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Keywords = epithelial-mesenchymal or mesenchymal-epithelial transition

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31 pages, 736 KB  
Review
Inside the Tumor: Decoding the Feline Mammary Tumor Microenvironment and Its Prognostic Value—A Review
by Joana Rodrigues-Jesus, Ana Canadas-Sousa, Hugo Vilhena and Patrícia Dias-Pereira
Vet. Sci. 2025, 12(10), 959; https://doi.org/10.3390/vetsci12100959 - 8 Oct 2025
Abstract
The tumor microenvironment (TME) comprises neoplastic and stromal cells, and extracellular matrix elements, all engaging in a complex interplay that ultimately dictates tumorigenesis, cancer progression, and therapeutic response. While extensive research on the TME has been conducted in human oncology, data on its [...] Read more.
The tumor microenvironment (TME) comprises neoplastic and stromal cells, and extracellular matrix elements, all engaging in a complex interplay that ultimately dictates tumorigenesis, cancer progression, and therapeutic response. While extensive research on the TME has been conducted in human oncology, data on its veterinary counterpart, particularly in feline mammary tumors (FMTs), are still scarce. In this review, we explore current understanding of feline mammary carcinoma (FMC) microenvironment, focusing on tumor necrosis, fibrosis, angiogenesis, adipose tissue tumor-associated inflammation, extracellular vesicles, and epithelial–mesenchymal transition (EMT) and their prognostic implications. In FMC, remodeling of collagen fibers, cancer-associated fibroblasts (CAFs), regulatory T cells (Tregs) and elevated serum leptin have been associated with poor prognosis, whereas stromal cytotoxic T cells correlate with more favorable outcomes. By contrast, findings on necrosis and pro-angiogenic factors remain inconsistent, and research on extracellular vesicles (EVs) is still in its early stages. This review presents insights from human breast cancer (HBC) that further support and elucidate the potential relevance of these TME components. As FMCs are highly aggressive tumors, a deeper understanding of their microenvironment could not only improve prognostic accuracy but also uncover novel therapeutic targets. Furthermore, due to their similarities, FMCs offer a potential valuable spontaneous model for HBC, particularly for the aggressive triple-negative phenotypes. Full article
(This article belongs to the Special Issue Comparative Oncology of Companion Animals)
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30 pages, 1765 KB  
Review
Adipocyte–Tumor Interactions in the Bone Marrow Niche: Implications for Metastasis and Therapy
by Alhomam Dabaliz, Mohammad Nawar Al Hakawati, Najmuddeen Alrashdan, Sarah Alrashdan, Mohamad Bakir and Khalid S. Mohammad
Int. J. Mol. Sci. 2025, 26(19), 9781; https://doi.org/10.3390/ijms26199781 - 8 Oct 2025
Abstract
Bone metastases continue to be a major cause of morbidity and mortality in patients with advanced cancers, driven by the dynamic remodeling of the bone marrow niche. Traditionally viewed as passive space-fillers, bone marrow adipocytes (BMAs) are now recognized as active regulators of [...] Read more.
Bone metastases continue to be a major cause of morbidity and mortality in patients with advanced cancers, driven by the dynamic remodeling of the bone marrow niche. Traditionally viewed as passive space-fillers, bone marrow adipocytes (BMAs) are now recognized as active regulators of tumor growth, therapeutic resistance, and skeletal pathology. BMAs comprise a significant portion of the adult marrow space, particularly in aging and obesity, and facilitate metastatic colonization through various mechanisms. These include metabolic coupling, where adipocyte-derived fatty acids fuel tumor oxidative phosphorylation; the secretion of adipokines such as leptin and IL-6, which promote epithelial-to-mesenchymal transition, invasion, and immune evasion; regulation of osteoclastogenesis via RANKL expression; and the release of extracellular vesicles that reprogram cancer cell metabolism. Clinical and experimental studies show that BMA expansion correlates with increased tumor burden and poorer outcomes in breast, prostate, lung cancers, and multiple myeloma. Additionally, BMAs actively promote therapeutic resistance through metabolic rewiring and drug sequestration. Experimental models, ranging from in vitro co-cultures to in vivo patient-derived xenografts, demonstrate the complex roles of BMAs and also reveal important translational gaps. Despite promising preclinical approaches such as metabolic inhibitors, PPARγ modulation, adipokine blockade, and lifestyle changes, no therapies directly targeting BMAs have yet reached clinical practice. This review compiles current evidence on the biology of BMAs, their tumor-promoting interactions, and potential therapeutic strategies, while also highlighting unresolved questions about BMA heterogeneity, lipid flux, and immunometabolic crosstalk. By revealing how bone marrow adipocytes actively shape the metastatic niche through metabolic, endocrine, and immunological pathways, this review highlights their potential as novel biomarkers and therapeutic targets for improving the management of bone metastases. Full article
(This article belongs to the Special Issue Novel Molecular Pathways in Oncology, 3rd Edition)
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14 pages, 286 KB  
Review
Molecular Landscape of Prostate Cancer Across Age Groups: Impact on Prognosis and Treatment Outcomes
by Magdalena Julita Orzechowska and Andrzej K. Bednarek
Int. J. Mol. Sci. 2025, 26(19), 9777; https://doi.org/10.3390/ijms26199777 - 8 Oct 2025
Abstract
Prostate cancer (PC) has long been considered a disease of older men. Still, a significant and concerning rise in diagnoses among younger men has revealed a biologically distinct and more aggressive clinical entity: early-onset prostate cancer (EO-PC). This comprehensive review synthesizes the molecular [...] Read more.
Prostate cancer (PC) has long been considered a disease of older men. Still, a significant and concerning rise in diagnoses among younger men has revealed a biologically distinct and more aggressive clinical entity: early-onset prostate cancer (EO-PC). This comprehensive review synthesizes the molecular and clinical evidence to demonstrate that PC is not a single disease, but a collection of distinct entities delineated by patient age. EO-PC is characterized by a strong genetic component, unique fusion events like TMPRSS2-ERG, and a highly plastic phenotype driven by intense Notch signaling and a hybrid epithelial-to-mesenchymal transition. In stark contrast, late-onset prostate cancer (LO-PC) is defined by a higher mutational burden, an epigenetic “field defect” that accumulates with age, and a predominantly immunosuppressive tumor microenvironment. These profound biological differences have significant implications for diagnosis, prognosis, and therapeutic strategies. Traditional prognostic tools, such as the Gleason score, are often insufficient to capture the full spectrum of risk in younger men. The divergent molecular landscapes of EO-PC and LO-PC necessitate a fundamental shift from a standard approach to an age-aware precision medicine framework. This review highlights key therapeutic targets and underscores the critical need for a new paradigm in PC management to improve patient outcomes. Full article
(This article belongs to the Collection Latest Review Papers in Molecular Oncology)
24 pages, 8968 KB  
Article
Oncogenic Role of SAMD4B in Breast Cancer Progression by Activating Wnt/β-Catenin Pathway
by Jia-Hui Li, Xin-Ya Wang, Huan-Xi Song, Xiao-Fei Nie and Li-Na Zhang
Biomolecules 2025, 15(10), 1423; https://doi.org/10.3390/biom15101423 - 7 Oct 2025
Abstract
The Sterile alpha motif domain-containing protein 4 (SAMD4) family consists of two evolutionarily conserved and highly homologous RNA-binding proteins, SAMD4A and SAMD4B. Previous studies have established SAMD4A as a tumor suppressor that is downregulated in breast cancer, while the function of SAMD4B in [...] Read more.
The Sterile alpha motif domain-containing protein 4 (SAMD4) family consists of two evolutionarily conserved and highly homologous RNA-binding proteins, SAMD4A and SAMD4B. Previous studies have established SAMD4A as a tumor suppressor that is downregulated in breast cancer, while the function of SAMD4B in tumorigenesis remains poorly defined. In this study, we observed that SAMD4B expression is upregulated in breast cancer. Functional assays demonstrated that SAMD4B facilitated breast cancer cell proliferation, migration, and invasion by inducing epithelial–mesenchymal transition (EMT). Furthermore, SAMD4B accelerated G1-to-S phase cell cycle progression by modulating p53 expression, collectively supporting an oncogenic function of SAMD4B in breast cancer. Mechanistically, we found that SAMD4B enhanced TCF/LEF transcriptional activity and upregulated the expression of β-catenin, Cyclin D1, c-Myc, and Axin2. Further investigations confirmed that SAMD4B activated the Wnt/β-catenin pathway by stabilizing β-catenin mRNA and increasing β-catenin protein expression level. Importantly, treatment with XAV-939, a specific Wnt/β-catenin pathway inhibitor, abrogated the pro-oncogenic effects of SAMD4B overexpression, including Wnt/β-catenin pathway activation, enhanced proliferation, and increased metastatic capacity. These results confirm that SAMD4B promotes the malignant phenotypes of breast cancer cells in a manner dependent on the Wnt/β-catenin pathway. In summary, our findings clarify that SAMD4B exerts an oncogenic role in breast cancer progression by activating the Wnt/β-catenin pathway. These data identify SAMD4B as a potential therapeutic target in breast cancer, although further in vivo investigations are required to validate its clinical relevance. Full article
(This article belongs to the Section Molecular Biomarkers)
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23 pages, 6082 KB  
Article
A Bibenzyl from Dendrobium pachyglossum Exhibits Potent Anti-Cancer Activity Against Glioblastoma Multiforme
by Hnin Mon Aung, Onsurang Wattanathamsan, Kittipong Sanookpan, Aphinan Hongprasit, Chawanphat Muangnoi, Rianthong Phumsuay, Thanawan Rojpitikul, Boonchoo Sritularak, Tankun Bunlue, Naphat Chantaravisoot, Claudia R. Oliva, Corinne E. Griguer and Visarut Buranasudja
Antioxidants 2025, 14(10), 1212; https://doi.org/10.3390/antiox14101212 - 7 Oct 2025
Abstract
Glioblastoma multiforme (GBM) is an aggressive brain tumor with limited treatment options and a poor prognosis. Natural phytochemicals from Dendrobium species, particularly bibenzyl derivatives, possess diverse pharmacological activities, yet their potential against GBM remains largely unexplored. Here, we investigated the anticancer activity of [...] Read more.
Glioblastoma multiforme (GBM) is an aggressive brain tumor with limited treatment options and a poor prognosis. Natural phytochemicals from Dendrobium species, particularly bibenzyl derivatives, possess diverse pharmacological activities, yet their potential against GBM remains largely unexplored. Here, we investigated the anticancer activity of 4,5,4′-trihydroxy-3,3′-dimethoxybibenzyl (TDB), a potent antioxidant bibenzyl derivative isolated from Dendrobium pachyglossum. In U87MG cells, TDB reduced viability in a dose- and time-dependent manner, suppressed clonogenic growth, induced apoptosis via Bax upregulation and Bcl-xL/Mcl-1 downregulation, and inhibited both mTORC1 and mTORC2 signaling. TDB also impaired cell migration and downregulated epithelial–mesenchymal transition (EMT)-associated proteins. Notably, TDB enhanced the cytotoxicity of temozolomide (TMZ), the current standard of care for GBM. These TMZ-sensitizing properties were further confirmed in patient-derived xenograft (PDX) Jx22 cells. To assess its potential for central nervous system delivery, blood–brain barrier (BBB) permeability was predicted using four independent in silico platforms—ADMETlab 3.0, LogBB_Pred, LightBBB, and BBB Predictor (Tree2C)—all of which consistently classified TDB as BBB-permeable. This predicted CNS accessibility, together with its potent anticancer profile, underscores TDB’s translational promise. Collectively, our findings identify TDB as a plant-derived antioxidant with multifaceted anti-GBM activity and favorable BBB penetration potential, warranting further in vivo validation and preclinical development as a novel therapeutic candidate for GBM. Full article
(This article belongs to the Special Issue Anti-Cancer Potential of Plant-Based Antioxidants)
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17 pages, 6519 KB  
Review
Fusobacterium Nucleatum in Colorectal Cancer: Relationship Among Immune Modulation, Potential Biomarkers and Therapeutic Implications
by Dalila Incognito, Giuliana Ciappina, Claudia Gelsomino, Antonio Picone, Pierluigi Consolo, Alessandra Scano, Tindara Franchina, Nicola Maurea, Vincenzo Quagliariello, Salvatore Berretta, Alessandro Ottaiano and Massimiliano Berretta
Int. J. Mol. Sci. 2025, 26(19), 9710; https://doi.org/10.3390/ijms26199710 - 6 Oct 2025
Viewed by 139
Abstract
Fusobacterium nucleatum (Fn) has been increasingly recognized as a crucial mediator of colorectal cancer (CRC) biology, particularly in microsatellite-stable (MSS) tumors, where immune checkpoint inhibitors (ICIs) have shown limited efficacy. Rather than representing a passive microbial passenger, Fn actively shapes tumor [...] Read more.
Fusobacterium nucleatum (Fn) has been increasingly recognized as a crucial mediator of colorectal cancer (CRC) biology, particularly in microsatellite-stable (MSS) tumors, where immune checkpoint inhibitors (ICIs) have shown limited efficacy. Rather than representing a passive microbial passenger, Fn actively shapes tumor behavior by adhering to epithelial cells, activating oncogenic signaling, and promoting epithelial–mesenchymal transition (EMT). At the same time, it remodels the tumor microenvironment, driving immune suppression through inhibitory receptor engagement, accumulation of myeloid-derived cells, and metabolic reprogramming of tumor-associated macrophages. These mechanisms converge to impair cytotoxic immunity and contribute to both intrinsic and acquired resistance to ICIs. Beyond immune escape, Fn interferes with conventional chemotherapy by sustaining autophagy and blocking ferroptosis, thereby linking microbial colonization to multidrug resistance. Most of these mechanisms derive from preclinical in vitro and in vivo models, where causal relationships can be inferred. In contrast, human data are mainly observational and provide correlative evidence without proving causality. No interventional clinical studies directly targeting Fn have yet been conducted. Its enrichment across the adenoma–carcinoma sequence and consistent detection in both tumor and fecal samples highlight its potential as a biomarker for early detection and patient stratification. Importantly, multidimensional stool assays that integrate microbial, genetic, and epigenetic markers are emerging as promising non-invasive tools for CRC screening. Therapeutic strategies targeting Fn are also under exploration, ranging from antibiotics and bacteriophages to multifunctional nanodrugs, dietary modulation, and natural microbiota-derived products. These approaches may not only reduce microbial burden but also restore immune competence and enhance the efficacy of immunotherapy in MSS CRC. Altogether, current evidence positions Fn at the intersection of microbial dysbiosis, tumor progression, and therapy resistance. A deeper understanding of its pathogenic role may support the integration of microbial profiling into precision oncology frameworks, paving the way for innovative diagnostic and therapeutic strategies in CRC. Full article
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23 pages, 7104 KB  
Article
A Patient-Derived Scaffold-Based 3D Culture Platform for Head and Neck Cancer: Preserving Tumor Heterogeneity for Personalized Drug Testing
by Alinda Anameriç, Emilia Reszczyńska, Tomasz Stankiewicz, Adrian Andrzejczak, Andrzej Stepulak and Matthias Nees
Cells 2025, 14(19), 1543; https://doi.org/10.3390/cells14191543 - 2 Oct 2025
Viewed by 202
Abstract
Head and neck cancer (HNC) is highly heterogeneous and difficult to treat, underscoring the need for rapid, patient-specific models. Standard three-dimensional (3D) cultures often lose stromal partners that influence therapy response. We developed a patient-derived system maintaining tumor cells, cancer-associated fibroblasts (CAFs), and [...] Read more.
Head and neck cancer (HNC) is highly heterogeneous and difficult to treat, underscoring the need for rapid, patient-specific models. Standard three-dimensional (3D) cultures often lose stromal partners that influence therapy response. We developed a patient-derived system maintaining tumor cells, cancer-associated fibroblasts (CAFs), and cells undergoing partial epithelial–mesenchymal transition (pEMT) for drug sensitivity testing. Biopsies from four HNC patients were enzymatically dissociated. CAFs were directly cultured, and their conditioned medium (CAF-CM) was collected. Cryopreserved primary tumor cell suspensions were later revived, screened in five different growth media under 2D conditions, and the most heterogeneous cultures were re-embedded in 3D hydrogels with varied gel mixtures, media, and seeding geometries. Tumoroid morphology was quantified using a perimeter-based complexity index. Viability after treatment with cisplatin or Notch modulators (RIN-1, recombination signal-binding protein for immunoglobulin κ J region (RBPJ) inhibitor; FLI-06, inhibitor) was assessed by live imaging and the water-soluble tetrazolium-8 (WST-8) assay. Endothelial Cell Growth Medium 2 (ECM-2) medium alone produced compact CAF-free spheroids, whereas ECM-2 supplemented with CAF-CM generated invasive aggregates that deposited endogenous matrix. Matrigel with this medium and single-point seeding gave the highest complexity scores. Two of the three patient tumoroids were cisplatin-sensitive, and all showed significant growth inhibition with the FLI-06 Notch inhibitor, while the RBPJ inhibitor RIN-1 induced minimal change. The optimized scaffold retains tumor–stroma crosstalk and provides patient-specific drug response data within days after operation, supporting personalized treatment selection in HNC. Full article
(This article belongs to the Special Issue 3D Cultures and Organ-on-a-Chip in Cell and Tissue Cultures)
28 pages, 1629 KB  
Article
Molecular Adaptations to Repeated Radiation Exposure in Triple-Negative Breast Cancer: Dysregulation of Cell Adhesion, Mitochondrial Function, and Epithelial–Mesenchymal Transition
by Noah Dickinson, Alyssa Murray, Megan Davis, Kaitlyn Marshall-Bergeron, Jessica Dougherty, Wuroud Al-Khayyat, Ramya Narendrula, Maggie Lavoie, Emma Mageau, Ronan Derbowka, A. Thomas Kovala, Douglas R. Boreham, Natalie Lefort, Christopher Thome, Tze Chun Tai and Sujeenthar Tharmalingam
Int. J. Mol. Sci. 2025, 26(19), 9611; https://doi.org/10.3390/ijms26199611 - 1 Oct 2025
Viewed by 201
Abstract
Radiation resistance presents a significant challenge in the treatment of triple-negative breast cancer (TNBC). To investigate the molecular adaptations associated with radiation therapy resistance, MDA-MB-231 cells were subjected to a repeated radiation (RR) regimen totaling 57 Gy over 11 weeks, followed by clonal [...] Read more.
Radiation resistance presents a significant challenge in the treatment of triple-negative breast cancer (TNBC). To investigate the molecular adaptations associated with radiation therapy resistance, MDA-MB-231 cells were subjected to a repeated radiation (RR) regimen totaling 57 Gy over 11 weeks, followed by clonal selection. The resulting radiation-adapted cells (MDA-MB-231RR) were analyzed using whole-transcriptome RNA sequencing, revealing substantial dysregulation of pathways related to cell adhesion, mitochondrial function, and epithelial–mesenchymal transition (EMT). These transcriptional changes were corroborated by functional assays. MDA-MB-231RR cells exhibited reduced expression of adhesion receptors (ITGB1, ITGA2, ITGA6) and extracellular matrix proteins (fibronectin, collagen, laminins), accompanied by significantly impaired cell adhesion to fibronectin, collagen, and laminin substrates. Mitochondrial dysfunction was supported by downregulation of oxidative phosphorylation genes (MTCO1, MTND1) and confirmed by JC-1 dye assays demonstrating a marked reduction in mitochondrial membrane potential. EMT-associated changes included increased mesenchymal markers and loss of epithelial markers (CTNNB1, SNAI2, CK19), consistent with enhanced migratory potential. Taken together, this study delineates key molecular features of radiation adaptation in TNBC, providing a foundation for the development of targeted therapies to overcome treatment resistance. Full article
(This article belongs to the Special Issue Cancer Progression and Therapeutic Resistance Mechanisms)
13 pages, 1249 KB  
Article
Dynamics of Telomerase-Based PD-L1 Circulating Tumor Cells as a Longitudinal Biomarker for Treatment Response Prediction in Patients with Non-Small Cell Lung Cancer
by Issei Sumiyoshi, Shinsaku Togo, Takahiro Okabe, Kanae Abe, Junko Watanabe, Yusuke Ochi, Kazuaki Hoshi, Shoko Saiwaki, Shuko Nojiri, Yuichi Fujimoto, Yukiko Namba, Yoko Tabe, Yasuo Urata and Kazuhisa Takahashi
Int. J. Mol. Sci. 2025, 26(19), 9583; https://doi.org/10.3390/ijms26199583 - 1 Oct 2025
Viewed by 235
Abstract
Noninvasive liquid biopsy for monitoring circulating tumor cells offers valuable insights for predicting therapeutic responses. We developed TelomeScan® (OBP-401), based on the detection of telomerase activity as a universal cancer cell marker and an indicator of the presence of viable circulating tumor [...] Read more.
Noninvasive liquid biopsy for monitoring circulating tumor cells offers valuable insights for predicting therapeutic responses. We developed TelomeScan® (OBP-401), based on the detection of telomerase activity as a universal cancer cell marker and an indicator of the presence of viable circulating tumor cells (CTCs) for patients with advanced non-small cell lung cancer (NSCLC). This system evaluated CTC subtypes characterized by programmed death ligand 1 (PD-L1), an immune checkpoint molecule, and vimentin, an epithelial–mesenchymal transition (EMT) marker, using a multi-fluorescent color microscope reader. The prognostic value and therapeutic responses were predicted by dynamically monitoring CTC counts in 79 patients with advanced NSCLC. The sensitivity and specificity values of TelomeScan® for PD-L1(+) cells (≥1 cell) were 75% and 100%, respectively, indicating high diagnostic accuracy. PD-L1(+) and EMT(+) in CTCs were detected in 75% and 12% of patients, respectively. Detection of PD-L1(+)CTCs and PD-L1(+)EMT(+) CTCs before treatment was associated with poor prognosis (p < 0.05). Monitoring of reducing and increasing PD-L1(+) CTC counts in two sequential samples (baseline, cycle 2 treatment) correlated significantly with partial response (p = 0.032) and progressive disease (p = 0.023), respectively. Monitoring PD-L1(+)CTCs by TelomeScan® will aid in anticipating responses or resistance to frontline treatments, optimizing precision medicine choices in patients with NSCLC. Full article
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24 pages, 1864 KB  
Article
SPP1 as a Potential Stage-Specific Marker of Colorectal Cancer
by Eva Turyova, Peter Mikolajcik, Michal Kalman, Dusan Loderer, Miroslav Slezak, Maria Skerenova, Emile Johnston, Tatiana Burjanivova, Juraj Miklusica, Jan Strnadel and Zora Lasabova
Cancers 2025, 17(19), 3200; https://doi.org/10.3390/cancers17193200 - 30 Sep 2025
Viewed by 137
Abstract
Background: Colorectal cancer is the third most diagnosed cancer and a leading cause of cancer-related deaths worldwide. Early detection significantly improves patient outcomes, yet many cases are identified only at late stages. The high molecular and genetic heterogeneity of colorectal cancer presents major [...] Read more.
Background: Colorectal cancer is the third most diagnosed cancer and a leading cause of cancer-related deaths worldwide. Early detection significantly improves patient outcomes, yet many cases are identified only at late stages. The high molecular and genetic heterogeneity of colorectal cancer presents major challenges in accurate diagnosis, prognosis, and therapeutic stratification. Recent advances in gene expression profiling offer new opportunities to discover genes that play a role in colorectal cancer carcinogenesis and may contribute to early diagnosis, prognosis prediction, and the identification of novel therapeutic targets. Methods: This study involved 142 samples: 84 primary tumor samples, 27 liver metastases, and 31 adjacent non-tumor tissues serving as controls. RNA sequencing was performed on a subset of tissues (12 liver metastases and 3 adjacent non-tumor tissues) using a targeted RNA panel covering 395 cancer-related genes. Data processing and differential gene expression analysis were carried out using the DRAGEN RNA and DRAGEN Differential Expression tools. The expression of six genes involved in hypoxia and epithelial-to-mesenchymal transition (EMT) pathways (SLC16A3, ANXA2, P4HA1, SPP1, KRT19, and LGALS3) identified as significantly differentially expressed was validated across the whole cohort via quantitative real-time PCR. The relative expression levels were determined using the ΔΔct method and log2FC, and compared between different groups based on the sample type; clinical parameters; and mutational status of the genes KRAS, PIK3CA, APC, SMAD4, and TP53. Results: Our results suggest that the expression of all the validated genes is significantly altered in metastases compared to non-tumor control samples (p < 0.05). The most pronounced change occurred for the genes P4HA1 and SPP1, whose expression was significantly increased in metastases compared to non-tumor and primary tumor samples, as well as between clinical stages of CRC (p < 0.001). Furthermore, all genes, except for LGALS3, exhibited significantly altered expression between non-tumor samples and samples in stage I of the disease, suggesting that they play a role in the early stages of carcinogenesis (p < 0.05). Additionally, the results suggest the mutational status of the KRAS gene did not significantly affect the expression of any of the validated genes, indicating that these genes are not involved in the carcinogenesis of KRAS-mutated CRC. Conclusions: Based on our results, the genes P4HA1 and SPP1 appear to play a role in the progression and metastasis of colorectal cancer and are candidate genes for further investigation as potential biomarkers in CRC. Full article
(This article belongs to the Special Issue Colorectal Cancer Metastasis (Volume II))
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38 pages, 1612 KB  
Review
Microengineered Breast Cancer Models: Shaping the Future of Personalized Oncology
by Tudor-Alexandru Popoiu, Anca Maria Cimpean, Florina Bojin, Simona Cerbu, Miruna-Cristiana Gug, Catalin-Alexandru Pirvu, Stelian Pantea and Adrian Neagu
Cancers 2025, 17(19), 3160; https://doi.org/10.3390/cancers17193160 - 29 Sep 2025
Viewed by 495
Abstract
Background: Breast cancer remains the most prevalent malignancy in women worldwide, characterized by remarkable genetic, molecular, and clinical heterogeneity. Traditional preclinical models have significantly advanced our understanding of tumor biology, yet consistently fall short in recapitulating the complexity of the human tumor [...] Read more.
Background: Breast cancer remains the most prevalent malignancy in women worldwide, characterized by remarkable genetic, molecular, and clinical heterogeneity. Traditional preclinical models have significantly advanced our understanding of tumor biology, yet consistently fall short in recapitulating the complexity of the human tumor microenvironment (TME), immune, and metastatic behavior. In recent years, breast cancer-on-a-chip (BCOC) have emerged as powerful microengineered systems that integrate patient-derived cells, stromal and immune components, and physiological stimuli such as perfusion, hypoxia, and acidic milieu within controlled three-dimensional microenvironments. Aim: To comprehensively review the BCOC development and application, encompassing fabrication materials, biological modeling of key subtypes (DCIS, luminal A, triple-negative), dynamic tumor–stroma–immune crosstalk, and organotropic metastasis to bone, liver, brain, lungs, and lymph nodes. Methods: We selected papers from academic trusted databases (PubMed, Web of Science, Google Scholar) by using Breast Cancer, Microfluidic System, and Breast Cancer on a Chip as the main search terms. Results: We critically discuss and highlight how microfluidic systems replicate essential features of disease progression—such as epithelial-to-mesenchymal transition, vascular invasion, immune evasion, and therapy resistance—with unprecedented physiological relevance. Special attention has been paid to the integration of liquid biopsy technologies within microfluidic platforms for non-invasive, real-time analysis of circulating tumor cells, cell-free nucleic acids, and exosomes. Conclusions: In light of regulatory momentum toward reducing animal use in drug development, BCOC platforms stand at the forefront of a new era in precision oncology. By bridging biological fidelity with engineering innovation, these systems hold immense potential to transform cancer research, therapy screening, and personalized medicine. Full article
(This article belongs to the Section Methods and Technologies Development)
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17 pages, 7291 KB  
Article
Salecan Suppresses Pancreatic Cancer Progression by Promoting Necroptosis via the RIPK1/MLKL Pathway
by Wenya Du, Rong Xu, Pengfei Chen, Jianxia Wen, Luchuanyang Sun and Xianggui Chen
Nutrients 2025, 17(19), 3090; https://doi.org/10.3390/nu17193090 - 28 Sep 2025
Viewed by 296
Abstract
Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor and leads to high human malignancy and mortality. Because PDAC is highly drug-resistant and current treatments have adverse reactions, exploring novel approaches for PDAC prevention and therapy is urgently needed. Methods: Antitumor activities of [...] Read more.
Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor and leads to high human malignancy and mortality. Because PDAC is highly drug-resistant and current treatments have adverse reactions, exploring novel approaches for PDAC prevention and therapy is urgently needed. Methods: Antitumor activities of Salecan were evaluated on multiple human pancreatic adenocarcinoma cells in vitro. Cell viability, colony formation, migration and invasion, flow cytometry, caspase-3 activity, qRT-PCR and Western blotting were monitored. RNA-seq was conducted to clarify the mechanism underlying Salecan’s inhibition of pancreatic cancer cell progression. Results: Here we show that Salecan, a naturally occurring polysaccharide of β-glucan, can significantly inhibit pancreatic cancer cell proliferation and exhibit no toxicity in normal cells. We find that Salecan impedes pancreatic cancer cell migration and invasion via the epithelial-to-mesenchymal transition (EMT) pathway. Mechanistically, through RNA sequencing, we reveal that Salecan induces pancreatic cancer cell necroptosis, instead of apoptosis. Moreover, Salecan’s anti-pancreatic cancer bioactivity is attributed to its promotion of the receptor-interacting protein kinase 1 (RIPK1) and mixed lineage kinase-like (MLKL) signaling pathway. Conclusions: Salecan can inhibit pancreatic cancer cell proliferation, migration and invasion in vitro and accelerate cell death by inducing the necroptosis via the MLKL/RIPK1 pathway. These findings identify that Salecan may become a potential functional food component for preventing and treating PDAC. Full article
(This article belongs to the Section Nutrition and Metabolism)
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37 pages, 1945 KB  
Review
Shikonin as a Dietary Phytochemical with Multi-Target Anti-Cancer Activities: From Molecular Mechanisms to Translational Applications
by Chun-Yik Lew, Yi-Teng Tang, Amanda Yee-Jing Lee, Zhi-Jian Chin, Wan-Ling Chang, Ching-Hsein Chen and Soi-Moi Chye
Nutrients 2025, 17(19), 3085; https://doi.org/10.3390/nu17193085 - 28 Sep 2025
Viewed by 479
Abstract
Shikonin, a dietary naphthoquinone phytochemical from the roots of Lithospermum erythrorhizon, has gained attention for its anticancer potential. Preclinical studies show that shikonin regulates multiple programmed cell death pathways, including apoptosis, necroptosis, ferroptosis, and pyroptosis, through mechanisms involving reactive oxygen species (ROS) [...] Read more.
Shikonin, a dietary naphthoquinone phytochemical from the roots of Lithospermum erythrorhizon, has gained attention for its anticancer potential. Preclinical studies show that shikonin regulates multiple programmed cell death pathways, including apoptosis, necroptosis, ferroptosis, and pyroptosis, through mechanisms involving reactive oxygen species (ROS) accumulation, mitochondrial dysfunction, and kinase-mediated signalling. Beyond cytotoxicity, shikonin suppresses metastasis by blocking epithelial–mesenchymal transition (EMT) and downregulating matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). It also disrupts tumour metabolism by targeting pyruvate kinase isoform M2 (PKM2) and modulating the Warburg effect. Evidence further indicates that shikonin can enhance the efficacy of chemotherapy, targeted therapy, immunotherapy, and radiotherapy, thereby contributing to the reversal of therapeutic resistance. To address limitations related to solubility and bioavailability, novel formulations such as nanoparticles, liposomes, and derivatives like β,β-dimethylacrylshikonin have been developed, showing improved pharmacological profiles and reduced toxicity in experimental models. Overall, the current literature identifies shikonin as a promising dietary phytochemical with diverse anticancer activities, therapeutic synergy, and formulation advances, while highlighting the need for clinical studies to establish its translational potential. Full article
(This article belongs to the Special Issue Anticancer Activities of Dietary Phytochemicals: 2nd Edition)
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15 pages, 780 KB  
Article
Reporter-Mediated Evaluation of the Circadian Oscillations of SNAIL Across In Vitro Models
by Kaitlyn Chhe, Bhavna Kalyanaraman, Sophie A. Spielberger, Hui-Hsien Lin, Stephanie R. Taylor and Michelle E. Farkas
Clocks & Sleep 2025, 7(4), 54; https://doi.org/10.3390/clockssleep7040054 - 28 Sep 2025
Viewed by 297
Abstract
The protein SNAIL has been widely studied for its roles in promoting cancer invasion and resistance to apoptosis. There are multiple contributors to its expression, including self- and circadian regulation, and it has been posited that SNAIL oscillates in a circadian manner. Given [...] Read more.
The protein SNAIL has been widely studied for its roles in promoting cancer invasion and resistance to apoptosis. There are multiple contributors to its expression, including self- and circadian regulation, and it has been posited that SNAIL oscillates in a circadian manner. Given the multiple factors involved, we sought to determine whether this is indeed the case. We developed a luciferase reporter that was used to demonstrate SNAIL’s rhythmic nature (SNAIL:luc) in the circadian model cell line, U2OS. Considering SNAIL’s relevance in breast cancer, we also assessed its oscillations in cellular models representing different levels of aggression. We incorporated the SNAIL:luc reporter in MCF10A breast epithelial cells, and MCF7 and MDA-MB-231 breast cancer cell lines, which are less and more aggressive, respectively. We found that SNAIL oscillations were present but weak in MCF7 and arrhythmic in MDA-MB-231 cells, correlating with those of core clock genes (BMAL1 and PER2) in these models. Surprisingly, MCF10A cells, whose core clock genes possess robust circadian expression patterns, did not have rhythmic oscillations of SNAIL. Our findings suggest that SNAIL is under circadian control, but this is cell line/tissue dependent, setting the stage for additional studies to better understand the impacts of various factors contributing to its expression. Full article
(This article belongs to the Section Human Basic Research & Neuroimaging)
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24 pages, 1263 KB  
Review
Shared and Context-Specific Mechanisms of EMT and Cellular Plasticity in Cancer and Fibrotic Diseases
by Victor Alexandre F. Bastos, Aline Gomes de Souza, Virginia C. Silvestrini Guedes and Thúlio M. Cunha
Int. J. Mol. Sci. 2025, 26(19), 9476; https://doi.org/10.3390/ijms26199476 - 27 Sep 2025
Viewed by 468
Abstract
Cellular plasticity enables cells to dynamically adapt their phenotype in response to environmental cues, a process central to development, tissue repair, and disease. Among the most studied plasticity programs is epithelial–mesenchymal transition (EMT), a transcriptionally controlled process by which epithelial cells acquire mesenchymal [...] Read more.
Cellular plasticity enables cells to dynamically adapt their phenotype in response to environmental cues, a process central to development, tissue repair, and disease. Among the most studied plasticity programs is epithelial–mesenchymal transition (EMT), a transcriptionally controlled process by which epithelial cells acquire mesenchymal traits. Originally described in embryogenesis, EMT is now recognized as a key driver in both tumor progression and fibrotic remodeling. In cancer, EMT and hybrid epithelial/mesenchymal (E/M) states promote invasion, metastasis, stemness, therapy resistance, and immune evasion. In fibrotic diseases, partial EMT (pEMT) contributes to fibroblast activation and excessive extracellular matrix deposition, sustaining organ dysfunction mainly in the kidney, liver, lung, and heart. This review integrates recent findings on the molecular regulation of EMT, including signaling pathways (TGF-β, WNT, NOTCH, HIPPO), transcription factors (SNAIL, ZEB, TWIST), and regulatory layers involving microRNAs and epigenetic modifications. Moreover, we discuss the emergence of pEMT states as drivers of phenotypic plasticity, functional heterogeneity, and poor prognosis. By comparing EMT in cancer and fibrosis, we reveal shared mechanisms and disease-specific features, emphasizing the translational relevance of targeting EMT plasticity. Finally, we explore how cutting-edge technologies, such as single-cell transcriptomics and lineage tracing, are reshaping our understanding of EMT across pathological contexts. Full article
(This article belongs to the Special Issue Cellular Plasticity and EMT in Cancer and Fibrotic Diseases)
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