Search Results (5,347)

The Hippo, as a central pathway regulating cell proliferation, apoptosis, stem cell homeostasis and organ development, is closely associated with the onset and progression of tumors, metabolic reprogramming, drug resistance and immune evasion when it is abnormally inactivated. The Hippo not only directly promotes tumor cell proliferation, maintains cancer stem cell properties, and mediates metabolic reprogramming and treatment resistance, but also reshapes the tumor microenvironment(TME) by regulating the formation, heterogeneity and function of cancer-associated fibroblasts (CAFs). Furthermore, it mediates tumor immunosuppression and immune evasion by modulating programmed death-ligand 1(PD-L1) expression, T-cell function, macrophage polarization and cytokine secretion. At the same time, inflammatory cytokines, growth factors, metabolites and physical signals within the TME can negatively regulate the activity of the Hippo, creating a pro-tumor positive feedback loop. This article provides a systematic review of the composition and regulation of the Hippo , its mechanisms of action in the biological behavior of tumor cells and interactions within the tumor microenvironment, as well as progress in the development of drugs targeting this pathway. It offers a theoretical basis for a deeper understanding of the role of the Hippo in tumors and for the development of novel anti-tumor therapeutic strategies. Full article

Ponatinib, a third-generation BCR::ABL1 inhibitor, has antileukemic activity but is associated with cardiovascular toxicity, for which transcriptome-level responses remain incompletely characterized. Here, we defined a ponatinib-associated transcriptomic signature and examined its mechanistic implications using two public RNA sequencing (RNA-Seq) datasets: GSE186341 (11 cancer cell lines treated with kinase inhibitors) and GSE217421 (induced pluripotent stem cell (iPSC)-derived cardiomyocytes treated with approved drugs). Principal component analysis (PCA) and k-means clustering were used to define expression-based subgroups of vehicle-treated (DMSO) controls. DESeq2, followed by fixed-effect meta-analysis, estimated subgroup-specific treatment effects and pooled effect estimates across subgroups. In GSE186341, we identified 2,639 meta-analytic differentially expressed genes (meta-DEGs). Among these, 81 genes were also differentially expressed in GSE217421 after ponatinib treatment, identifying an overlapping gene set across datasets. In contrast, imatinib showed no overlap with these 81 genes under the same cross-dataset analysis framework. Cardiotoxicity-relevant functions were represented by directionally consistent genes linked to cardiac repolarization-associated ion handling (KCNN3), insulin-responsive metabolic regulation (FOXO1, HK2), cyclic adenosine monophosphate (cAMP)-responsive stress signaling (RAPGEF3), and mitochondrial homeostasis and redox regulation (MCL1, GCH1). Collectively, these results define a ponatinib-associated transcriptomic signature and nominate cross-dataset transcript-level candidates for subsequent mechanistic and experimental validation in ponatinib-associated cardiotoxicity. Full article

Background: Carbonic Anhydrases (CAs) represent regulators of cell adaptation to hypoxia, pH regulation, and metabolic fitness. Among cancers, multiple myeloma (MM) is a plasma cell malignancy sustained by hypoxia-driven metabolic adaptation, extracellular acidification, and redox imbalance. Tight regulation of tumor extracellular pH, mediated by Carbonic Anhydrases IX and XII, is crucial for myeloma survival, progression, and stemness, making these isoforms attractive therapeutic targets. Methods: We designed and synthesized a library of terpenoid-based hybrids by derivatizing chlorothymol and 4-isopropyl-3-methylphenol with either the natural coumarin umbelliferon or the 2,2′-dipicolylamine (DPA) scaffold. This chemical strategy aimed to selectively inhibit tumor-associated CAs IX/XII through coumarin- or DPA-mediated recognition, while terpenoid fragments were introduced to enhance lipophilicity, membrane permeability, and potential redox-modulating properties. The compounds were tested by a Stopped-Flow assay for CA inhibition, in cell-based assays for antiproliferative properties and by means of several antioxidant assays. Results: The most active compounds, connecting the coumarin core to a terpenoid tail, inhibited the targeted CAs in the nanomolar range, showing up higher selectivity over off-target isoforms (I and II). In studies performed on MM cell lines, selected derivatives reduced viability (IC₅₀ = 15.8–85.4 µM) and displayed favorable selectivity over normal cells. In silico investigations suggested that the compounds were able to interact selectively with the target enzymes. Conclusions: Collectively, these results support a dual-targeting strategy in which selective inhibition of tumor-associated CAs, combined with redox modulation, interferes with adaptive mechanisms of MM cells, providing a rational framework for the development of multifunctional agents against metabolically resilient hematological malignancies. Full article

Background/Objectives: Pancreatic adenocarcinoma remains one of the most lethal malignancies, largely due to aggressive biological behavior and limited available insight into biomarker-based prognostic stratification. The aim of our research was to investigate the role of macrophage migration inhibitory factors (MIFs), interleukin-8 (IL-8/CXCL8), and stem cell factors (SCFs) in pancreatic adenocarcinoma. Methods: In this single-center study, sixty hospitalized patients diagnosed with pancreatic adenocarcinoma were prospectively enrolled, and a cross-sectional analysis of baseline cytokine levels was performed. Serum MIF, IL-8/CXCL8, and SCF were assessed in a single analytical run using Luminex xMAP technology. Results: Elevated MIF and IL-8/CXCL8 levels characterized an inflammatory phenotype, associated with leukocytosis, neutrophilia, increased fibrinogen levels, and unequal prevalence of new-onset diabetes. Higher MIF levels were further associated with larger tumor dimension, while IL-8/CXCL8 was associated with increased bilirubin level and recent weight loss (p < 0.05). In contrast, increased SCF predicted a dissemination phenotype as defined by metastasis occurrence (65.4% vs. 28.6%, p = 0.012). SCF demonstrated significant discriminatory ability for metastasis (AUC 0.712, p = 0.013) and remained significantly associated in multivariable analysis. Conclusions: MIF and IL-8/CXCL8 primarily reflect inflammation-driven processes, whereas SCF identifies a dissemination-dominant phenotype, suggesting distinct biological pathways underlying disease progression in pancreatic cancer. Full article

New anticancer therapeutic strategies, including targeting of iron dysregulation in affected cancer types and stages, are urgently needed to decrease the associated annual cancer death rate of about 10 million worldwide. Many tumours evade treatment and support metastatic potential by effluxing iron and upregulating antioxidant systems, leading to suppression of lipid peroxidation and ferroptotic cell death. Similarly, many tumours manipulate the tumour microenvironment (TME) by ensuring the continuous supply of iron. This involves phenotypic modulation of immune cells, including macrophages, neutrophils, regulatory T lymphocytes, and natural killer cells, as well as fibroblasts, contributing to immune evasion and tumour growth. In particular, tumour-associated macrophages (TAMs), which may account for about half of the tumour’s bulk, become progressively heavily loaded with iron and can be detected by magnetic resonance imaging (MRI) technologies. Clinically effective iron chelation therapy protocols in iron-overloaded conditions using the chelating drugs deferoxamine, deferasirox, and especially deferiprone can also potentially remove excess iron from TAMs and may decrease tumour malignancy. Deferiprone can also remove excess iron from iron-loaded renal cancer cells and potentially prevent metastasis in renal carcinoma. The anticancer potential of deferiprone has also been shown in other cancers, including iron removal in prostate cancer and through cancer stem cell inhibition in breast cancer. Many ongoing clinical trials using different drugs and experimental agents for inducing or modulating ferroptosis also support the translational potential of ferroptosis-based therapeutic strategies in selected categories of cancer patients. These advances highlight ferroptosis as a potential key metabolic vulnerability with relevance for treatment-resistant and metastatic tumours. Overall, iron chelation therapeutic approaches and ferroptosis-targeting may be considered for significant use as monotherapies or in combination with other anticancer drugs and could potentially improve therapeutic outcomes and limit disease progression and mortality in many cancers. Full article

Triple-negative breast cancer (TNBC) is one of the most aggressive and clinically challenging subtypes of breast cancer, defined by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. The lack of actionable molecular targets contributes to limited therapeutic options, frequent recurrence, and a high propensity for distant metastasis. Metastatic dissemination remains the principal cause of mortality in patients with TNBC and is driven by complex molecular mechanisms involving multiple interconnected signaling networks. This review summarizes current knowledge of the molecular mechanisms underlying metastatic progression in TNBC, with particular emphasis on signaling pathways that regulate tumor invasion, migration, and colonization of distant organs. We discuss the roles of key pathways, including PI3K/Akt, TGF-β, Wnt/β-catenin, NF-κB, and Rho/ROCK signaling, in the regulation of epithelial–mesenchymal transition, cytoskeletal remodeling, cancer stem cell phenotypes, and tumor–microenvironment interactions. A deeper understanding of these signaling networks may facilitate the identification of novel therapeutic targets and support the development of more effective strategies to limit metastatic disease in TNBC. Full article

Plant-derived peptides have become one of the most promising classes of compounds in cancer research due to their specificity, safety, and different therapeutic actions. Generally, plant peptides have a size of 2 to 100 amino acids, and they can be extracted from different parts of the plant including leaves, seeds, stems, and roots. The present review brings together more than 300 prominent plant peptides, their sources, structural classes, extraction methods, anticancer effects, and mechanisms of action. We show the cytotoxicity of plant peptides against a wide range of human cancer cell lines (such as MCF-7, A549, HL-60, and HCT-116), as well as their effectiveness in preclinical animal models of cancer, where they resulted in lesser tumor growth and metastasis. Moreover, we go into the anticancer activity of plant peptides and reveal the interconnectedness of apoptosis, cell cycle arrest, angiogenesis inhibition, metastasis suppression, and the modulation of signaling pathways as some of the mechanisms through which plant peptides perform. In addition to their therapeutic potential, many of these peptides are derived from edible plant sources and can be delivered through functional foods or dietary supplements, offering a promising avenue for cancer prevention and adjunctive nutritional support. The review also touches upon the major hurdles in peptide drug development at present, such as stability, oral bioavailability, and large-scale production, while at the same time giving future perspectives that include bioengineering, nanotechnology-based delivery systems, and combination therapies for translating these natural products into clinical oncotherapeutics and health-promoting foods Full article

Hematological malignancies, including multiple myeloma (MM), leukemia, and lymphoma, represent a major global health burden, accounting for approximately 6.6% of all cancer cases and contributing to significant mortality. The evolutionary conserved WNT/β-catenin signaling pathway is a critical regulator of normal hematopoietic stem cell homeostasis, and its dysregulation is a hallmark of various hematological malignancies. Aberrant activation through mutations, overexpression of ligands, or disruption of the destruction complex drives uncontrolled proliferation, impaired differentiation, and therapeutic resistance to therapy in acute and chronic leukemias, lymphomas, and multiple myeloma. Therapeutic interventions targeting this pathway, such as GSK-3 inhibitors, β-catenin antagonists, and small molecules like CWP291 and salinomycin, have demonstrated promising antitumor effects. Furthermore, combining WNT/β-catenin inhibition with targeted or epigenetic therapies, such as venetoclax and chidamide, can produce synergistic antitumor effects and overcome chemoresistance. Despite this potential, clinical translation is hampered by on-target toxicities in healthy tissues, pathway complexity, and a lack of predictive biomarkers. We conclude that the future of WNT-directed therapy lies in developing biomarker-selective agents, advanced drug delivery systems to improve specificity, and exploring novel combinations with immunotherapy to harness the anti-tumor immune response. Full article

Background: Preparing patients for oncological therapy requires the elimination of foci of infection in accordance with Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) guidelines. Complications of dental caries, such as abscesses, can lead to sepsis. In Poland, the pre-oncologic dental treatment of patients with hematopoietic disorders does not yet meet MASCC/ISOO standards; however, an inventory of the current status of dental care for these patients is ongoing. The aim of this study was to investigate the frequency of dental caries and to define the local caries risk factors in adult patients prior to Hematopoietic Stem Cell Transplantation (HSCT) as a part of anticancer therapy. Additionally, the time available for dental treatment was assessed. Methods: A total of 302 patients were examined. Dental status was determined based on the number of decayed, missing and filled teeth and on treatment needs. Local caries risk factors, such as poor dietary habits, insufficient oral hygiene, and symptoms of reduced salivary flow, were examined. The diet was assessed using a questionnaire; tooth cleaning efficiency was assessed as a percentage of dental surfaces with biofilm. Symptoms of reduced salivary flow were determined by subjective and clinical signs of low salivary secretion. Results: Active (progressive) dental caries was diagnosed in 85.2% of patients. Insufficient oral hygiene had been found in 71.52% of those examined. Symptoms of hyposalivation were present in 85% of patients. In 31% of cases, time available for dental treatment prior to HSCT was too short. Conclusions: Tooth decay, the presence of caries risk factors, and insufficient time for oral treatment in patients submitted to HSCT represent a serious clinical problem. There is a clear need to establish comprehensive oral health protocols aimed at providing patients with appropriate, urgent dental care. Furthermore, coordination between oncologists and dentists in Poland must be improved. Currently patients are rarely referred to a dentist before starting anticancer therapy; those scheduled to hematopoietic stem cell transplantation, usually see a dentist too late. Full article

Triple-negative breast cancer (TNBC) remains a significant challenge in oncology, contributing to a significant portion of cancer-related deaths among women. Current therapeutic options, including chemotherapy, surgery, radiation, and hormonal targeting therapies, exhibit limited efficacy, necessitating the exploration of innovative treatment modalities. The emergence of drug resistance and the persistence of cancer stem cells (CSCs) further emphasize the urgent need for novel therapeutic strategies. In this context, natural killer cell-derived extracellular vesicles (NK-EVs) have emerged as a promising cell-free therapeutic approach that exhibits high tumor infiltration and cytotoxicity against cancer cells and CSCs. This study aims to investigate the efficacy of NK-EVs as a therapeutic strategy for TNBC using various clinically relevant models, including patient-derived xenografts. Pathway analysis suggests strong activation of apoptosis via canonical caspase activation, as well as necrosis, thereby confirming the important cytotoxic effect of NK-EVs. Interestingly, NK-EVs were also found to suppress TNBC CSCs by disrupting their functionality and viability, and NK-EV treatment increased the expression of apoptosis markers in both CSCs and non-CSCs. By elucidating the therapeutic efficacy and translational potential of NK-EV-based interventions in TNBC, these findings offer critical insights for the development of future immunotherapeutic strategies against this aggressive subtype of breast cancer. Full article

Breast cancer stem-like cells (bCSCs) fundamentally represent a highly dynamic “immune-adaptive functional state” rather than a fixed cellular lineage, serving as the core engine driving tumor recurrence, metastasis, and therapeutic resistance. Despite rapid advances, the heterogeneity of bCSC states and their intricate interactions with the immune microenvironment lack systematic integration. This review centers on the dynamic evolution and niche adaptation of bCSCs. First, we systematically dissect the multilayered regulatory network maintaining stemness, encompassing core transcription factors, epigenetic–metabolic coupling, and the synergistic mechanisms of critical signaling pathways such as Wnt and Notch. Second, we propose a trinary “stemness–immune–spatial” feedback model, elucidating how bCSCs achieve active immune evasion by downregulating antigen presentation, secreting immunosuppressive factors, and embedding within perivascular “immune-cold niches.” Finally, leveraging a multi-omics integration perspective, we reconstruct precision intervention strategies, exploring the synergistic potential of targeting stemness pathways in conjunction with immunotherapies like PD-1/PD-L1 blockade and STING agonists. Furthermore, we highlight the pivotal role of integrating organoids, PDX models, and AI-assisted decision systems in overcoming heterogeneity and enabling personalized treatment. By establishing a closed-loop framework spanning mechanistic insight to spatially precise intervention, this review aims to provide novel theoretical foundations and translational pathways to surmount the bottleneck of therapeutic resistance in breast cancer. Full article

Advances in organoid and other three-dimensional culture systems, single-cell and spatial transcriptomics, multi-omics, and high-resolution imaging are reshaping our understanding of the cellular origins and evolutionary trajectories of glioblastoma. When integrated with modern data science approaches, these technologies enable the construction of increasingly detailed molecular biographies of normal neural stem and progenitor cells as well as malignant stem-like cellular states. Such molecular biographies illuminate how developmental programs, cellular plasticity, and microenvironmental cues are co-opted during gliomagenesis. At the same time, progress in machine learning, immunotherapy, and precision molecular targeting is beginning to translate these biological insights into therapeutic strategies that specifically disrupt glioblastoma stem-like states. Together, these converging approaches provide a conceptual and technological framework for improved tumor modeling, earlier detection, and increasingly personalized therapies for malignant gliomas. Full article

Cancer progression is influenced by the dynamic interplay between tumor cells and the surrounding stromal microenvironment. Therapy-induced senescence (TIS) of stromal fibroblasts represents a common outcome of anticancer treatments, contributing to tumor progression through the senescence-associated secretory phenotype (SASP). While SASP cytokines promote cancer malignancy, the contribution of secreted metabolites from senescent cells remains poorly understood. Here, we investigate the role of senescent stromal metabolism in regulating prostate and ovarian cancer cell invasion. Conditioned media (CM) from TIS-induced human prostate (HPFs) and ovarian fibroblasts (HOFs) promote enhanced invasion of cancer cells. Invasion is partially preserved after exposure to boiled CM, suggesting a role for heat-stable metabolic factors. Metabolomic profiling of senescent fibroblasts-derived CM reveals a significant increase in Glutamine (Gln) levels, identifying senescent stromal fibroblasts as a previously unrecognized source of extracellular Gln in the tumor microenvironment (TME). Exposure of cancer cells to senescent CM increases Gln uptake, together with upregulation of the transporter SLC1A5 and increased intracellular Gln. This metabolic adaptation is associated with increased malignant phenotype including epithelial-to-mesenchymal transition (EMT) and stemness features. Extracellular Gln depletion, pharmacological inhibition of glutaminase-1 (GLS1) in cancer cells, or Gln synthetase (GS) silencing in fibroblasts markedly impair senescent fibroblasts CM-induced invasion, EMT markers expression, and stemness features in cancer cells. Stromal-derived Gln is associated with increased cancer cell invasion through activation of a redox-dependent NRF2/ETS1 signaling axis. Analysis of patient-derived transcriptomic datasets further suggests chemotherapy-associated upregulation of Gln metabolism and ETS1 expression. These findings identify senescent stromal-derived Gln as a key metabolic driver of prostate and ovarian cancer aggressiveness and reveal a TIS-associated metabolic vulnerability that could be explored in future preclinical studies. Full article

Genome editing is widely used and conceptually simple, yet in practice, it is hindered by laborious workflows and high costs. These challenges stem from the difficulty of identifying and isolating cells that contain the desired user-defined modifications, a problem compounded by the wide variability in editing efficiencies across cell types. While homology-directed repair (HDR) provides a mechanism for precise genome modification following nuclease-induced double-strand breaks (DSBs), it is frequently outcompeted by the dominant mutagenic non-homologous end-joining (NHEJ) pathway in mammalian cells. Therefore, we developed a novel enrichment method, Essential HDRescue, to increase the frequency of HDR events at a target site by co-targeting an essential genomic locus. Using both intrinsic positive and negative selection at a common essential gene, we enabled enrichment of precise editing events at a second, unlinked target site. We demonstrated that co-targeting essential genes in cancer cell lines and iPSCs increased HDR rates without the need for an exogenous reporter or selective drug. Analysis of resulting clones revealed that Essential HDRescue produced up to a 6-fold increase in single-allele edits and an ~4-fold increase in homozygous edits relative to single-targeted controls. By harnessing the intrinsic cellular dependencies that arise from DSB repair at essential loci, Essential HDRescue offers a widely applicable method to improve precise genome editing outcomes in mammalian cells, leaving only a minimal, protein-silent scar at the essential gene. Full article

Triple-negative breast cancer (TNBC) remains one of the most challenging subtypes of breast cancer to treat, defined by its molecular heterogeneity, absence of hormone receptors, and poor clinical outcomes. While this difficulty with cancer cells persists even in the presence of chemotherapy and immune checkpoint inhibitors (ICIs), one critical factor linked to both chemoresistance and immune escape is autophagy. Autophagy is a cellular process with lysosomal recycling function. In TNBC, autophagy paradoxically shifts from tumor-suppressive to a tumor-promoting role. Autophagy was initially known to maintain genomic stability and alleviate oxidative damage. In TNBC, cancer cells use autophagy to detoxify platinum-induced DNA. damage, clear damaged mitochondria via mitophagy, recycle critical macromolecules, and sustain dormancy in cancer stem-like cells (CSCs). At the same time, the process of autophagic flux facilitates immune evasion, including PD-L1 expression stabilization, MHC-I degradation, and the establishment of an immunosuppressive tumor microenvironment (TME). The review encapsulates the progressive concepts of molecular regulation of autophagy, which involve key factors such as ULK1, VPS34, and non-coding RNAs (ncRNAs). These factors play a significant role in chemoresistance, taxanes, anthracyclines, and platinum compounds. The review also discusses various strategies for translation that aim to circumvent or suppress autophagy-mediated chemoresistance, including autophagy inhibitors, natural compounds, and nanoparticle-based formulations, with a focus on their synergistic potential with ICIs and chemotherapeutic agents. Targeting autophagy has shown considerable potential for effectively addressing chemoresistance in TNBC. Future studies should focus on addressing chemoresistance and immunoresistance through autophagy-based therapies. Full article