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At least 19 recordsLinked to original sources
PubMed2025

Colorectal Liver Metastasis Pathomics Model: Integrating Single-Cell and Spatial Transcriptome Analysis With Pathomics for Predicting Liver Metastasis in Colorectal Cancer.

The liver is the primary target organ for hematologic metastasis of colorectal cancer (CRC), and CRC liver metastasis (CRLM) often precludes radical resection, making it the leading cause of death in patients with CRC. To improve the identification and prediction of liver metastasis risk, we identified a cell type of liver metastasis--triggering malignant cells (LMTMCs) through integrating single-cell RNA sequencing and spatial transcriptome analysis. Multiomics cell communication analysis indicated that the interaction between fibroblasts and LMTMCs through the COL1A1-CD44/SDC4 and LAMA4-CD44 signaling axes could promote CRLM. By applying the one-class logistic regression algorithm, we developed a CRLM scoring system in the bulk RNA-sequencing data according to the abundance of LMTMCs in each individual. Using the grouping labels derived from the CRLM scoring system in the bulk data and the corresponding whole-slide images without any manual annotations at the region or pixel level, processed via slide-level weakly supervised learning, a deep-learning model based on the ResNet18 architecture, called Colorectal Liver Metastasis Pathomics Model, was developed to predict the risk of liver metastasis in patients with CRC. The Colorectal Liver Metastasis Pathomics Model achieved an area under the curve of 0.84 at the internal test set of The Cancer Genome Atlas-CRC histology images. In the external independent validation sets, namely the Affiliated Hospital of Southwest Medical University and the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University cohorts, the areas under the curve were 0.89 and 0.72, respectively, indicating effective classification performances. This study provided new insights and tools for the early identification of CRLM and demonstrated the potential of combining multiomics with deep learning-based pathomics in cancer research.

Humans↗
PubMed1977

Platelet-cancer cell interaction in metastasis formation: a possible therapeutic approcach to metastasis prophylaxis.

The mechanism of the early stage of metastasis formation by sticky blood-born cancer cells is discussed. Abnormal platelet aggregation to circulating and lodged cancer cells, as well as alterations of blood coagulation and fibrinolysis play an important role. The reducing effect of several platelet aggregation inhibitors on cancer cell stickiness and tumor embolism mortality has been investigated in rats after intravenous transplantation of 1 X 10(6) Walker-256 carcinosarcoma cells. The tested substances diminished platelet aggregation to circulating cancer cells, leading to a dose-dependent inhibition of cancer cell lodgment to the endothelium. Furthermore, some of the substances prevented lethal pulmonary tumor cell embolism which was observed in 60% of the controls. These results are interpreted by assuming an inhibition of disseminated intravascular coagulation which occured after intravenous transplantation of Walker-256 carcinosarcoma. On this basis a clinical long-term study for metastasis prophylaxis was started more than 4 years ago with one of the tested substances, the dipyridamole derivative RA 233, in 40 patients with sarcoma or malignant lymphoma of the head and neck region. The provisional results obtained in matched pairs are discussed.

Animals↗
PubMed2026

Integrated multi-omics analysis of metabolomics and proteomics uncovers dysregulated amino acid metabolism in HCC metastasis.

BACKGROUND: Metastasis is the primary cause of treatment failure and adverse prognosis in hepatocellular carcinoma (HCC), and the molecular basis of HCC metastasis remains poorly defined. This work investigated the potential mechanisms underlying HCC metastasis through integrated multi-omics analysis of metabolomics and proteomics. METHOD: This retrospective study included 105 individuals with HCC, with comparative analysis between metastatic and non-metastatic cases. We further evaluated the effects of metastasis on serum metabolomics and proteomics in HCC patients. RESULT: Widespread disturbances in amino acid metabolism were identified via untargeted metabolomics in HCC patients with metastasis, closely governing inflammation-related metabolic remodeling and oxidative stress responses. Specifically, we identified 91 and 59 distinct differential metabolites capable of indicating HCC metastasis, with the screening criteria set as log2 fold change > 1.5, adjusted P value < 0.05, and VIP > 1.5 in positive and negative modes, respectively. The alanine, aspartate and glutamate metabolism pathway correlated with HCC-associated lung metastasis, while the gluconeogenesis pathway was linked to HCC-associated bone metastasis. Compared with HCC (non-metastatic hepatocellular carcinoma), the key molecular alterations in the multi-omics network of HCC_M (HCC with metastasis) are implicated in inflammatory metabolic reprogramming, oxidative stress response, gluconeogenesis, glycolysis, and the tricarboxylic acid (TCA) cycle. Twenty-five proteins, including PKM2, PERCK, ALDH2, CPS1, GLS1, GLUD1, GOT1, and SLC38A2, were identified as potential biomarkers for HCC metastasis. CONCLUSION: By integrating untargeted metabolomic and proteomic profiling, we identified distinct metabolic and proteomic changes linked to HCC metastasis. This work also characterized the pathological characteristics and core pathways underlying HCC metastasis, while identifying potential therapeutic candidates.

Humans↗
PubMed2026

Postoperative chemoradiotherapy in Wilms tumor with concurrent lung and lymph node metastasis.

BACKGROUND: An effective treatment strategy is essential for metastatic Wilms tumor (WT) management. To improve prognostic accuracy, this study examined metastatic patterns and key prognostic factors. METHODS: Children diagnosed with WT from 2010 to 2021 were identified from the SEER database. All patients underwent chemotherapy and surgical resection. Metastatic patterns, metastasis-related predictors, and prognostic factors were evaluated. RESULTS: Of the 1040 patients analyzed, 226 (21.7%) experienced lung metastasis, 31 (3.0%) liver metastasis, 6 (0.6%) bone metastasis, and 220 (21.2%) regional lymph node metastasis. Distant metastasis was associated with a higher incidence of lymph node metastasis (OR = 1.506, 95% CI 1.346-1.685, p < 0.001). Age 3-17 years (OR = 1.933, 95% CI 1.406-2.680, p < 0.001), left-sided (OR = 1.383, 95% CI 1.016-1.890, p = 0.040), bilateral (OR = 2.303, 95% CI 1.215-4.243, p = 0.009), and tumor size &#x2265;135 mm (OR = 2.020, 95% CI 1.481-2.749, p < 0.001) were identified as predictors of metastasis. Both lymph node (p < 0.001) and lung metastasis (p < 0.001) were high-risk factors for WT. Radiotherapy provided long-term survival benefits for the metastatic population (p = 0.027), while postoperative chemotherapy showed better outcomes than preoperative or other strategies (p < 0.001). Further analysis demonstrated that the concurrent lung and lymph node metastasis group benefited more from postoperative chemoradiotherapy, with HRs of 0.226 (p = 0.028) for overall survival and 0.255 (p = 0.048) for cancer-specific survival. CONCLUSION: WT with concurrent lung and lymph node metastasis represents a distinct and aggressive metastatic phenotype associated with a significantly poor prognosis. Postoperative chemoradiotherapy may provide superior survival benefits for this high-risk population.

Humans↗
PubMed1979

Metastasis of human tumors in athymic nude mice.

The incidence of metastasis of xenogeneic tumors transplanted to nude mice is controversial. We studied 106 malignant human tumor lines in a total of 1,045 nude mice, and observed metastasis in only 14 instances (1.3%), involving 11 different tumor lines. Three of the lines showed repeated metastasis. Breast tumor lines metastasized with significantly greater frequency than other tumor types. None of the sarcoma lines metastasized. Tumors derived from human metastases were no more prone to metastasizing in nude mice than were tumors derived from primary sites. However, deep penetration of the body wall during growth of the tumor transplant was highly correlated with metastasis (p less than 0.001). Such factors as nude mouse health, tumor size and growth rate, and age and sex of the host mouse were not correlated with metastasis. Serial passage in nude mice did not select for a more malignant tumor line, since the incidence of metastasis did not differ at various passage levels. Thus, metastasis of human malignant tumors in nude mice would appear to depend primarily upon the site of tumor growth in the nude mouse, and upon the intrinsic metastasizing capability of the tumor line employed.

Animals↗
PubMed2025

Glutamate molecular structure and protein affect the inhibition of breast cancer cell metastasis: Cell-derived exosomes inhibitory effects through the MAPK signaling pathway.

The aim of this study was to investigate the inhibitory effect of glutamate molecular structure and protein on breast cancer cell metastasis and the potential inhibitory mechanism of cell-derived exosomes via MAPK signaling pathway. Breast cancer cell lines with high metastatic potential were selected by in vitro cell culture technique. The effects of specific inhibitors of glutamic acid on the proliferation and metastasis of breast cancer cells were studied. Changes in protein expression profiles were analyzed by proteomics techniques to identify key proteins associated with breast cancer metastasis. Breast cancer cells were treated with inhibitors of the MAPK signaling pathway to evaluate their effect on cell metastasis and compare with exosome treatment. The results showed that the specific inhibitors of glutamate molecular structure could significantly inhibit the proliferation and metastasis of breast cancer cells. Proteomic analysis revealed several down-regulated proteins that are closely related to breast cancer metastasis.

Humans↗
PubMed2025

KLF5 facilitates lung adenocarcinoma metastasis by regulating the epithelial-mesenchymal transition pathway through RHPN2.

BACKGROUND: Distant metastasis is a primary factor contributing to the significantly shorter survival time of patients with advanced lung adenocarcinoma. The transcription factor Kruppel-like factor 5 (KLF5) facilitates the progression of lung adenocarcinoma. However, the specific mechanism by which KLF5 is involved in the tumor metastasis of lung adenocarcinoma metastasis remains largely unclear. METHODS: Using bioinformatic analysis, Rhophilin Rho GTPase Binding Protein 2 (RHPN2) was identified as a potential downstream target gene for KLF5; it plays a crucial role in the regulation of the epithelial-mesenchymal transformation pathway in lung adenocarcinoma. Western blotting and immunohistochemistry were performed to examine RHPN2 expression in lung adenocarcinoma. In vivo and in vitro experiments were conducted to explore the regulatory role of RHPN2 on the cell growth and metastasis of lung adenocarcinoma. Chromatin immunoprecipitation sequencing was used to analyze the direct binding activity between KLF5 and RHPN2 promoter regions. Luciferase activity assay was performed to verify the transcriptional activation effect of KLF5 on RHPH2. RESULTS: RHPN2 was highly expressed in lung adenocarcinoma; patients with lung adenocarcinoma who showed high RHPN2 expression had a poor prognosis. In vivo and in vitro experiments showed that RHPN2 promoted cell growth and metastasis and activated the epithelial-mesenchymal transformation pathway in lung adenocarcinoma. KLF5 directly bound to the promoter region of RHPN2 and upregulated its expression in lung adenocarcinoma through transcriptional activation. In addition, rescue experiments confirmed that KLF5 facilitated the progression of lung adenocarcinoma in an RHPN2-dependent manner. CONCLUSION: Our study offers insights into the potential mechanisms of metastasis in lung adenocarcinoma and highlights RHPN2 as a potential therapeutic target.

Humans↗
PubMed2026

Identification of Critical Genes Related to Breast Cancer with Brain Metastasis Through Bioinformatics Analysis.

INTRODUCTION: Distant metastasis accounts for the majority of Breast Cancer (BC)-related mortality. The brain is one of the most common regions of metastasis. However, the underlying molecular mechanisms remain uncertain. METHODS: In this study, gene expression profiles were downloaded from the Gene Expression Omnibus (GEO) database. Datasets GSE100534 and GSE52604, containing 16 primary brain tumor samples and 38 breast cancer brain metastasis samples, were used to identify the Differentially Expressed Genes (DEGs). The Metascape database was used to analyze enriched Gene Ontology (GO) entries and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway entries in DEGs. The STRING database was then used to construct a Protein-Protein Interaction (PPI) network, and the Cytoscape platform was employed to visualize the network. Furthermore, the Kaplan-Meier curve was used to analyze the Relapse-Free Survival (RFS) among the hub genes. Finally, the iRegulon plugin was used to construct a regulatory network to find the transcription factors (TFs) that regulate the expression of the hub genes. RESULTS: A total of 344 DEGs, including 182 up-regulated and 162 down-regulated genes, were identified by using the limma package in R. A module with 18 nodes and 9 hub genes was selected from the PPI network by using the plugins MCODE and Cyto- Hubba, respectively. KEGG pathway analysis demonstrated that brain metastasis in BC was closely related to the oocyte cell cycle. The Kaplan-Meier curve showed that high expression of these 9 hub genes was associated with poor RFS in BC patients. TFs' analysis showed that E2F4, SIN3A, FOXM1, and TFDP1 interacted with these hub genes. DISCUSSION: This study revealed that Breast Cancer Brain Metastasis (BCBM) may have a promoting effect on the cell cycle of oocytes and affect the maturation and division of oocytes through the KEGG and GO analyses of 344 DEGs. The selected 9 hub genes (ASPM, BUB1, BUB1B, CCNA2, CCNB1, CDK1, NDC80, NCAPG, and TOP2A) and 4 transcription factors (E2F4, SIN3A, FOXM1, TFDP1) may play a critical role in brain metastasis of BC. CONCLUSION: The results of this study may aid in the early diagnosis and suggest potential targets for the treatment of BCBM.

Brain Neoplasms↗
PubMed2026

Genome-Wide In Vivo RNAi Screening Identifies HOXD4 as a Tumor Metastasis Suppressor in Colorectal Cancer.

Metastasis remains a major therapeutic challenge in colorectal cancer, highlighting an urgent need to elucidate its underlying molecular mechanisms. In this study, an in vivo screening system integrating genome-wide short hairpin RNA library and next-generation sequencing identifies six candidate metastasis suppressors, among which Homeobox D4 (HOXD4) shows the most pronounced effects. Clinicopathological analyses reveal significant HOXD4 downregulation in tumor tissues relative to adjacent normal tissues, with reduced expression strongly correlating with aggressive tumor features. Functional assays demonstrate that HOXD4 depletion enhances migration, invasion, and tumorsphere formation in HCT116 cells, while ectopic HOXD4 overexpression reverses these malignant phenotypes in SW620 cells. Mechanistically, HOXD4 suppresses epithelial-mesenchymal transition (EMT) by directly binding to the promoter of Forkhead box Q1 (FOXQ1), a key driver of EMT and stemness, and thereby transcriptionally repressing its expression. Immunohistochemistry confirms an inverse correlation between HOXD4 and FOXQ1 expression in clinical specimens. Rescue experiments substantiate that HOXD4 exerts its metastasis-suppressing functions via FOXQ1 regulation. Collectively, these findings not only establish an efficient platform for screening tumor metastasis suppressors, but also identify HOXD4 as a master transcriptional regulator of the FOXQ1-EMT axis, providing a promising target for metastasis interception.

Humans↗
PubMed1979

Some characteristics of metastasis in man.

The studies of experimental cancer metastasis are only truly meaningful to the degree that knowledge applicable to the therapeutic problem of cancer metastasis in man ensues from them. The salient features of cancer metastasis in man, therefore, are important to the laboratory researcher, for they provide a framework for which the relevance of an experimental model system must be judged. This brief discussion of some of the clinical characteristics of metastasis in man demonstrates the wide spectrum of biologic behavior and the complex multifaceted nature of this problem. It must be concluded that a complex interaction between tumor cells and host mechanisms eventually governs whether or not metastasis occurs in man.

Carcinoma, Squamous Cell↗
PubMed2026

Exon 21 skipping in ARHGAP10: A splicing switch that governs breast cancer metastasis.

Rho GTPase-activating protein 10 (ARHGAP10) is recognized as a tumor suppressor, yet the functional impact of its alternative splicing isoforms on breast cancer metastasis remains unclear. This study aimed to elucidate the role and regulatory mechanism of ARHGAP10 exon 21 skipping in breast cancer progression. Our research results indicate that in metastatic breast cancer cells, the full-length isoform ARHGAP10-L is downregulated, whereas the truncated ARHGAP10-S is upregulated. The RNA-binding protein HNRNPA0 directly binds to intron 21 of ARHGAP10 pre-mRNA, promoting exon-21 skipping and ARHGAP10-S production. Functionally, ARHGAP10-L and ARHGAP10-S exert opposing effects on breast cancer cell malignancy: ARHGAP10-L suppresses migration, invasion, and lung metastasis, whereas ARHGAP10-S promotes these aggressive phenotypes. Moreover, ARHGAP10-S exhibits enhanced binding to CDC42 and is associated with increased AKT phosphorylation. In a nude mouse model, HNRNPA0 drove lung metastasis by upregulating ARHGAP10-S. These findings establish the HNRNPA0-ARHGAP10 splicing axis as a key regulator of breast cancer metastasis, in which ARHGAP10-S promotes progression via the AKT pathway whereas ARHGAP10-L acts as a tumor suppressor, highlighting the therapeutic potential of targeting this splicing event to combat metastasis.

ARHGAP10 (RhoGTPase activating protein 10)↗
PubMed2025

Identification of key genes related to bone metastasis of breast cancer using bioinformatics methods and construction of a prognostic model.

Breast cancer (BC) ranks among the most prevalent cancers in females, with bone metastasis significantly compromising patients' quality of life and survival rates. Enhancing our comprehension of BC bone metastasis mechanisms at the molecular level holds promise for improving BC treatment and prognosis. Leveraging bioinformatics tools, we integrated multiple datasets, conducted comprehensive analyses across various databases, identified biomarkers associated with BC bone metastasis, and constructed a prognostic model. Firstly, 3 BC bone metastasis-related datasets were downloaded from gene expression omnibus, the data were merged, and batch effects were removed, followed by identification of differentially expressed genes (DEGs). Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on the DEGs. A protein-protein interaction network was constructed using the STRING database to screen hub genes. Then, survival analysis of hub genes was performed using the Cancer Genome Atlas (TCGA) database. A prognostic model was constructed using key genes with survival differences, and the model was evaluated. Two hundred ninety-two DEGs were identified. Gene ontology and KEGG pathway enrichment analysis yielded 769 biological processes (BPs), 78 cellular components, 43 molecular functions, and 50 KEGG pathways. Fifteen hub genes were selected from the protein-protein interaction network. Survival analysis revealed 6 genes related to BC survival. The prognostic model identified 4 genes with important predictive value for BC prognosis. Our study utilized bioinformatics analysis to identify a series of DEGs related to BC bone metastasis. Based on further selection of hub genes, we constructed a relatively ideal prognostic model for BC, and identified 4 genes (DLGAP5, TPX2, PLK1, and CENPN) with valuable predictive value for BC prognosis.

Humans↗
PubMed2026

Unraveling the Enigma of Melanoma Brain Metastasis: New Molecular Insights and Therapeutic Directions.

Melanoma, a highly aggressive and metastatic cancer, poses significant challenges due to its propensity to spread to distant organs, with brain metastasis representing a particularly devastating complication. This review synthesizes preclinical and clinical evidence on the molecular, cellular, and microenvironmental mechanisms driving melanoma metastasis, emphasizing mechanisms of blood-brain barrier traversal, tumor-stroma co-option, and brain-specific genomic and transcriptional programs. We summarize advances in therapeutic strategies to combat melanoma brain metastasis including novel small molecules, immunotherapies, and combination approaches tailored for brain metastases. The review also highlights the immunological landscape of the brain, translational models, and multidisciplinary clinical management strategies. Finally, we identify critical research gaps, including the need for brain metastasis-specific clinical trials, AI-driven predictive models, and preventive strategies, to guide future efforts in improving outcomes for patients with melanoma brain metastasis.

Humans↗
PubMed2026

Hepatocyte-derived LRG1 primes the liver for metastasis and impairs immunotherapy.

The liver undergoes active remodeling by the primary tumor prior to metastatic spread. However, the mechanisms by which hepatocytes dictate the liver-specific tropism of tumors remain elusive. Here, we identify hepatocyte-derived leucine-rich alpha-2-glycoprotein 1 (LRG1) as a key mediator of liver premetastatic niche (PMN) formation. Clinically, elevated serum LRG1 levels are correlated with an increased risk of liver metastasis in patients and multiple mouse models. Mechanistically, LRG1 remodels the hepatic microenvironment by driving immunosuppressive neutrophil accumulation, impairing the function of effector T cells and dendritic cells, and enhancing angiogenesis in the liver, thereby fostering a prometastatic landscape. Hepatocyte-specific ablation of LRG1 dampens premetastatic niche formation and significantly reduces the metastatic burden in vivo. Hepatic LRG1 induced by tumor-associated inflammation via IL-6/STAT3 signaling promotes liver metastasis through the formation of TGFBR/PI3K/AKT axis-driven neutrophil extracellular traps (NETs). Importantly, therapeutic blockade of LRG1 not only suppressed liver metastasis but also reprogrammed the hepatic niche toward an immune-activated state, sensitizing tumors to anti-PD-1 therapy. Collectively, our findings reveal a hepatocyte-LRG1 axis that drives liver premetastatic niche remodeling and highlight LRG1 as a promising target for the prevention and treatment of liver metastasis.

Animals↗
PubMed2025

Tumors hijack macrophages for iron supply to promote bone metastasis and anemia.

Bone marrow is both a primary site for hematopoiesis and a fertile niche for metastasis. The mechanism of the common occurrence of anemia among patients with bone metastasis remains poorly understood. Here, we show that a specialized population of VCAM1+CD163+CCR3+ macrophages, normally essential for erythropoiesis by transporting iron to erythroblasts, are highly enriched in the bone metastatic niche in mouse models. Tumor cells hijack these macrophages for iron supply, reducing iron availability for erythroblasts, impairing erythropoiesis, and contributing to anemia. Increased iron supply enables tumor cells to produce hemoglobin in response to hypoxia, mimicking erythroblasts. We identify macrophages with similar iron-transporting features in human bone metastases and show that elevated HBB expression correlates with increased risk of bone metastasis. These findings establish iron-transporting macrophages as an essential component of the metastatic bone niche, revealing a critical interplay between immune cells, metal metabolism, and tumor cell plasticity in driving metastasis and anemia.

Animals↗
PubMed2024

LINC00887 promotes GCN5-dependent H3K27cr level and CRC metastasis via recruitment of YEATS2 and enhancing ETS1 expression.

Recent observations have revealed upregulation of H3K27cr in colorectal cancer (CRC) tissues; however, the underlying cause remains elusive. This study aimed to investigate the mechanism of H3K27cr upregulation and its roles in CRC metastasis. Clinically, our findings showed that H3K27cr served as a highly accurate diagnostic marker to distinguish CRC tissues from healthy controls. Elevated levels of LINC00887 and H3K27cr were associated with a poorer prognosis in CRC patients. Functionally, LINC00887 and H3K27cr facilitated the migration and invasion of CRC cells. Mechanistically, LINC00887 interacted with SIRT3 protein. Overexpressed of LINC00887 obstructed the enrichment of SIRT3 within GCN5 promoter, thereby elevating H3K27ac but not H3K27cr level within this region, subsequently activating GCN5 expression. This activation increased the global level of H3K27cr, promoting the enrichment of GCN5, H3K27cr, and YEATS2 within ETS1 promoter, activating ETS1 transcription and ultimately promoting the metastasis of CRC. The in vivo study demonstrated that inhibition of LINC00887 suppressed CRC metastasis, but this inhibitory effect was nullified when mice were treated with NaCr. In conclusion, our results confirmed the diagnostic biomarker potential of H3K27cr in individuals with CRC, and proposed a functional model to elucidate the involvement of LINC00887 in promoting CRC metastasis by elevating H3K27cr level.

Humans↗