Search Results (67)

Soft tissue sarcomas (STS) comprise a rare and highly heterogeneous group of mesenchymal-derived malignancies, accounting for less than 1% of all cancers and characterized by diverse histologic and molecular subtypes. Despite their low incidence, STS account for a disproportionate burden of cancer-related morbidity and mortality, largely driven by their risk of metastatic dissemination. Early detection of metastatic spread is a cornerstone of preoperative staging, treatment planning, and postoperative monitoring in patients with STS. Although conventional imaging modalities remain fundamental for surveillance of metastatic disease, they may fail to accurately detect metastatic sites and provide limited insight into tumor biology. Advances in precision medicine have positioned liquid biopsy as a minimally invasive approach for the analysis of tumor-derived material, facilitating characterization of tumor biology and identification of prognostic biomarkers. Circulating tumor cells (CTCs) represent intact and viable tumor cells that provide unique genomic and phenotypic traits that could not be assessed using acellular tumor-derived material. They have emerged as promising biomarkers for monitoring disease progression, assessing treatment response, and stratifying prognosis. Particularly, their clinical value as prognostic biomarkers has been established in epithelial-derived malignancies. Despite these advances, the role of CTCs in STS remains largely investigational, mainly due to STS heterogeneity and the lack of standardized protocols for detection across platforms. Therefore, this narrative review summarizes the biomolecular mechanisms underlying CTCs in STS, including the role of phenotypic plasticity in tumor intravasation, anoikis resistance and its interaction with the tumor microenvironment, and stem cell-like phenotypes in tumor initiation at distant sites. Furthermore, we discuss current methodologies for CTC detection, highlighting emerging approaches developed to address the limitations of conventional methods. Finally, we provide a critical overview of subtype-specific detection strategies, as well as their clinical implications in treatment response monitoring and prognostic assessment. Full article

Multicellular cancer cell aggregates, termed spheroids, are anoikis-resistant, avascular, heterogeneous structures responsible for transcoelomic metastasis of ovarian clear cell carcinoma (OCCC). OCCC is a rare subtype of ovarian cancer with high ARID1A gene mutation rates, resulting in genome-wide changes to H3K27Ac levels and histone deacetylase (HDAC) function. Our study investigated the utility of HDAC inhibitor (HDACi) treatment and H3K27Ac dynamics in OCCC spheroids. By comparing KOC-7c and 105C OCCC cell lines, which have opposing abilities to proliferate as spheroids, we revealed that KOC-7c and 105C spheroids differentially regulated H3K27Ac levels, which correlated with the sensitivity of KOC-7c and the resistance of 105C spheroids to H3K27Ac-altering HDACi treatment. RNA-seq of Entinostat-treated versus vehicle-treated spheroids resulted in a dramatic change in the 105C spheroid transcriptome such that it more closely resembled the proliferative KOC-7c transcriptome over the short term. Comparative pathway analysis identified preferential de-repression of a G2/M checkpoint gene program in 105C spheroids upon Entinostat treatment when compared directly to the KOC-7c spheroids. Our results suggest that the utility of HDACi in OCCC is highly context-dependent. Full article

Lactate dehydrogenase (LDH) is a key glycolytic enzyme that catalyzes the interconversion of pyruvate and lactate, with LDHA gaining particular attention for its overexpression in various malignancies and pivotal role in the Warburg effect-driven metabolic reprogramming. Elevated LDHA activity supports rapid ATP production under hypoxic conditions, maintains NAD⁺ regeneration, and promotes lactate accumulation, creating an acidic tumor microenvironment (TME) that favors invasion and immune evasion. Accumulating evidence demonstrates that LDHA is essential for primary tumor growth and critically involved in circulating tumor cell (CTC) survival, anoikis resistance, and metastatic spread. These functions are mediated by its regulation of adhesion molecules, cytoskeletal remodeling, and energy adaptation that enable CTCs to withstand mechanical shear stress and immune surveillance in the bloodstream. Pharmacological inhibition of LDHA, particularly via sodium oxamate (oxamate), has shown substantial potential in reducing metastasis and enhancing chemotherapy sensitivity in preclinical models. Oxamate has emerged as a promising candidate for metabolic cancer therapy due to its unique double effects on tumor metabolism and anti-tumor immunity, which are an advantage rarely highlighted in broader LDHA-focused reviews. This review synthesizes the molecular mechanisms through which LDHA drives tumor progression, dissects its context-specific functions in CTC biology, and evaluates the translational potential of LDHA-targeted strategies, with a focused emphasis on oxamate, as a transformative anti-metastatic therapeutic paradigm. By filling a critical gap in synthesizing oxamate’s distinct metabolic–immune regulatory actions, this work addresses an unmet need in the management of advanced, treatment-refractory cancers. Full article

Objective: Emphysema is an important chronic obstructive pulmonary disease (COPD) phenotype characterized by the destruction of air spaces distal to the terminal bronchiole. Aiming to detect potential emphysema biomarkers and to assess the systemic effects of emphysema in blood plasma, we conducted a small cross-sectional shotgun proteomics study. Methods: This study included N = 40 participants divided into four subgroups (N = 10 per group): patients with emphysema and COPD (CE), patients with COPD but without emphysema (CN), healthy smokers (HS) and healthy never-smokers (HN). The participants were sampled non-probabilistically to be similar in terms of age, sex and comorbidities. Participants’ blood plasma was analyzed using liquid chromatography–mass spectrometry. Bioinformatic analysis included detection of differentially expressed proteins (DEPs) and overrepresentation analysis (ORA). Results: Across all groups, a total of 994 proteins were identified, with NADP-dependent malic enzyme (NADP-ME; encoded by ME1) being the only DEP in the CE vs. CN contrast. Proteins such as BMP1, ADAMTSL-2, -4 and IGFBP4, -5, 6 were identified to be upregulated in CE vs. HN. Fibulin-1, -3 and several immunoglobulin components were identified to be downregulated in the CE vs. HN contrast. ORA revealed several enriched processes, including serine-type endopeptidase activity, insulin-like growth factor I and II binding, and signaling receptor binding. Conclusion: We propose NADP-ME, an important enzyme of intermediary metabolism and redox homeostasis, as a potential biomarker candidate of emphysema. Notably, NADP-ME is also implicated in anoikis resistance. Additionally, changes in the expression levels of BMP1, ADAMTSL-2 and -4, and fibulin suggest potential major systemic effects of extracellular matrix perturbation. As all data was derived from LC-MS analysis, these findings need to be further evaluated with complementary methods. Full article

To assess the therapeutic relevance of BRIP1 in gastric cancer (GC), we examine its functional role in conferring resistance to anoikis within GC cells and elucidate the oncogenic signaling pathways modulated by BRIP1. By integrating the Cancer Genome Atlas (TCGA) and Gene Set Enrichment Analysis (GSEA) databases with Least Absolute Shrinkage and Selection Operator (LASSO) regression, a novel risk score to stratify GC patients based on prognosis was generated, and a significantly differentially expressed gene, BRIP1, was validated through reverse transcription quantitative polymerase chain reaction (RT-qPCR). Protein expression associated with apoptosis, cell cycle, and epithelial-mesenchymal transformation (EMT) was quantified via RT-qPCR and Western blot (WB). 5-Ethynyl-2′-deoxyuridine (EdU) and cell counting kit-8 (CCK-8) assays were conducted to quantify proliferative activity. The protein level in axillary tumor tissues of nude mice was detected by immunohistochemistry (IHC). We established an eight-gene anoikis-related prognostic risk assessment model (DUSP1, VCAN, P3H2, TXNIP, BRIP1, FGD6, GPX3, and RLN2) for GC. Multivariate Cox regression confirmed the risk score as an independent prognostic factor. Among these genes, BRIP1 showed significant differential expression between tumor and normal tissues, as well as normal gastric mucosal epithelial cells and GC cells. Mechanistically, BRIP1 conferred anoikis resistance to GC cells by suppressing the generation of reactive oxygen species (ROS). We found that the PI3K inhibitor LY294002 counteracted BRIP1-driven oncogenic effects, which was evidenced by restored expression of key regulators governing apoptosis, cell cycle progression, and EMT, in addition to suppressed proliferation in GC cells. BRIP1 is postulated to function upstream of the PI3K/Akt signaling cascade. This study establishes a risk scoring model and identifies BRIP1 as a potential prognostic marker for GC. Full article

P-type ATPases constitute a diverse superfamily of ATP-driven transporters essential for ion homeostasis, membrane asymmetry, and organelle function. Among them, the P2-type Na⁺,K⁺-ATPase and the P5-type ATP13A2 have recently emerged as key regulators of cancer progression and neurodegeneration, respectively. In this review, we highlight new insights into the pathological roles of the Na⁺,K⁺-ATPase α3 isoform (α3NaK) in malignant cells and ATP13A2 in Parkinson’s disease (PD). Cancer tissues frequently overexpress α3NaK which is aberrantly localized to intracellular vesicles and undergoes adhesion-dependent intracellular trafficking. Upon cell detachment, α3NaK translocates to the plasma membrane to sustain survival signaling, thereby promoting anoikis resistance and facilitating the persistence of circulating tumor cells (CTCs). Cardiac glycosides selectively inhibit α3NaK at nanomolar concentrations, suppressing cancer cell proliferation through GLUT1 endocytosis, metabolic inhibition, and downregulation of THADA and LAT1, ultimately inducing anoikis in CTCs and reducing metastasis in vivo. Conversely, ATP13A2 is genetically linked to early-onset parkinsonism and regulates lysosomal integrity, polyamine homeostasis, and neuronal resilience. Recent animal studies demonstrate that adult-onset ATP13A2 loss causes progressive nigrostriatal degeneration, while heterozygous deficiency produces distinct age-dependent cognitive and α-synuclein phenotypes. Beyond its established role in polyamine transport, emerging evidence suggests that ATP13A2 can function as an H⁺,K⁺-ATPase-like transporter, contributing to proton and cation handling within the endolysosomal system. Together, these findings underscore the broader physiological and pathological significance of intracellular P-type K⁺-ATPases and highlight α3NaK and ATP13A2 as promising therapeutic targets in cancer metastasis and PD. Full article

Metastasis is the leading cause of cancer-related mortality. Although aspirin has been associated with reduced metastatic risk, existing evidence is fragmented across experimental systems, and a comprehensive mechanistic synthesis remains lacking. In particular, the relative contributions of platelet aggregation, thromboxane A₂ (TXA₂) signaling, and epithelial–mesenchymal transition (EMT) to aspirin’s antimetastatic effects have not been systematically integrated across preclinical and clinical studies. This systematic review was conducted in accordance with PRISMA 2020 guidelines, with the protocol registered in PROSPERO (CRD420251231581). PubMed, Scopus, and Web of Science were searched for studies published between January 2015 and December 2025, alongside ClinicalTrials.gov for completed mechanistic clinical trials. Eligible studies included in vitro, in vivo, and clinical investigations evaluating aspirin or its active metabolite in cancer-related settings and reporting mechanistic outcomes related to metastasis. Clinical studies reporting only survival or incidence outcomes without mechanistic analysis were excluded. The included studies demonstrated that aspirin suppresses metastatic dissemination across multiple cancer types through coordinated platelet-dependent and tumor-intrinsic mechanisms. Aspirin consistently inhibited platelet aggregation and COX-1-dependent TXA₂ production, disrupting platelet–tumor cell interactions, intravascular metastatic niche formation, and platelet-mediated immune suppression. Clinical mechanistic studies confirmed inhibition of thromboxane biosynthesis and reductions in circulating tumor cells. Beyond platelet effects, aspirin suppressed EMT, migration, and invasion through modulation of EMT transcriptional regulators and inflammatory signaling pathways. Additional mechanisms included activation of AMPK, inhibition of c-MYC signaling, regulation of redox-responsive pathways and impairment of anoikis resistance. This review provides the first integrated mechanistic synthesis of aspirin’s antimetastatic actions across preclinical and clinical evidence, addressing a critical gap in understanding how platelet biology, TXA₂ signaling, EMT, and tumor-intrinsic survival pathways converge in metastatic suppression. By focusing exclusively on mechanistically informative studies, this work clarifies the biological basis of aspirin’s antimetastatic effects and highlights unresolved questions regarding pathway hierarchy, cancer-type specificity, and translational biomarkers, thereby informing future mechanistic and clinical investigations. Full article

BST2 has emerged as a multifunctional molecule that bridges antiviral defense, membrane architecture, and tumor immunity. Originally characterized as an interferon-inducible restriction factor that tethers virions to the plasma membrane, BST2 is now recognized as an oncogenic driver and immunoregulatory hub in diverse malignancies. In cancer, BST2 expression is frequently upregulated through promoter hypomethylation and transcriptional activation. Functionally, BST2 promotes proliferation, epithelial–mesenchymal transition, anoikis resistance, and chemoresistance, whereas its loss sensitizes tumor cells to proteotoxic and metabolic stresses. Beyond tumor cells, BST2 modulates the tumor microenvironment by promoting M2 macrophage infiltration, dendritic cell exhaustion, and natural killer (NK)-cell resistance, thereby contributing to immune evasion. Elevated BST2 expression correlates with poor prognosis in glioblastoma, breast, nasopharyngeal, and pancreatic cancers, and it serves as a circulating biomarker within small extracellular vesicles. In conclusion, BST2 is a dual-function molecule that integrates oncogenic signaling and immune regulation, making it an attractive diagnostic and therapeutic target for hematological and solid tumors. Full article

Epithelial, endothelial, and many connective tissue cells are normally attached to the extracellular matrix (ECM). These cells rely on the ECM for structural support, signaling, and regulation of their behavior. When these cells lose this attachment or are in an inappropriate location, these cells soon die by a mechanism called anoikis (homelessness). Anoikis is a programmed cell death of an apoptotic nature; however, it can, in certain cases, be overcome, and detached cells can survive in the absence of the correct signals from the ECM. This is the case of malignant cells, where anoikis resistance is a prerequisite for invasion and metastasis. Without anoikis resistance (anchorage-independency), tumors would be unable to abandon their normal sites and would invade neighboring tissues and metastasize at distant locations. Anoikis is the natural barrier against cancer progression. Therefore, overcoming anoikis is a major step in cellular transformation. Cancer cells have developed many successful strategies to bypass anoikis. The main mechanism, albeit not the only one, involves hyper-activating survival pathways and over-expressing anti-apoptotic molecules. There is a strong and intertwining association between epithelial–mesenchymal transition and anoikis resistance that is discussed in depth. A better understanding of these anoikis resistance mechanisms has led to the research and development of pharmaceuticals that can counteract them. Full article

Ovarian cancer (OC) represents the most lethal gynecologic malignancy because the majority of patients with OC are diagnosed at advanced stages with peritoneal colonization of OC cells owing to subtle and nonspecific nature of symptoms. Thus, peritoneal colonization-directed therapeutic approaches are urgently needed for patients with advanced OC. Here, we investigated whether Ring-finger protein 126 (RNF126), an E3 ubiquitin ligase that is aberrantly upregulated in epithelial OC tissues, contributes to the peritoneal colonization of OC. RNF126-depleted OC cells showed comparable proliferation under normal culture conditions but displayed decreased growth under floating (anchorage-independent) conditions in vitro. Further analyses showed that RNF126 promoted anoikis resistance in vitro and increased peritoneal colonization in immunodeficient mice in a RING domain-dependent manner. Mechanistically, RNF126 activated the transcriptional factor NF-κB in OC cells under floating conditions in a RING domain-dependent manner, and this NF-κB activation was essential for anchorage-independent growth and peritoneal colonization of OC cells. Thus, RNF126 is a possible target for the prevention and/or therapy of peritoneally colonized OC. Full article

Background: Oligomeric proanthocyanidins (OPCs) are natural polyphenolic compounds with strong antitumor properties and have gained attention as potential agents to overcome drug resistance. Hepatocellular carcinoma (HCC) remains a major cause of cancer deaths worldwide, and although Lenvatinib is widely used, its effectiveness is limited by acquired resistance. This study explores the potential of OPCs to overcome Lenvatinib resistance in HCC. Methods: To evaluate the potential of OPCs to overcome Lenvatinib resistance in HCC, we established Lenvatinib-resistant Huh-7 and PLC-PRF-5 cell lines and conducted systematic cell culture experiments to assess their antitumor effects. Furthermore, genome-wide transcriptomic profiling, network pharmacology approaches, and pathway enrichment analysis were performed to identify resistance-associated signaling pathways that could serve as therapeutic targets. Results: The combination of OPCs and Lenvatinib demonstrated a significant synergistic anti-proliferative effect in resistant hepatocellular carcinoma cells, with the most synergistic dose combinations showing Bliss synergy scores exceeding 10. Transcriptomic profiling revealed that the adhesion molecule ITGA3 is a key factor in Lenvatinib resistance and contributes to the acquisition of anoikis resistance. The combination treatment suppressed ITGA3–EGFR–AKT signaling, restored anoikis sensitivity, significantly reduced spheroid formation (fold change = 0.10–0.12; p < 0.001), and markedly increased apoptosis (fold change = 2.7–5.0; p < 0.001). Conclusions: This study is the first to demonstrate that OPCs can overcome chemotherapy resistance by targeting the integrin pathway, providing scientific evidence for their potential use as an adjunctive therapy for chemotherapy-resistant HCC. Full article

Cancer cell spheroids autonomously form in the ascites fluid and are considered a conduit for epithelial ovarian cancer metastasis within the peritoneal cavity. Spheroids are homotypic, avascular 3D structures that acquire resistance to anoikis to remain viable after cellular detachment. We used in vitro spheroid model systems to interrogate pathways critical for spheroid cell proliferation, distinct from those driving monolayer cancer cell proliferation. Using the 105C and KOC-7c human ovarian clear cell carcinoma (OCCC) cell lines, which have distinct proliferative phenotypes as spheroids but the same prototypical OCCC gene mutation profile of constitutively activated AKT signaling with the loss of ARID1A, we revealed therapeutic targets that efficiently kill cells in spheroids. RNA-seq analyses compared the transcriptome of 3-day monolayer and spheroid cells from these lines and identified the characteristics of dormant spheroid cell survival, which included the G2/M checkpoint, autophagy, and other stress pathways induced in 105C spheroids, in sharp contrast to the proliferating spheroid cells of the KOC-7c cell line. Next, we assessed levels of various G2/M checkpoint regulators and found a consistent reduction in steady-state levels of checkpoint regulators in dormant spheroid cells, but not proliferative spheroids. Our studies showed that proliferative spheroid cells were sensitive to Wee1 inhibition by AZD1775, but the dormant spheroid cells showed a degree of resistance to AZD1775, both in terms of EC50 values and spheroid reattachment abilities. Thus, we identified biomarkers of dormant spheroids, including the G2/M checkpoint regulators Wee1, Cdc25c, and PLK1, and showed that, when compared to proliferating spheroid cells, the transcriptome of dormant OCCC spheroids is a source of therapeutic targets. Full article

Background: High dissemination potential and resistance to standard therapy significantly contribute to high mortality associated with ovarian cancer. Cancer stem cells (CSCs) drive tumor progression, metastasis, and recurrence after treatments’ failure. Here, we provide the first evidence of TIMP1 overexpression in ovarian CSCs, suggesting its potential role as a prognostic biomarker. Methods: Different ovarian cancer cell models were used to explore the potential link between TIMP1 and stem-like phenotypes. Experiments included spheroid formation, drug treatments, gene expression, functional assays, and zebrafish xenograft models to assess cell behavior and molecular changes. Results: TIMP1 was overexpressed in CSCs, and its expression was also upregulated in chemoresistant and anoikis-resistant cells. Our database analysis revealed a correlation between TIMP1 expression levels and poor patient prognosis. Overexpression of TIMP1 in ovarian cancer cell lines was able to recapitulate several features of the ovarian cancer stem cell phenotype, including treatment resistance, expression of stem cell markers, and anoikis resistance. TIMP1-overexpressing cells also exhibited enhanced migration potential in vitro and increased metastatic potential in vivo. Moreover, TIMP1 overexpression significantly altered the transcriptome landscape of cells, highlighting its role in modulating critical pathways associated with cell migration and inflammation. Conclusions: This study identifies the pivotal role of TIMP1 in ovarian CSCs and its contribution to therapy resistance, recurrence, and metastasis. Full article

Pancreatic ductal adenocarcinoma (PDAC) presents significant oncological challenges due to its aggressive nature and poor prognosis. The tumor microenvironment (TME) plays a critical role in progression and treatment resistance. Non-neoplastic cells, such as cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), contribute to tumor growth, angiogenesis, and immune evasion. Although immune cells infiltrate TME, tumor cells evade immune responses by secreting chemokines and expressing immune checkpoint inhibitors (ICIs). Vascular components, like endothelial cells and pericytes, stimulate angiogenesis to support tumor growth, while adipocytes secrete factors that promote cell growth, invasion, and treatment resistance. Additionally, perineural invasion, a characteristic feature of PDAC, contributes to local recurrence and poor prognosis. Moreover, key signaling pathways including Kirsten rat sarcoma viral oncogene (KRAS), transforming growth factor beta (TGF-β), Notch, hypoxia-inducible factor (HIF), and Wnt/β-catenin drive tumor progression and resistance. Targeting the TME is crucial for developing effective therapies, including strategies like inhibiting CAFs, modulating immune response, disrupting angiogenesis, and blocking neural cell interactions. A recent multi-omic approach has identified signature genes associated with anoikis resistance, which could serve as prognostic biomarkers and targets for personalized therapy. Full article

Anoikis, a form of apoptosis resulting from the loss of cell–extracellular matrix interaction, is a significant barrier to cancer cell metastasis. However, the epigenetic regulation of this process remains to be explored. Here, we demonstrate that the histone deacetylase sirtuin 6 (SIRT6) plays a pivotal role in conferring anoikis resistance to colorectal cancer (CRC) cells. The protein level of SIRT6 is negatively correlated with anoikis in CRC cells. The overexpression of SIRT6 decreases while the knockdown of SIRT6 increases detachment-induced anoikis. Mechanistically, SIRT6 inhibits the transcription of N-myc downstream-regulated gene 1 (NDRG1), a negative regulator of the AKT signaling pathway. We observed the up-regulation of SIRT6 in advanced-stage CRC samples. Together, our findings unveil a novel epigenetic program regulating the anoikis of CRC cells. Full article