The histological growth pattern (HGP) at the interface of colorectal adenocarcinoma liver metastases (CRCLM) and liver parenchyma provides important prognostic information. This study aimed to identify transcriptomic signatures underlying the predominant HGPs in CRCLM. We retrospectively evaluated the HGP of 495 CRCLM of 232 patients with metastasectomy at the University Hospital Regensburg between 2003 and 2016. A representative subset of 106 metastases from 53 patients was analyzed for RNA expression at the metastasis-liver interface using the NanoString nCounter® PanCancer Progression Panel. The most common HGPs in the NanoString subcohort were the infiltrative replacement (rHGP, 47.2%) and the non-infiltrative desmoplastic type (dHGP, 46.3%). Unsupervised clustering of CRCLM gene expression profiles identified four gene clusters, two significantly enriched for pure dHGP or pure rHGP. Differential expression analysis between pure dHGP and all other HGPs (i.e., non-pure dHGP) identified 55 significantly differentially expressed genes. Gene set enrichment analysis corroborated previously reported signals (extracellular matrix organization, stromal/endothelial gene sets, and epithelial-mesenchymal transition enrichment in pure dHGP; glucose metabolism in non-pure dHGP) and additionally revealed α6β4 integrin signaling as feature of non-pure dHGP. Patient identity, rather than HGP, was the dominant driver of gene expression variance, though AGR2 was consistently and significantly overexpressed in non-pure dHGP across different analytical strategies. These findings corroborate known transcriptomic differences between HGPs, identify α6β4 integrin signaling as an additional candidate pathway enriched in non-pure dHGP CRCLM, and underscore the substantial contribution of patient-specific factors to gene expression variability in CRCLM outweighing HGP.

Stereotactic body radiotherapy (SBRT) and conventional external beam radiotherapy (cEBRT) are widely used treatment options for the management of painful bone metastases. Randomized phase III trials have provided direct comparative evidence for SBRT and cEBRT; however, their results vary according to treatment regimen and clinical endpoint, supporting a broader quantitative synthesis of pain response, local control, retreatment, and safety outcomes. A systematic search was conducted in PubMed, Scopus, the Cochrane Library, and Google Scholar from database inception through January 2026. Comparative clinical studies evaluating SBRT versus cEBRT for bone metastases were included. Outcomes assessed encompassed pain-related measures (change in Visual Analog Scale scores at 3 and 6 months; complete, partial, stable, and progressive pain response), opioid consumption at 3 and 6 months, radiologic local progression or treatment failure at 8 months, re-irradiation at 12 months, skeletal-related events (vertebral and non-vertebral compression fractures), spinal cord compression, treatment-related toxicity, and overall survival at 1 year. Pooled analyses were performed using random-effects models. Early pain reduction at 3 months, partial and stable pain response, and opioid consumption at 3 and 6 months were comparable between SBRT and cEBRT (all p > 0.05). However, SBRT demonstrated superior mid-term outcomes, with a significantly higher complete pain response at 6 months (RR = 1.43; p = 0.001) and a significantly lower rate of progressive pain response at 6 months (RR = 0.61; p = 0.03). SBRT was also associated with markedly improved local disease control, reflected by lower rates of radiologic local progression or treatment failure at 8 months (RR = 0.36; p < 0.001) and a substantially reduced need for re-irradiation at 12 months (RR = 0.13; p < 0.001). Rates of vertebral and non-vertebral compression fractures, spinal cord compression, treatment-related toxicity, and overall survival at 1 year did not differ significantly between treatment modalities. This meta-analysis demonstrates that both SBRT and cEBRT are safe and effective treatment options for patients with painful bone metastases. While early pain palliation and safety outcomes are comparable, SBRT provides superior durability of pain control, reduced pain progression, improved local tumor control, and a markedly lower need for re-irradiation. SBRT may be particularly advantageous for patients with longer expected survival, oligometastatic disease, or lesions at higher risk of progression, whereas cEBRT remains an effective and accessible option for rapid symptom palliation in patients with limited prognosis.

Breast cancer (BC) is characterised by multiple metastasis to various organs and remains a leading contributor to the approximately 10 million annual cancer-related deaths worldwide. The choice of organ for a metastatic site is not random and follows the principle of organotropism. This review develops the concept that exosomes-small extracellular vesicles 30-150 nm in diameter-play a substantial role in forming the pre-metastatic niche by selectively reprogramming target cells and tissues, thereby preparing the organ for the arrival of tumour cells. We examine in detail the molecular mechanisms whereby exosome-contained microRNAs, annexins, tetraspanins and other components drive osteolysis of bone tissue, increase the permeability of the blood-brain barrier (brain metastases arise in roughly 25-27% of triple-negative and 11-20% of HER2-positive BC), and induce fibro-inflammatory changes in the lungs and liver. Particular attention is given to the translational potential of exosomes as diagnostic markers-recent exosome-based classifiers reach a diagnostic accuracy of about 90%-and as agents of targeted therapy. Through a structured comparison of more than twenty primary studies, we provide a critical analysis of the methodological heterogeneity of exosome research and of the status of current clinical trials (8 of 13 catalogued BC trials are purely observational). On this basis, the review outlines concrete, source-supported ways to overcome the existing barriers on the path "from the bench to the bedside".

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with an unfavorable prognosis, and the molecular mechanisms underlying its metastatic progression remain incompletely defined. Here, we investigated the functional role of ephrin type-B receptor 1 (EPHB1), a member of the ephrin receptor family, in ESCC metastasis. Integrated analyses of RNA-sequencing data and publicly available databases demonstrated that EPHB1 expression is significantly upregulated in ESCC tissues and is positively associated with advanced tumor grade and poor patient survival. Gain- and loss-of-function assays revealed that EPHB1 knockdown markedly inhibited ESCC cell migration, invasion, and epithelial-mesenchymal transition (EMT), whereas EPHB1 overexpression exerted the opposite effects. Consistently, in vivo metastasis assays further confirmed that EPHB1 promotes lung metastasis of ESCC cells. Mechanistically, we identified SRY-box transcription factor 2 (SOX2) as a critical upstream regulator that directly binds to the EPHB1 promoter and transcriptionally activates its expression. Rescue experiments demonstrated that SOX2-induced EMT and invasive capacity are largely mediated through EPHB1. Collectively, these findings uncover a previously unrecognized SOX2/EPHB1 signaling axis that drives ESCC metastasis and suggest EPHB1 as a potential therapeutic target for ESCC.

Circulating tumour cells (CTCs) are rare cells frequently profiled on a single cell level. A key indicator of single-cell transcriptome quality is the percentage of reads encoded by genes in the mitochondrial genome (MT-reads). No systematic data exists on MT-reads content in CTCs, making it unclear whether this parameter can reliably indicate CTCs' transcriptome quality. We collected RNA-Seq profiles of 349 single breast cancer (BC) CTCs and 129 white blood cells (WBCs) enriched with four methods to assess the level of MT-reads and the expression of markers of the most abundant blood components-red blood cells (RBCs) and platelets (PLTs). The median percentage of PLTs and RBCs transcripts in CTCs was 2% (0-38%) and 0.8% (0.0006-84%), respectively, with significant differences between enrichment methods (p < 2.2-16). As a result, 44% of CTCs showed MT-reads level exceeding 10%, commonly considered a threshold indicating low-quality cells. Level of MT-reads in CTCs was frequently positively correlated with PLTs and RBCs markers; though in selected datasets increased MT-reads correlated with higher expression of oxidative phosphorylation and mitochondria biogenesis genes. Isolated CTCs themselves showed varied degree of cancer cells characteristics depending on the applied criterion (BC and WBC marker levels, aneuploidy score), underlining the challenges in CTCs identification. To conclude, the proportion of MT-reads in single CTCs is not a reliable standalone indicator of CTCs' transcriptome. Elevated MT-read fraction in CTCs may arise from multiple factors, including technical aspects of blood sample processing, potential contributions of platelet- and erythroid-derived transcripts or intrinsic biological processes occurring in CTCs.

Lymph node (LN) metastasis is a major determinant of prognosis in gastric cancer, yet the immune microenvironment of metastatic versus non-metastatic nodes remains incompletely defined. Spatial resolution of tumor-immune interactions may clarify mechanisms of immune escape associated with nodal progression. We performed compartment-resolved spatial transcriptomic profiling to characterize immune gene expression in gastric cancer LNs. Forty-seven formalin-fixed paraffin-embedded LNs from 13 patients with T2-T4, M0 gastric adenocarcinoma (N1-2: n = 7; N3: n = 6) were analyzed using the NanoString GeoMx Digital Spatial Profiler and an 84-gene immune pathways panel. Twenty-nine non-metastatic and 18 metastatic LNs were profiled. Regions of interest were segmented into tumor and immune compartments, yielding 65 spatially defined compartments. Differential expression was assessed across three comparisons: metastatic versus non-metastatic LNs; metastatic LNs from N1-2 versus N3 patients; and non-metastatic LNs from N1-2 versus N3 patients. Within the immune compartments, non-metastatic LNs showed higher expression of T-cell activation and checkpoint genes (CD3E, CD27, PDCD1, CTLA4), consistent with preserved immune surveillance. Metastatic LNs were enriched for WNT signaling and adhesion-related genes (CTNNB1, ITGAV) and epithelial markers (EPCAM), indicating tumor-driven immune remodeling. N3 metastatic LNs demonstrated increased ICOSLG, IL6, and IFNGR1 expression, suggesting chronic inflammatory activation and immune dysfunction. Notably, non-metastatic LNs from N3 patients upregulated antigen-presentation genes (CD74, HLA-DRB), consistent with early immune conditioning. No significant differences emerged in tumor compartments or pseudo-bulk analyses. Spatial transcriptomic profiling reveals nodal burden-associated immune remodeling, and identifies candidate biomarkers and therapeutic targets for precision immunotherapy in gastric cancer.

Bone metastasis remains a major source of morbidity and mortality in breast cancer. Bone marrow adipose tissue (BMAT) is an active but incompletely defined component of the metastatic niche. This review uses an evidence-tiered framework to integrate four questions: how bone marrow adipocytes exchange lipids and signals with tumor cells; which observations are specific to breast cancer in bone; how broader bone-microenvironment and cross-cancer findings inform biological plausibility; and whether anticancer therapy reshapes BMAT in ways that could influence residual disease. Direct breast cancer evidence supports colonization of adipocyte-rich human bone explants and links adipocyte-derived signals with tumor migration, whereas several metabolic, dormancy, immune, and senescence pathways remain supported mainly by animal, in vitro, or other-cancer studies. Tumor cells, rather than bone marrow adipocytes, can increase fatty-acid transport, activation, and oxidation in response to adipocyte-derived lipids. Chemotherapy and aromatase inhibition can increase marrow adiposity, alter stromal lineage commitment, and promote bone loss; however, a direct causal pathway from treatment-induced BMAT expansion to breast cancer persistence, resistance, or relapse has not been established clinically. Accordingly, we distinguish documented treatment effects from proposed tumor consequences and separate established bone-directed therapy from experimental BMAT-targeted approaches. This framework positions BMAT as a testable and potentially modifiable niche component while avoiding the assumption that all adipocyte-rich marrow states are uniformly pro-metastatic.

Cardiac metastasis from colorectal cancer (CRC) is exceedingly rare and remains poorly defined in the literature. As survival improves and metastatic patterns evolve, recognizing the clinical and anatomical characteristics of cardiac involvement is increasingly important. This systematic review synthesizes published cases of CRC with cardiac metastases identified through a systematic search to clarify presentation, metastatic pathways, management, and outcomes. Following PRISMA 2020 guidelines, we systematically searched PubMed, Scopus, and Web of Science from inception to October 2025 for case reports and case series describing CRC metastasis to the heart. Eligible reports were screened by two independent authors. Detailed clinical, pathological, imaging, management, and outcome data were extracted using a standardized template. Descriptive statistics were performed using Jamovi v2.7 without inferential analyses given the nature of the data. Fifty-three cases met inclusion. The mean age was 62.7 ± 11.75 years (median 66; IQR 55.5-71), with a slight male predominance (53.8%). Left-sided primaries were most common (50.9%), followed by rectal (26.4%) and right-sided tumors (15.1%). Most cardiac lesions were intracardiac (78%) and solitary (92.2%), with a marked predilection for the right ventricle (45.8%) and right atrium (35.4%). Dyspnea was the leading symptom (65.4%), while 19.2% were asymptomatic. Extra-cardiac metastases preceded cardiac involvement in 60.8%, mainly to the liver (46%) and lungs (32%). Curative-intent treatment was attempted in 52.8%; palliative care in 28.3%. Overall mortality was 64.2%. CRC cardiac metastasis typically manifests as a solitary right-sided intracavitary lesion in the context of systemic disease and carries a poor prognosis. Early multimodality imaging and individualized multidisciplinary management are essential. Collaborative registries are needed to establish evidence-based guidance.

FLAIR hyperintensity extending beyond a cerebral quadrant (FEQ+) after stereotactic radiosurgery (SRS) for brain metastases (BM) was a recently established imaging biomarker for steroid-dependent adverse radiation effects (ARE). In this study, we investigated the clinical and treatment‑related variables associated with the development of FEQ + ARE following SRS. Exploratory analyses were conducted in an initial cohort of 214 consecutively treated patients with 1,106 SRS‑treated brain metastases and subsequently validated in an independent cohort of 149 consecutively treated patients comprising 708 SRS‑treated lesions from a second institution. In the discovery cohort, 62 of 214 patients (29%) developed FEQ + ARE after SRS. On univariate analysis, the likelihood of FEQ + ARE increased with prior whole-brain radiation therapy (pWBRT; OR 4.97, p < 0.001), cumulative intracranial tumor volume (CITV; OR 1.02, p = 0.018), and the number of repeat SRS courses (OR 1.32, p = 0.049). These associations remained robust in multivariate modeling adjusted for follow-up duration. Variance analysis indicated that pWBRT accounted for the largest share of risk. These findings were confirmed in an independent cohort of 149 patients using a pre-specified multivariate model. In this validation cohort, 56 patients (38%) developed FEQ + ARE after SRS. The odds of FEQ + ARE were 22.2 (p = 0.006), 1.18 (p = 0.007), and 2.04 (p = 0.045) for pWBRT, CITV, and repeat SRS, respectively. Variance analysis again showed that pWBRT accounted for the largest share of FEQ + ARE risk. Across two institutional cohorts of consecutively treated patients with > 1,800 SRS-treated BM, prior WBRT, repeat radiosurgery, and higher cumulative intracranial tumor volume were consistently associated with the development FEQ + ARE.

Colorectal cancer liver metastases (CRLM) are characterized by distinct histopathological growth patterns (HGPs), desmoplastic (dHGP) also called encapsulated, replacement (rHGP) and pushing (pHGP) types, which have major prognostic and therapeutic implications. HGPs can only be determined histologically after surgical resection. This review explores molecular imaging as a potential in vivo approach to predict and characterize HGPs non-invasively. Based on the biological hallmarks of each pattern regarding glucose metabolism, angiogenesis, hypoxia, fibrotic stromal activation and immune contexture, we outline how specific PET tracers can capture these features. [18F]FDG PET reflects glycolytic activity; angiogenesis-specific tracers such as arginine-glycine-aspartic acid (RGD) peptides targeting integrins or VEGF-based agents may reflect the neovascularization typical of dHGP. Hypoxia PET may detect oxygen-deprived tumour regions. Fibroblast activation protein inhibitor (FAPI) tracers provide a quantitative marker of fibrotic stromal encapsulation, and immune PET may help distinguish between immune-active dHGP lesions and immune-cold rHGP types. These proposed molecular imaging signatures provide a biologically informed framework for the non-invasive HGPs characterization but remain hypothesis-generating and require prospective translational and clinical validation.

Cancer metastasis is a multistep and highly inefficient process that depends on reciprocal interactions between tumor cells and the host microenvironment. Among the most important host contributors, platelets have emerged as active facilitators of metastatic dissemination, supporting the survival of circulating tumor cells, immune evasion, endothelial arrest, extravasation, and early colonization. More recently, platelet-derived mitochondrial transfer has been recognized as a novel mechanism by which platelets may enhance tumor aggressiveness through metabolic reprogramming. This review critically synthesizes the current literature on platelet-mediated mitochondrial transfer in cancer, with emphasis on its biological mechanisms, functional consequences, and translational implications. Emerging evidence in selected osteosarcoma and triple-negative breast cancer models indicates that activated platelets can donate functional mitochondria to cancer cells through direct contact and microparticle-mediated pathways, potentially increasing oxidative phosphorylation, ATP production, redox adaptability, proliferative capacity, and migratory behavior. Mechanistically, platelet mitochondrial transfer may involve pathways linked to mitochondrial quality control and trafficking, including PINK1/Parkin-MFN2 signaling, while also intersecting with broader platelet-tumor crosstalk that promotes epithelial-mesenchymal transition, anoikis resistance, and immune escape. In parallel, platelet-derived mitochondrial cargo and related extracellular vesicle signatures may offer new opportunities for liquid biopsy-based biomarker development. However, major challenges remain, including the need for rigorous in vivo validation, discrimination of intact mitochondria from fragmented mitochondrial material, and clarification of context-dependent effects across tumor types. Collectively, platelet-derived mitochondrial transfer represents an emerging layer of intercellular communication that may link thrombosis, metabolism, and metastasis, and it offers promising avenues for both biomarker discovery and therapeutic intervention.

Thrombospondin-2 (THBS2) has emerged as a pivotal yet paradoxical regulator within the breast cancer (BC) tumor microenvironment (TME). This review synthesizes current evidence to elucidate its context-dependent duality and its potential as a novel therapeutic target. While THBS2 can function as a tumor suppressor by inhibiting angiogenesis, it more frequently exhibits pro-tumorigenic activities in aggressive subtypes like triple-negative breast cancer (TNBC). Here, THBS2, predominantly secreted by cancer-associated fibroblasts, drives metastasis by activating key oncogenic pathways including PI3K/AKT, Notch, and Wnt/β-catenin, thereby promoting epithelial-mesenchymal transition (EMT) and stemness. Its expression and functional output are further complicated by competitive endogenous RNA (ceRNA) network regulation, explaining contradictory clinical associations. Crucially, THBS2 is a key architect of an immunosuppressive "cold" TME. It constructs dual barriers: a physical barrier through extracellular matrix remodeling that impedes T-cell infiltration, and a chemical barrier by potentially suppressing CD36[+] T-cell function. Consequently, therapeutic inhibition of THBS2 presents a promising integrative "cold-to-hot" conversion strategy. By simultaneously dismantling stromal architecture and alleviating local immune suppression, targeting THBS2 could enhance T-cell trafficking and reactivate anti-tumor immunity, potentially overcoming resistance to current immunotherapies. Future research must adopt a network-based approach to decipher THBS2's contextual roles and translate its targeting into effective combination strategies for advanced breast cancer.