2 and Twist1 in mice, providing protection against B16F1 melanoma and 4T1 breast cancer metastasis, respectively. Both mucosal (intranasal) and systemic (intraperitoneal) vaccine administration provided effective protection against intravenously injected tumor cells, with intranasal administration leading to superior induction of CD4+ T cells at metastatic sites. When comparing antigens admixed with CTA1-DD to those fused with a CTA1-based adjuvant, the fusion construct elicited the strongest immunogenicity. Nevertheless, by administrating a 20-fold higher antigen dose also the admix formulation provided efficient protection against metastasis.

Total flavonoids from Litchi chinensis Sonn. (Sapindaceae) seeds (TFLS) effectively attenuate stem cell-like properties in breast cancer cells. However, their pharmacological effects and mechanisms in suppressing breast cancer metastasis remain unclear.

This study aimed to elucidate the inhibitory effects and underlying mechanisms of TFLS on breast cancer metastasis.

The antiproliferative, migratory, and invasive activities of breast cancer cells following TFLS treatment were evaluated using CCK-8, wound-healing, and transwell assays. The epithelial-mesenchymal transition (EMT) biomarkers were evaluated via Western blot analysis. The anti-metastatic effects of TFLS were further validated in vivo using zebrafish and mouse models. Network pharmacology methodology was utilized to predict potential targets and signaling pathways, which were subsequently corroborated by Western blot. Potential active compounds were identified through molecular docking, and the chemical constituents of TFLS were analyzed and characterized using UPLC-QTOF/MS.

TFLS suppressed the proliferation of MDA-MB-231 and MDA-MB-468 cells, with IC50 values of 44.47 μg/mL and 37.35 μg/mL at 72 h, respectively. It effectively suppressed breast cancer metastasis in vitro, demonstrated by a marked reduction in cellular motility and invasiveness, alongside the reversal of EMT. Consistent with pathway enrichment analysis, network pharmacology revealed that TFLS reduced the phosphorylation levels of PI3K, AKT, mTOR, JNK, ERK, and p38 in breast cancer cells. Molecular docking identified seven potential active ingredients, and UPLC-MS/MS confirmed the presence of key compounds, including procyanidin A2.

TFLS effectively inhibits breast cancer cell proliferation, migration, and invasion in vitro by reversing the EMT phenotype, while suppressing metastasis in vivo. These effects are likely mediated via the attenuation of the PI3K/AKT/mTOR and MAPK signaling pathways.

Pulmonary fibrosis (PF) is always exacerbated by the comorbidity of lung adenocarcinoma (LUAD), and patients frequently died from the complications of PF instead of lung cancer. Although many studies have unveiled the mechanisms underlying PF exacerbation due to lung cancer resection and radiotherapy, the influence of lung cancer itself on PF remains enigmatic.

We cocultivated mouse pulmonary cells with mouse LUAD cells to explore the influence of LUAD on the pathogenesis and progression of PF. Additionally, a comorbidity model of PF with LUAD was established in mice via intratracheal injection of bleomycin (BLM) followed by in situ transplantation of LUAD cells. Furthermore, immunofluorescence, immunohistochemistry, and molecular analyses were employed to elucidate the mechanisms underlying the exacerbation of PF by the comorbidity of LUAD.

We found that PF was significantly exacerbated by LUAD. In the microenvironment of LUAD, the epithelial-mesenchymal transition (EMT) was predominantly activated in lung epithelial cells, while the transformation of lung fibroblasts into myofibroblasts was markedly induced. The TGF-β and GSK-3β pathways were differentially activated in lung epithelial cells and fibroblasts. Furthermore, clinical samples confirmed the involvement of these pathways in the process of PF exacerbation induced by LUAD in patients' lung lesions of PF with LUAD.

This study initially reveals that LUAD exacerbates PF by modulating epithelial cells and fibroblasts through TGF-β and GSK-3β pathways differentially. Practically, targeting the pathways of TGF-β and GSK-3β may promise a potential strategy for the prophylaxis of PF exacerbation in patients with LUAD.

Liver metastases represent a late-stage manifestation of numerous cancers, often associated with poor patient prognosis. Kupffer cells (KCs), resident liver macrophages, play a critical role in liver metastasis (LM). However, the mechanisms by which the polarization of KCs facilitate colorectal cancer (CRC) liver metastases remain elusive. Here, we established a CRC liver metastasis mouse model and employed a co-culture system, found that KCs were recruited and polarized to M2 phenotype. We isolated and purified highly metastatic cell lines to reveal potential changes in CRC cells during metastasis. Through bulk RNA sequencing, we identified and validated CXCL16 as a positive mediator in liver-metastatic CT26-LM cells that induced an M2-like KC phenotype. Knock down of CXCL16 reduced the M2 polarization of KCs and inhibited the formation of liver metastasis lesions. Next, this polarization process was shown to be achieved through the PI3K/AKT/FOXO3a pathway. Further investigation revealed FOXO3a transcriptionally activates CD206(MRC1) in this process. Pharmacological inhibition of the CXCL16-PI3K-FOXO3a axis to disrupt the polarization of KCs attenuated CRC liver metastasis in vivo. Our findings collectively indicate that targeting the CXCL16/PI3K/AKT/FOXO3a pathway in KCs may represent a promising therapeutic strategy for preventing CRC liver metastasis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease. Baihe Gujin decoction (BHGJ), a traditional Chinese medicine consisting of ten medicine food homology herbs, has shown therapeutic effects in various lung diseases; however, its efficacy in ameliorating IPF and the underlying mechanisms remain unclear.

This study aimed to evaluate the effects of BHGJ on IPF and investigate its potential mechanisms.

We established a bleomycin (BLM)-induced IPF model and performed proteomic analysis. The therapeutic effects of BHGJ on IPF were assessed by measuring lung index, hydroxyproline (HYP) content, lung function parameters, and histopathological changes. Mechanistic insights were further explored using Western blot and RT-qPCR analyses.

Our results demonstrated that BHGJ significantly alleviated BLM-induced IPF, improved lung function, reduced histopathological damage, and decreased collagen deposition. BHGF reduced apoptosis and inhibited EMT in TGF-β-induced A549 cells. Proteomic analysis revealed that its effects were associated with the modulation of the proline metabolism pathway.

BHGJ effectively attenuated IPF progression via regulating proline metabolism, providing a potential therapeutic strategy for pulmonary fibrosis.

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.

Gastric cancer-associated mesenchymal stem cells (GC-MSCs) as integral components of the tumor microenvironment potentiate gastric cancer growth and metastasis. SALL4 is aberrantly upregulated in gastric cancer and pivotal for malignant progression. Whether GC-MSCs is responsible for SALL4 upregulation and the underlying mechanisms remains elusive.

Cancer growth and metastasis capacities were assessed by cell colony formation assay, transwell assay, and epithelial-mesenchymal transition protein detection in vitro as well as subcutaneous xenograft and peritoneal metastasis models in vivo. SALL4 was measured by qPCR, western blot and immunohistochemistry staining. Gain- and loss-functional analysis were performed for miRNA and target gene. β-catenin signaling was assessed by immunofluorescence staining and Top/FopFlash luciferase assay. Transcriptional regulation was conducted using chemicals, luciferase reporter and ChIP assay. Clinical tissues and TCGA-STAD database were included for expression profile, correlation and clinical relevance analysis.

GC-MSCs promoted gastric cancer growth and metastasis along with elevation of SALL4 and miR-4669 in cancer cells and tissues. Overexpression of miR-4669 mimicked GC-MSC effects, while miR-4669 knockdown eliminated their oncogenic roles. TIMP3 was identified as a target of miR-4669 and mediated its functions. TIMP3 overexpression counteracted GC-MSC-induced cancer progression and SALL4 expression. GC-MSCs activated SALL4 transcription through the miR-4669/TIMP3/β-catenin pathway. The regulatory axis was aberrantly expressed in gastric cancer tissues, correlated with each other in certain cancer tissues and associated with lymph node metastasis.

GC-MSCs transcriptionally upregulate SALL4 to facilitate gastric cancer cell growth and metastasis via miR-4669/TIMP3/β-catenin pathway, highlighting the crucial role of GC-MSCs in the aberrant upregulation of SALL4.

Epithelial-mesenchymal transition (EMT) is a key phenotypic switch in cancer metastasis, leading to fatal consequences for patients. Under geometric constraints, the morphology of cancer cells changes in both cellular and subcellular levels, whose effects on EMT are, however, not fully understood. Herein, we designed and fabricated chimeric micropatterns of polystyrene (PS) with adhesion contrast to reveal the impacts of cell shapes and nuclear shapes on EMT in a decoupled way. Cell elongation was modulated via microwell aspect ratios (ARs), and nuclear deformation was generated through a micropillar array in the microwell. Human non-small cell lung cancer cells (A549) were cultured on the quasi-three dimensional micropatterned surfaces, and transforming growth factor-β1 (TGF-β1) was added to induce EMT. We found that chimeric micropatterns upregulated EMT with an increase of cellular AR and nuclear indentation under given TGF-β1. The subsequent assessment of the contractility and oriented assembly of microfilaments elucidated the key role of mechanotransduction in cell elongation and EMT, as proved by myosin inhibition, while it was obstructed by micropillars in the chimeric micropattern. Hence, the micropillar array possessed a nonmonotonic influence, enhancing the EMT of cells with AR of 1, but hindering the EMT with an impact more significant on microwells with large ARs due to the impeded cytoskeleton assembly. This fundamental research has illustrated the complex of cellular and subcellular geometries on cell behaviors including phenotype transition in cancer metastasis.

Tumor metastasis is a complex phenomenon that poses significant challenges to current cancer therapeutics. While the biochemical signaling involved in promoting motile phenotypes is well understood, the role of biomechanical interactions has recently begun to be incorporated into models of tumor cell migration. Specifically, we propose the unjamming transition, adapted from physical paradigms describing the behavior of granular materials, to better discern the transition toward an invasive phenotype. In this review, we introduce the jamming transition broadly and narrow our discussion to the different modes of 3D tumor cell migration that arise. Then we discuss the mechanical interactions between tumor cells and their neighbors, along with the interactions between tumor cells and the surrounding extracellular matrix. We center our discussion on the interactions that induce a motile state or unjamming transition in these contexts. By considering the interplay between biochemical and biomechanical signaling in tumor cell migration, we can advance our understanding of biomechanical control in cancer metastasis.

Cells undergoing epithelial-to-mesenchymal transition (EMT) exhibit significant plasticity, making them more tumorigenic, invasive, and stem-like. PLCG2 has been identified as being linked to EMT. Specifically, the PLCG2-high subpopulation of tumor cells shows strong correlations with metastasis. However, it remains unclear whether PLCG2 serves as a direct driver of EMT. In this study, we employ an in vivo photostimulation method using tightly focused femtosecond-laser scanning to activate intracellular Ca2+ signaling and induce PLCG2 upregulation. By constructing a subcutaneous tumor model with prostate cancer PC3 cells and single-cell RNA sequencing, we identify distinct cell populations, including cancer stem cells, epithelial tumor cells, proliferating cells, and EMT cells. Upon photostimulation, EMT cells are notably expanded among the primary tumor cells, while epithelial tumor cells decrease in number. During the tumor progression, treatment with a specific PLCG2 inhibitor effectively suppresses the growth of the primary tumor but has no significant impact on metastatic cells. These findings offer valuable insights into the role of PLCG2 in regulating EMT and tumor development.

Metabolic reprogramming occurs alongside tumor development. As cancers advance from precancerous lesions to locally invasive tumors and then to metastatic tumors, metabolic patterns exhibit distinct changes, including mutations in metabolic enzymes and modifications in the activity of metabolic regulatory proteins. Alterations in metabolic patterns can influence tumor evolution, either establishing or alleviating metabolic burdens and facilitating cancer growth. To fully understand how metabolic reprogramming helps tumors grow and find the metabolic activities that are most useful for treating tumors, we need to have a deeper understanding of how metabolic patterns are controlled as tumors grow. Post-translational modifications (PTMs), a critical mechanism in the regulation of protein function, can influence protein activity, stability, and interactions in several ways. In tumor cells, PTMs-mediated metabolic reprogramming is a crucial mechanism for adapting to the challenging microenvironment and sustaining fast growth. This article will deeply explore the intricate regulatory mechanism of PTMs on metabolic reprogramming and its role in tumor progression, with the expectation of providing new theoretical basis and potential targets for tumor treatment.

The rising mortality rate from cancer, driven by the absence of reliable biomarkers, highlights the pressing need for advanced diagnostic and prognostic strategies. This study investigates LZTS2's role as a pan-cancer biomarker, emphasizing its predictive value for immunotherapy and therapeutic targeting. Unlike existing biomarkers such as AFP in hepatocellular carcinoma or HER2 in gastric cancer, which exhibit tissue-specific utility, LZTS2 demonstrates unique cross-cancer applicability, as evidenced by its consistent dysregulation in both liver hepatocellular carcinoma (LIHC) and stomach adenocarcinoma (STAD) alongside emerging associations with other malignancies. Leveraging advanced bioinformatics tools and databases including UALCAN, KM-plotter, and The Cancer Genome Atlas (TCGA), alongside experimental validation in LIHC and STAD cell lines, we analyze LZTS2 expression patterns and their clinical relevance. Notably, LZTS2's dual role-acting as a tumor suppressor in some cancers while promoting oncogenesis in others-distinguishes it from conventional single-function markers, offering novel insights into its regulatory versatility. Our findings reveal that LZTS2 mutations and expression levels are closely associated with cancer progression and patient survival, solidifying its potential as a prognostic biomarker. Notably, LZTS2 expression correlates with various clinicopathological parameters, underscoring its significance in cancer biology. Pathway analysis highlights LZTS2's involvement in critical biological processes, providing actionable insights for therapeutic interventions. Quantitative real-time polymerase chain reaction (qRT-PCR) and quantitative methylation-specific PCR (qMSP) experimental validations confirm these results, further establishing LZTS2's utility as a multi-dimensional biomarker that integrates genetic, epigenetic, and immunological features-a capability rarely observed in existing markers. This comprehensive analysis positions LZTS2 as a pivotal player in cancer progression, opening promising avenues for enhanced clinical management.

Metastasis, the leading cause of cancer-associated deaths, is promoted by transcription factors SNAIL, SLUG, ZEB1 and TWIST through the activation of epithelial-mesenchymal transition (EMT). MicroRNAs can suppress EMT, emerging as candidate molecular biomarkers and novel therapeutic targets. Herein, we evaluated microRNAs downregulated in breast cancer (BC) tissues expressing EMT transcription factors, to find new potential regulators of EMT.

Candidate microRNAs were selected from microarray data by their inversely correlated expression with SNAIL, SLUG, ZEB1 and TWIST, evaluated in BC tissues through immunohistochemistry. We selected eight microRNAs predicted in silico as probable modulators of SNAIL, SLUG, ZEB1 and TWIST, and validate their interaction through the 3'UTR region in luciferase reporter gene assays. MDA-MB-231 cells were transfected with selected microRNAs to perform migration, invasion and cell proliferation assays, and western blot was used to evaluate protein levels.

MiR-30a-5p, miR-1271-5p, miR-196a-5p, miR-202-3p, miR-210-3p, miR-22-3p and miR-331-3p decreased luciferase activity through SNAIL, SLUG, ZEB1 and/or TWIST 3'UTR. These microRNAs, including miR-34b-3p, decreased migration, invasion and cell proliferation in MDA-MB-231 cells. MiR-30a-5p, miR-202-3p and miR-22-3p decreased vimentin expression, whereas miR-196a-5p and miR-22-3p decreased endogenous ZEB1 levels. MiR-196a-5p, miR-202-3p and miR-30a-5p also decreased CCR7 expression, a chemokine receptor involved in lymph node metastasis.

microRNAs selected in this work can regulate gene expression trough 3'UTR region of EMT-transcription factors. In BC cells, miR-196a-5p and miR-22-3p decrease ZEB1 levels, being novel modulators of EMT. Also, the eight evaluated microRNAs, reduced the metastatic hallmarks in BC cells.

Pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of all pancreatic malignancies. Despite the remarkable improvement concerning treatment, late detection and resistance to clinically used chemotherapeutic agents remain major challenges. Trichostatin A (TSA), a histone deacetylase inhibitor, has been recognized as an effective therapeutic agent against PDAC by inhibiting proliferation, inducing apoptosis, and sensitizing PDAC cells to chemotherapeutic agents such as gemcitabine. Microgravity has become a useful tool in cancer research due to its effects on various cellular processes. This paper presents a deep molecular and proteomic analysis investigating cell growth, the modulation of cytokeratins, and proteins related to apoptosis, cellular metabolism, and protein synthesis after TSA treatment in simulated microgravity (SMG)-exposed PaCa44 3D cells. Our analysis concerns the effects of TSA treatment on cell proliferation: the impairment of the cell cycle with the downregulation of proteins involved in Cdc42 signaling and G1/G2- and G2/M-phase transitions. Thus, we observed modification of survival pathways and proteins related to autophagy and apoptosis. We also observed changes in proteins involved in the regulation of transcription and the repair of damaged DNA. TSA treatment promotes the downregulation of some markers involved in the maintenance of the potency of stem cells, while it upregulates proteins involved in the induction and modulation of the differentiation process. Our data suggest that TSA treatment restores the cell phenotype prior to simulated microgravity exposure, and exerts an intriguing activity on PDAC cells by reducing proliferation and inducing cell death via multiple pathways.

Populations are heterogeneous, deviating in numerous ways. Phenotypic diversity refers to the range of traits or characteristics across a population, where for cells this could be the levels of signalling, movement and growth activity, etc. Clearly, the phenotypic distribution - and how this changes over time and space - could be a major determinant of population-level dynamics. For instance, across a cancerous population, variations in movement, growth, and ability to evade death may determine its growth trajectory and response to therapy. In this review, we discuss how classical partial differential equation (PDE) approaches for modelling cellular systems and collective cell migration can be extended to include phenotypic structuring. The resulting non-local models - which we refer to as phenotype-structured partial differential equations (PS-PDEs) - form a sophisticated class of models with rich dynamics. We set the scene through a brief history of structured population modelling, and then review the extension of several classic movement models - including the Fisher-KPP and Keller-Segel equations - into a PS-PDE form. We proceed with a tutorial-style section on derivation, analysis, and simulation techniques. First, we show a method to formally derive these models from underlying agent-based models. Second, we recount travelling waves in PDE models of spatial spread dynamics and concentration phenomena in non-local PDE models of evolutionary dynamics, and combine the two to deduce phenotypic structuring across travelling waves in PS-PDE models. Third, we discuss numerical methods to simulate PS-PDEs, illustrating with a simple scheme based on the method of lines and noting the finer points of consideration. We conclude with a discussion of future modelling and mathematical challenges.

Lumbar spinal stenosis (LSS) represents a major global healthcare burden resulting in back pain and disorders of the limbs among the elderly population. The hypertrophy of ligamentum flavum (HLF), marked by fibrosis and inflammation, significantly contributes to LSS. Fibroblasts and endothelial cells are two important cells in the pathological process of ligamentum flavum (LF) fibrosis and inflammation. These two cells exhibit heterogeneity in various fibrotic diseases, yet their heterogeneity in LF fibrosis remains poorly defined.

Using single-cell RNA-seq, we examined the alterations of fibroblasts, endothelial cells, and key genes in the hypertrophic LF, aiming to establish a comprehensive single-cell atlas of LF to identify high-priority targets for pharmaceutical treatment of LSS.

Here, we find there are five distinct subpopulations of LF fibroblasts: secretory-papillary, secretory-reticular, mesenchymal, pro-inflammatory, and unknown. Importantly, in HLF, the proportion of mesenchymal fibroblast subpopulations increases significantly compared to normal LF (NLF), reflecting their close association with the pathogenesis of HLF. Furthermore, critical target genes that might be involved in HLF and fibrosis, such as MGP, ASPN, OGN, LUM, and CTSK, are identified. In addition, we also investigate the heterogeneity of endothelial cells and highlight the critical role of AECs subpopulation in LF fibrosis.

This study will contribute to our understanding of the pathogenesis of HLF and offer possible targets for the treatment of fibrotic diseases.

The remarkable biophysical properties of metastatic migrating cells, such as their exceptional motility and deformability, enable them to migrate through physical confinements created by neighboring cells or extracellular matrix. This study explores the adaptive responses of breast cancer (BC) cell sublines derived from the highly aggressive, metastatic triple-negative MDA-MB-231 and the non-metastatic MCF7 human BC cell lines, after undergoing three rounds of confined migration (CM) stress. Our findings demonstrate that CM elicits common and cell-type specific adaptive responses in BC cell sublines. In particular, both cell sublines exhibit a similar enhancement of clonogenicity and nanoparticle (NP) uptake activity, indicating tumorigenic potential. We have, for the first time, shown that stimulation with CM induces a hybrid epithelial-to-mesenchymal transition (EMT) phenotype of MDA-MB-231 cells. This transition is characterized by a significant rise in the expression of stage-specific embryonic antigen-4 (SSEA4), alongside a substantial decline in the population of CD133+ cells and a marked reduction in Ki67 expression in the MDA-MB-231-derived subline following Cis-Platin treatment. These changes are likely associated with heightened resistance of this subline to cisplatin. In contrast, CM induces far fewer such alterations in the MCF7-derived counterpart with a notable increase of CD133+ population, which seems to be insufficient to change cell susceptibility to cisplatin exposure. This study contributes to our understanding of the adaptive mechanisms underlying metastasis and drug resistance in breast cancer, emphasizing the need for personalized approaches in cancer treatment that consider the heterogeneous responses of different cancer subtypes to environmental stresses.

Snail is a zinc finger transcription factor encoded by the SNAI1 gene and triggers a cellular process termed epithelial-mesenchymal transition (EMT) upon its increased expression and/or functional activation. Snail expression and activity are regulated by various extracellular stimuli, including cytokines and environmental factors. Transforming growth factor-β (TGF-β) is a Snail inducer that functions via Smad3-mediated transcriptional activation. In the present study, we identified a distal enhancer that modulates TGF-β-induced SNAI1 expression. ChIP-seq and Hi-C analyses showed that the enhancer is located 46 kb downstream of the SNAI1 gene; in TGF-β-stimulated cells, it associates with Smad3 and interacts with the SNAI1 proximal promoter. Inhibiting the activity of the enhancer using CRISPRi attenuated TGF-β-induced SNAI1 expression, stress fiber formation, and cell motility enhancement, suggesting that the enhancer mediates TGF-β-induced EMT. The enhancer contains a Smad-binding CAGA motif and an activator protein-1 (AP-1) binding motif that function in transcriptional activation. Ras-responsive element binding protein 1 (RREB1), a transcription factor required for TGF-β-induced Snail expression, regulated the basal activity of the enhancer but not its inducibility by TGF-β. In contrast to the enhancer, the association of Smad3 with the proximal promoter was not evident. These findings suggest that the proximal promoter and the distal enhancer respond to distinct signaling cues, integrate them, and cooperatively function to drive SNAI1 expression.

LUAD, a prevalent lung cancer with high mortality, has seen increased focus on molecular targeted therapies due to patient heterogeneity. Among these prospects, dystrophin-associated protein 2 (DRP2), a critical component of the dystrophin complex, underpins membrane-associated structures vital for intercellular interactions in vertebrates. Aberrations in DRP2 function have been linked to the occurrence and development of multiple diseases, prompting an inquiry into its potential link with LUAD progression. To delve into the potential roles of DRP2 in LUAD, we initiated a comprehensive investigation. First, we analyzed DRP2 expression patterns in LUAD using bioinformatics tools. This was subsequently validated through immunohistochemical staining, quantitative PCR, and Western blot analyses. Furthermore, we assessed the functional implications of DRP2 in LUAD cells, both in vitro and in vivo, utilizing assays such as cell cycle analysis, CCK-8 proliferation assay, Colony formation assay EdU incorporation, Transwell migration test, scratch wound healing assay, flow cytometry, and mouse models for tumor xenograft and metastasis. Results showed a strong correlation between high DRP2 expression in LUAD and poorer survival. Notably, DRP2 knockdown accelerated LUAD progression via the EMT pathway. These findings highlight DRP2's crucial role in LUAD and its potential as a therapeutic target.

Androgen receptor (AR), a member of the nuclear receptor superfamily controls prostate epithelial cell plasticity by repressing a panel of genes involved in epithelial-mesenchymal transition (EMT), including the human CDH2 gene encoding N-cadherin. At the opposite, pathological AR variants such as AR-V7 associated with prostate tumor progression upregulate those EMT genes. Here, focusing on the human CDH2 gene, we show that this duality between AR and AR-V7 relies on a potential human accelerated region present in the intron 1. This fastest-evolving region of the human genome is actually a variable number tandem repeat (VNTR) comprising 24 repetitions of a DNA sequence that englobes binding sites for steroid hormone receptors, recombination signal binding protein for immunoglobulin kappa j region (RBPJ) an effector of the Notch pathway, and zinc finger e-box binding homeobox 1 (ZEB1). Genomic DNA sequencing, multiple sequence alignment, data mining, as well as protein-DNA interaction and gene expression analyses indicate that this VNTR constitutes a potential transcriptional hub for different transcription factors to control human CDH2 expression. Also, our data suggest that prostate tumor cells may unlock an up to now unknown molecular mechanism associated with a fine-tuned control of human CDH2 gene expression.

Personalized medicine in cancer treatment has the potential to enhance therapeutic efficacy while simultaneously reducing adverse effects. Molecular characterization of circulating tumor cells (CTCs) offers invaluable insight into metastatic tumor heterogeneity, making them a perfect candidate for metastatic cancer drug screening. However, they are extremely rare. This study presents the development of melt-electrowritten membrane filters designed for the capture, culture, and drug testing of CTCs. By varying the collector speeds, filters with optimized pore sizes and polymer densities were produced, enabling selective capture of CTCs while minimizing co-capture of white blood cells. Biocompatibility tests showed that the filter supported the proliferation of multiple cancer cell lines. The filter successfully captured and cultured colorectal cancer patient-derived CTC44 and CTC45 cells, which formed 3D clusters observable over several weeks. Drug testing with chemotherapeutic agents 5-fluorouracil/oxaliplatin (FOX) and 5-fluorouracil/irinotecan (FIRI) revealed that CTCs in 3D clusters on the filters exhibited significantly higher drug resistance compared to 2D monolayers. These findings demonstrate the potential of the filter as a versatile platform for studying CTC biology and for screening anticancer drugs, providing a more physiologically relevant environment than traditional 2D cultures.

Human induced pluripotent stem cells (hiPSCs) hold great potential for regenerative medicine. However, optimizing their differentiation into specific lineages within three-dimensional (3D) scaffold-based culture systems that mimic in vivo environments remains challenging. This study examined the trilineage differentiation of hiPSCs under various 3D conditions using synthetic peptide hydrogel matrices with and without embryoid body (EB) medium induction. hiPSC 3D colonies (spheroids), naturally formed from single cells or small clusters in 3D culture, were used for differentiation into the three germ lineages. Differentiated spheroids exhibited distinct morphological characteristics and significantly increased expression of key lineage-specific markers-FOXA2 (endoderm), Brachyury (mesoderm), and PAX6 (ectoderm)-compared to undifferentiated controls. Marker expression varied depending on the 3D culture conditions. Differentiation efficiency improved significantly, increasing from 16% to 71% for endoderm, 61% to 80% for mesoderm, and 35% to 48% for ectoderm, by selecting the appropriate 3D matrix and applying EB induction. Comprehensive data analysis from RT-qPCR, immunocytochemistry staining, and flow cytometry confirmed that the Synthegel Spheroid (SGS) is a viable 3D matrix for evaluating all three germ lineages using a commercial trilineage differentiation kit. While EB induction is essential for endodermal differentiation, it is not required for mesodermal and ectodermal lineages. These findings are valuable not only for screening initial differentiation potential at the lineage level but also for optimizing 3D differentiation protocols for deriving somatic cells from hiPSCs.

Integrins, a family of transmembrane cell adhesion receptors, mediate intercellular and cell-extracellular matrix crosstalk via outside-in and inside-out signaling pathways. Integrins, categorized into 24 distinct combinations of α and β subunits, exhibit tissue-specific expression and perform unique or overlapping roles in physiological and pathophysiological processes. These roles encompass embryonic angiogenesis, tissue repair, and the modulation of tumor cell angiogenesis, progression, invasion, and metastasis. Notably, integrins are significant contributors to tumor development, offering valuable insights into the potential of integrin-targeted diagnostics and therapeutics. Currently, there are various preclinical and clinical trials aiming to harness integrin antagonists that are safe, efficacious, and exhibit low toxicity. Owing to the functional redundancy across integrin types and the complexity of the mechanisms of integrin-mediated multiple key processes associated with tumor biology, challenges exist that impede advancements in integrin-targeted therapy. Nevertheless, innovative strategies focused on integrin modulation represent significant breakthroughs for improving patient care and promoting comprehensive insights into the underlying mechanisms of tumor biology. This review elucidates the impact of integrins on three distinct cell types in multiple key processes associated with tumor biology and explores the emerging integrin-targeted therapeutic approaches for the treatment of tumors, which will provide ideas for optimal therapeutic approaches in the future.

Epithelial-to-mesenchymal transition (EMT), a key process in cancer metastasis and fibrosis, disrupts cellular adhesion by replacing epithelial E-cadherin with mesenchymal N-cadherin. While, how the shift from E-cadherin to N-cadherin impacts molecular-scale adhesion mechanics and cluster dynamics-and how these changes weaken adhesion under varying mechanical and environmental conditions-remains poorly understood, limiting our ability to target EMT-driven pathological adhesion dynamics. Here, we developed a unified lattice-clutch model to investigate cadherin clustering, cortical tension, and adhesion strength during EMT. Using atomic force microscopy experiments, we measured the mechanical properties of single cadherin trans-bonds and cadherin-mediated cell-cell and cell-matrix adhesions across varying conditions. Our results demonstrate that N-cadherin trans-bonds are mechanically weaker than E-cadherin trans-bonds, leading to reduced adhesion strength during EMT. Computational modeling and experimental validation further revealed that EMT impairs cadherin clustering and cortical tension regulation, which collectively weaken both cell-cell and cell-matrix adhesions, particularly on stiff substrates. These findings highlight how EMT disrupts adhesion strength at multiple scales-from individual cadherin bonds to collective cluster dynamics. Our study elucidates how EMT-driven changes in cadherin type weaken adhesion strength and mechanotransduction, providing insights into cellular adhesion mechanics and potential therapeutic strategies for targeting EMT-associated diseases such as cancer metastasis and tissue remodeling.

Noncoding RNAs (ncRNAs) are a class of RNA molecules with little or no protein-coding potential. Emerging evidence indicates that ncRNAs are frequently dysregulated and play pivotal roles in the pathogenesis of pancreatic cancer. Their aberrant expression can arise from chromosomal abnormalities, dysregulated transcriptional control, and epigenetic modifications. ncRNAs function as protein scaffolds or molecular decoys to modulate interactions between proteins and other biomolecules, thereby regulating gene expression and contributing to pancreatic cancer progression. In this review, we summarize the mechanisms underlying ncRNA dysregulation in pancreatic cancer, emphasize the biological significance of ncRNA-protein interactions, and highlight their clinical relevance. A deeper understanding of ncRNA-protein interactions is essential to elucidate molecular mechanisms and advance translational research in pancreatic cancer.

Lysyl oxidase-like-1 (LOXL1) is a copper-dependent amine oxidase that maintains the structural integrity of the extracellular matrix (ECM) by catalyzing the cross-linking of collagen and elastin. However, aberrations in LOXL1 expression can contribute to diseases like glaucoma, tissue fibrosis, and cancer. LOXL1 has been found to be overexpressed in various malignancies, playing a pivotal role in tumor growth and metastasis. Although some studies suggest tumor-suppressive attributes of LOXL1, its role in tumorigenesis remains controversial. Research on LOXL1 has been primarily focused on pseudoexfoliation syndrome/glaucoma, with limited reviews on its impact on cancer. This review aims to explore LOXL1 comprehensively, including its structure, biological effects, and regulatory processes. Emphasis is placed on understanding the relationship between LOXL1 and tumorigenesis, specifically how LOXL1 influences tumor microenvironment remodeling, tumorigenesis, and metastasis. The review also discusses potential therapeutic strategies targeting LOXL1 for anti-fibrosis and anti-tumor interventions.

Benzaldehyde (BA) is an aromatic aldehyde found in fruits that has been studied as a potential anticancer agent on the basis of its ability to inhibit transformation in mouse embryo cells and to suppress metastasis in mice.

We investigated the cytotoxic effects of BA on cancer cells, and probed its effects on intracellular signaling pathways. The anticancer effects of BA in vivo were studied by using a mouse orthotopic transplantation model of pancreatic cancer.

BA inhibited the growth of osimertinib- or radiation-resistant cancer cells as well as the interaction between 14-3-3ζ and its client proteins. The interaction of 14-3-3ζ with the Ser28-phosphorylated form of histone H3 (H3S28ph) was implicated in treatment resistance and the transcriptional regulation of genes related to epithelial-mesenchymal transition and stemness, including E2F2, SRSF1, and ID1. Treatment of mice with a BA derivative inhibited pancreatic tumor growth and lung metastasis, as well as suppressed a state of epithelial-mesenchymal plasticity (EMP) of tumor cells.

The interaction between 14-3-3ζ and H3S28ph plays a key role in EMP and treatment resistance in cancer. The ability of BA to inhibit this and other interactions of 14-3-3ζ offers the potential to overcome treatment resistance and to suppress metastasis.

Following prolonged liver injury, a small fraction of hepatocytes undergoes reprogramming to become cholangiocytes or biliary epithelial cells (BECs). This physiological process involves chromatin and transcriptional remodeling, but the epigenetic mediators are largely unknown. Here, we exploited a lineage-traced model of liver injury to investigate the role of histone post-translational modification in biliary reprogramming. Using mass spectrometry, we defined the repertoire of histone marks that are globally altered in quantity during reprogramming. Next, applying an in vivo CRISPR screening approach, we identified seven histone-modifying enzymes that alter the efficiency of hepatobiliary reprogramming. Among these, the histone methyltransferase and demethylase Nsd1 and Kdm2a were found to have reciprocal effects on H3K36 methylation that regulated the early and late stages of reprogramming, respectively. Although loss of Nsd1 and Kdm2a affected reprogramming efficiency, cells ultimately acquired the same transcriptomic states. These findings reveal that multiple chromatin regulators exert dynamic and complementary activities to achieve robust cell fate switching, serving as a model for the cell identity changes that occur in various forms of physiological metaplasia or reprogramming.

Posterior capsular opacification (PCO) causes the vision that has been restored after cataract surgery to become blurred again. YAG laser treatment for PCO not only incurs additional costs but also poses risks of complications, including glaucoma and retinal disorders. Effective prevention and management of PCO remain an area requiring active research. Photodynamic therapy (PDT) utilizes a photosensitizer (PS) to transform oxygen into reactive oxygen species (ROS) under specific wavelengths of light, thereby inducing apoptosis. Given its minimal invasiveness and high specificity, PDT has been extensively applied in the treatment of conditions characterized by abnormal cell proliferation, such as tumors. Considering the pathogenesis of PCO, PDT has demonstrated promising clinical application potential in ophthalmic disease treatment. This review examines the impact of photodynamic therapy on the biological behavior of lens epithelial cells (LECs) and its efficacy in treating PCO. It also discusses the advantages and disadvantages of different photosensitizers and their clinical application potential.

Cellular biomechanics plays a critical role in cancer metastasis and tumor progression. Existing studies on cancer cell biomechanics are mostly conducted in flat 2D conditions, where cells' behavior can differ considerably from those in 3D physiological environments. Despite great advances in developing 3D in vitro models, probing cellular elasticity in 3D conditions remains a major challenge for existing technologies. In this work, optical Brillouin microscopy is utilized to longitudinally acquire mechanical images of growing cancerous spheroids over the period of 8 days. The dense mechanical mapping from Brillouin microscopy enables us to extract spatially resolved and temporally evolving mechanical features that were previously inaccessible. Using an established machine learning algorithm, it is demonstrated that incorporating these extracted mechanical features significantly improves the classification accuracy of cancer cells, from 74% to 95%. Building on this finding, a deep learning pipeline capable of accurately differentiating cancerous spheroids from normal ones solely using Brillouin images have been developed, suggesting the mechanical features of cancer cells can potentially serve as a new biomarker in cancer classification and detection.

The insulin-like growth factor receptor (IGF-1R) axis drives cellular growth, survival and chemoresistance in colorectal cancer (CRC) by promoting proliferative signaling, anti-apoptotic effects and epithelial-mesenchymal transition (EMT). Targeting the IGF-1R pathway is therefore a promising strategy, not only for overcoming drug resistance, but also for reducing migration and metastatic behavior related to EMT. The present study aimed to evaluate the potential of picropodophyllin (PPP), a selective IGF-1R inhibitor, to enhance the effects of oxaliplatin (OX) in HCT116 and OX-resistant HCT116-R cells. Cell viability was evaluated using a resazurin-based assay following 48-h combination treatment with OX at its IC50 concentrations (HCT116 cells, 53 µM and HCT116-R cells, 324 µM) and PPP (1 µM). Migration was assessed using wound healing assays, with images captured and analyzed at 0 and 48 h. Additionally, immunofluorescence staining was performed to assess E-cadherin and vimentin expression, evaluating epithelial and mesenchymal characteristics. In HCT116-R cells, the combination of OX (53 µM) and PPP significantly reduced cell viability by 0.65-fold compared with OX alone (P=0.0286). Wound healing assays demonstrated that combining PPP with OX (53 and 324 µM) significantly decreased migration, with 0.34-fold and 0.22-fold reductions, respectively (P<0.05). Immunofluorescence staining revealed that this combination also significantly increased E-cadherin expression, by 1.37- and 1.63-fold, respectively (P<0.05), indicating the role of PPP in enhancing epithelial characteristics and reducing EMT-related drug resistance. These findings highlight the potential for combining PPP with OX to enhance the cytotoxic and anti-metastatic effects of OX in chemo-resistant CRC cells, thus offering a promising strategy for overcoming drug resistance and improving patient outcomes in CRC treatment.

Cellular processes such as proliferation, differentiation, and tissue homeostasis are significantly influenced by the Wnt/β-catenin signaling pathway. Dysregulation of this pathway has been implicated in the development of various types of cancer. This study focuses on the emerging role of kinesin superfamily proteins (KIFs) in modulating cancer signaling. KIFs, a group of motor proteins, have attracted attention for their dual roles in intracellular transport: facilitating the cellular entry of Wnt ligands and contributing to the assembly of the β-catenin destruction complex. The study explores the interactions between KIFs and the Wnt/β-catenin pathway, identifying specific KIFs that interact with key components of the signaling cascade and examining their roles in cancer progression. Furthermore, it evaluates therapeutic strategies targeting KIFs to suppress aberrant Wnt activity in cancer and investigates how KIF-mediated transport spatially and temporally regulates Wnt signaling. The insights provided could guide future research into the role of KIFs in cancer biology and their involvement in oncogenic signaling pathways.

Epithelial-mesenchymal transition (EMT) plays critical roles in cancer progression and metastasis. Thus, the exploration of the molecular mechanism regulating EMT would provide potential opportunities for the therapy of metastatic ovarian cancer (OC). Herein, we investigated the putative role of KMT2A in modulating EMT and metastasis in OC. The expression of KMT2A in OC was detected by Western blot and immunohistochemistry and its relationship with clinicopathological factors was analyzed. The effect of KMT2A on the biological behavior of OC cells was examined. Moreover, the expressions of EMT-associated proteins were detected in vivo and vitro by Western blot, immunofluorescence, and immunohistochemistry. KMT2A was highly expressed in OC cell lines and tissues and was positively correlated with advanced International Federation of Gynecology and Obstetrics (FIGO) stage, pathological grade, and metastasis. KMT2A overexpression was correlated with poor prognosis. Suppression of KMT2A inhibited OC cells proliferation, migration, and invasion and induced their apoptosis in vitro and vivo. In contrast, the ectopic expression of KMT2A had the opposite effects. Furthermore, KMT2A knockdown inhibited TGF-β-induced EMT in OC and reduced the phosphorylation levels of Smad2. Taken together, these observations demonstrate that KMT2A could promote the malignant behavior of OC by activating TGF-β/Smad signaling pathway and may be a potential prognostic biomarker and therapeutic target for OC.