Tumor Cell Invasion Research Articles

Molecular and cellular mechanisms of PDAC progression based on RETN-CAP1-mediated macrophage-fibroblast crosstalk: Action of ITGB5 and ITGB1 recombinant proteins.

Pancreatic ductal adenocarcinoma (PDAC) has a very poor prognosis, and the main objective of this study was to reveal the specific mechanism of action of TN-CAP1-mediated macrophage-fibroblast crossinulation in the progression of PDAC, and to evaluate the function and potential therapeutic value of ITGB5 and ITGB1 recombinant proteins in this process. The expression of TN-CAP1 in tumor tissues of PDAC patients was analyzed by immunohistochemistry and compared with normal pancreatic tissues. The co-culture system of macrophages and fibroblasts was constructed using in vitro cell culture model. The intercellular interactions and their effects on the proliferation, migration and invasion of tumor cells were observed by adding or knocking down ITGB5 and ITGB1 proteins. Western blot and RT-PCR were also used to detect the expression changes of related signaling pathway proteins and mRNA, which verified the effects of ITGB5 and ITGB1 recombinant proteins on tumor growth and metastasis in vivo. In vitro experiments showed that the addition of ITGB5 and ITGB1 recombinant proteins significantly enhanced the interaction between macrophages and fibroblasts, and promoted the proliferation and migration of tumor cells. Specifically, ITGB5 and ITGB1 recombinant proteins promote tumor cell aggressiveness by activating the FAK/PI3K/AKT signaling pathway.

The role and molecular mechanism of GDF5 in regulating cell migration and angiogenesis via the Hippo-YAP signaling pathway in colorectal cancer.

292 Background: Distant metastasis is a leading cause of poor prognosis and mortality in colorectal cancer (CRC) patients, with angiogenesis playing a crucial role in tumor progression. The TGF-β superfamily has been shown to significantly influence tumor angiogenesis, yet the biological function and molecular mechanism of Growth Differentiation Factor 5 (GDF5), a member of this superfamily, remain unexplored in CRC. Given that the efficacy of current anti-angiogenic therapies is limited to a subset of patients, identifying new therapeutic targets involved in tumor angiogenesis is of great clinical importance. GDF5, with its potential role in angiogenesis regulation, presents a promising candidate to bridge this therapeutic gap. Methods: In this study, we analyzed GDF5 expression in CRC tissue samples using both the TCGA dataset and samples from our center, revealing significantly lower GDF5 expression in tumors compared to adjacent normal tissues. Moreover, GDF5 downregulation correlated with lymph node metastasis and disease recurrence. Functional assays in vitro demonstrated that GDF5 overexpression reduced tumor cell migration and invasion, while its knockdown produced the opposite effect. Co-culture assays showed that GDF5 knockdown significantly enhanced endothelial cell migration and angiogenesis, whereas overexpression diminished these effects. Additionally, F-actin cytoskeletal staining indicated that GDF5 overexpression led to cytoskeletal remodeling in endothelial cells. Mechanistically, we found that GDF5 overexpression in tumor cells downregulated the epithelial-mesenchymal transition (EMT) marker Slug and upregulated E-cadherin, while downregulating N-cadherin. In endothelial cells, GDF5 inhibited the Hippo-YAP signaling pathway, increasing YAP phosphorylation and reducing nuclear YAP levels. Conversely, GDF5 knockdown suppressed YAP phosphorylation and promoted its nuclear translocation. Results: Our findings demonstrate that GDF5 functions as a tumor suppressor in CRC by regulating cell migration and angiogenesis. This study reveals that GDF5 exerts its anti-cancer effects by modulating both EMT in tumor cells and cytoskeletal changes in endothelial cells, leading to the inhibition of the Hippo-YAP signaling pathway and reduced angiogenic potential. These results identify GDF5 as a promising new target for anti-angiogenic therapy in CRC, offering potential avenues for improving treatment strategies in patients resistant to current therapies. Conclusions: GDF5 acts as a tumor suppressor in colorectal cancer by inhibiting cell migration and angiogenesis through modulation of the Hippo-YAP signaling pathway, making it a promising therapeutic target for anti-angiogenic treatment in patients resistant to current therapies.

Utilization of SDC2 gene in conjunction with SEPTIN9 gene methylation analysis for the diagnosis and efficacy assessment of colorectal cancer.

240 Background: SDC2 gene encodes the transmembrane proteoglycan molecule Syndecan-2. Syndecan-2 protein affects the proliferation, migration and invasion of colorectal cancer cells by participating in the regulation of cell adhesion, tissue differentiation and angiogenesis. Plasma methylated SEPTIN9 gene has been shown to be a sensitive and specific biomarker for the detection of CRC, which is involved in apoptosis, pseudopod projection, tumor cell migration and invasion. The aim of this study is to validate the value of SDC2 and S9 gene methylation detection in the diagnosis and efficacy evaluation of CRC. Methods: A total of 102 patients were enrolled in the study. The methylation levels of fecal SDC2 gene and blood SEPTIN9 gene were detected by fluorescence PCR. The clinical diagnostic accuracy of SDC2 kit was evaluated by patients with benign gastrointestinal lesions, gastrointestinal tumors and healthy subjects. Combined detection of SDC2 and S9 to improve the detection rate of CRC. SDC2m levels were analyzed in 26 patients with partial remission or stable disease after palliative treatment and 32 patients with complete remission after radical surgery. Results: The detection rate of SDC2 in patients was 0.0% for UC and CD, 66.7% for AA and 60.0% for NA, 25.0% for HOP. For 8 healthy subjects with negative colonoscopies, the true negative rate was 100%. The detection rates of GC and EC were 50.0% and 0.0%, respectively. Data from 72 patients with CRC were evaluated, with a sensitivity of 89.1% (41/46,95%CI 0.798-0.985) for patients with untreated CRC. The sensitivity of SDC2 was 46.2% (12/26,95%CI 0.256-0.667) in patients with partial response or stable disease after palliative treatment. The difference was statistically significant (P < 0.001). The sensitivity of S9 for CRC detection was 88.2% (15/17, 95%CI 0.712-1.053). By two tests, 94.1%(16/17, 95%CI 0.816-1.066) of CRC cases could be detected.The sensitivity was 89.1% (41/46 95%CI 0.798-0.985) in untreated CRC and 46.2% (12/26 95%CI 0.256-0.667) in patients with PR and SD after chemotherapy/radiotherapy/targeted/immunotherapy. The difference rate of SDC2m between two groups was statistically significant (P < 0.001). Among 46 untreated patients with CRC, 32 patients with positive SDC2m underwent radical surgery, of which 30 CR patients turned SDC2m test negative after surgery. We found reduced SDC2m in stool from patients with clinical benefit (CR+PR+SD). Conclusions: Detection of SDC2m in untreated CRC patients has high sensitivity and has the potential to become a non-invasive diagnostic tool for CRC. Combination of S9 and fecal SDC2 could improve the detection rate of SDC2 in non-dominant population. The methylation level of SDC2 may be helpful for postoperative follow-up of CRC after radical surgery, prediction of recurrence, and monitoring the efficacy of a series of palliative treatments for CRC.

CD155 promotes the progression of colorectal cancer by restraining CD8+ T cells via the PI3K/AKT/NF-κB pathway.

CD155 is a crucial factor in the regulation of T cell function and contributes to immune escape. CD155 upregulation has been found in several types of cancer. However, the mechanism by which CD155 regulates CD8+ T cell function in colorectal cancer remains unclear. Here we investigated the role and mechanism of CD155 in the regulation of CD8+ T cell function. We studied the expression of CD155 in colorectal cancer tissues through western blot, immunohistochemistry, and the TCGA database. We verified the effects of CD155 on the functions of colorectal cancer cells and CD8+ T cells through in vitro experiments. We demonstrated that CD155 affects CD8+ T cell migration and thus promotes tumor growth in a mouse subcutaneous tumor model. We then tested the changes in the PI3K/AKT/NF-κB pathway in CD8+ T cells by flow cytometry. We demonstrated that stable CD155 expression was negatively correlated with prognosis in colorectal cancer patients. In vitro experiments confirmed that CD155 does not affect tumor cell proliferation, migration, or invasion. We also revealed that CD155 downregulated the function and migration of CD8+ T cells in vivo and in vitro. Furthermore, CD155 might regulate CD8+ T cells function via the PI3K/AKT/NF-κB pathway. This study revealed that CD155 can promote the progression of colorectal cancer by regulating the PI3K / AKT-NF-κB pathway to promote the depletion of CD8+ T cells and reduce their migration to the tumor microenvironment. CD155 may become an important prognostic biomarker and an effective target for colorectal cancer immunotherapy.

Single-cell sequencing reveals cell heterogeneity and aberrantly activated pathways associated with microvascular invasion in hepatocellular carcinoma

IntroductionHepatocellular carcinoma (HCC) is the most common primary liver cancer, with microvascular invasion (MVI) identified as a major predictor of early recurrence. However, the intratumor cellular heterogeneity of MVI, the identification of pertinent biomarkers, and the role of intercellular signalling interactions in MVI progression are unclear. This study aims to explore these aspects using single-cell transcriptomic analysis.MethodsThe present study utilized single-cell transcriptomic data from public databases to conduct an in-depth transcriptome analysis of tumour tissues and adjacent nontumor tissues from five patients with hepatocellular carcinoma, with a particular focus on samples from three patients exhibiting microvascular invasion. Bioinformatics tools were employed to analyze gene expression patterns and signalling pathways.ResultsThe findings indicated that MVI-positive malignant cells activate multiple signalling pathways to facilitate invasion and metastasis. Specific malignant cell subtypes strongly associated with MVI were identified, exhibiting distinctive gene expression patterns related to proliferation, invasion, and metabolic reprogramming of tumour cells. Further analysis revealed that the laminin and VEGF signalling pathways are crucial for remodelling the tumour microenvironment and angiogenesis associated with MVI. The MARCKSL1 gene was predominantly expressed in MVI-positive malignant cells and may contribute to MVI progression by interacting with the PTN signalling network. Additionally, MARCKSL1 is linked to tumour resistance to multiple anticancer drugs.DiscussionThis study sheds light on the molecular characteristics and functional heterogeneity of MVI-associated malignant cell subpopulations. The single-cell transcriptome and bioinformatics analyses provided insights into the mechanisms driving MVI, potentially aiding the development of targeted diagnostic and therapeutic strategies. Future research should further validate the role of MARCKSL1 in MVI progression and explore its potential clinical applications.

Formin protein DAAM1 positively regulates PD-L1 expression via mediating the JAK1/STAT1 axis in pancreatic cancer

BackgroundDishevelled-associated activator of morphogenesis1 (DAAM1) is a member of the evolutionarily conserved Formin family and plays a significant role in the malignant progression of various human cancers. This study aims to explore the clinical and biological significance of DAAM1 in pancreatic cancer.MethodsMultiple public datasets and an in-house cohort were utilized to assess the clinical relevance of DAAM1 in pancreatic cancer. The LinkedOmics platform was employed to perform enrichment analysis of DAAM1-associated molecular pathways in pancreatic cancer. Subsequently, a series of in vitro and in vivo experiments were conducted to evaluate the biological roles of DAAM1 in pancreatic cancer cells and its effects on intratumoral T cells.ResultsDAAM1 was found to be upregulated in pancreatic cancer tissues, with higher expression levels observed in tumor cells. Additionally, high expression of DAAM1 was associated with poor prognosis. DAAM1 acted as an oncogene in pancreatic cancer, and its inhibition suppressed tumor cell proliferation, migration, and invasion, while promoted apoptosis. Furthermore, DAAM1 was involved in the JAK1/STAT1 signaling pathway and regulated PD-L1 expression in pancreatic cancer cells. The inhibition of DAAM1 also significantly reduced the exhaustion levels of CD8+ T cells.ConclusionIn conclusion, DAAM1 functions as an oncogene and is immunologically implicated in pancreatic cancer, these findings suggest that DAAM1 may serve as a promising therapeutic target for the clinical management of pancreatic cancer.

Trends in Research of Odontogenic Keratocyst and Ameloblastoma.

Odontogenic keratocyst (OKC) and ameloblastoma (AM) are common jaw lesions with high bone-destructive potential and recurrence rates. Recent advancements in technology led to significant progress in understanding these conditions. Single-cell and spatial omics have improved insights into the tumor microenvironment and cellular heterogeneity in OKC and AM. Fibroblast subsets in OKC and tumor cell subsets in AM have been analyzed, revealing mechanisms behind their biological behaviors, including OKC's osteolytic features and AM's recurrence tendencies. Spatial transcriptomics studies of AM have identified engineered fibroblasts and osteoblasts contributing to matrix remodeling gene and oncogene expression at the invasion frontier, driving AM progression. Three-dimensional culture technologies such as organoid models have refined analysis of AM subtypes; uncovered the role of AM fibroblasts in promoting tumor cell proliferation and invasion; and identified signaling pathways such as FOSL1, BRD4, EZH2, and Wnt as potential therapeutic targets. Organoid models also served as preclinical platforms for testing potential therapies. Although preclinical models for AM exist, reliable in vitro and in vivo models for OKC remain scarce. Promising mimic models, including human embryonic stem cells-derived epithelial cells, human oral keratinocytes, human immortalized oral epithelial cells, and HaCaT keratinocytes, show promise, but the advancements in 3-dimensional culture technology are expected to lead to further breakthroughs in this area. Artificial intelligence, including machine learning and deep learning, has enhanced radiomics-based diagnostic accuracy, distinguishing OKC and AM beyond clinician capability. Pathomics-based models further predict OKC prognosis and differentiate AM from ameloblastic carcinoma. Clinical studies have shown positive outcomes with targeted therapies. In a study investigating SMO-targeted treatments for nevoid basal cell carcinoma syndrome, nearly all OKC lesions resolved in 3 patients. A recent clinical trial with neoadjuvant BRAF-targeted therapy for AM demonstrated promising radiologic responses, potentially enabling organ preservation. This review highlights recent advancements and trends in OKC and AM research, aiming to inspire further exploration and progress in these fields.

Polyoxometalate-based injectable coacervate inhibits HCC metastasis after incomplete radiofrequency ablation via scavenging ROS

BackgroundIncomplete radiofrequency ablation (iRFA) stimulates residual hepatocellular carcinoma (HCC) metastasis, leading to a poor prognosis for patients. Therefore, it is imperative to develop an effective therapeutic strategy to prevent iRFA-induced HCC metastasis.ResultsOur study revealed that iRFA induced an abnormal increase in ROS levels within residual HCC, which enhanced tumor cell invasiveness and promoted macrophage M2 polarization, ultimately facilitating HCC metastasis. Molybdenum-based polyoxometalate (POM) is an excellent ROS-scavenging nanocluster, but its size is too small to be easily cleared by the kidneys, limiting its effectiveness in scavenging iRFA-induced ROS. To overcome this limitation, we synthesized an injectable POM-loaded coacervate delivery system named POM@Coa, which can sustainably scavenge iRFA-induced ROS by slowly releasing POM. POM@Coa markedly reduced HCC invasiveness, reversed macrophage polarization from M2 to M1, and promoted the infiltration and activation of CD8+ T cells, ultimately inhibiting HCC metastasis. Importantly, POM@Coa showed superior therapeutic efficacy to free POM in the absence of systemic toxicity.ConclusionsPOM@Coa exhibits the potential to decrease HCC invasiveness and activate anti-tumor immunity, opening up new avenues for the safe and effective treatment and prevention of HCC metastasis when combined with RFA.

Cellular senescence in the tumor with a bone niche microenvironment: friend or foe?

Cellular senescence is understood to be a biological process that is defined as irreversible growth arrest and was originally recognized as a tumor-suppressive mechanism that prevents further propagation of damaged cells. More recently, cellular senescence has been shown to have a dual role in prevention and tumor promotion. Senescent cells carry a senescence-associated secretory phenotype (SASP), which is altered by secretory factors including pro-inflammatory cytokines, chemokines, and other proteases, leading to the alteration of the tissue microenvironment. Though senescence would eventually halt the growth of cancerous potential cells, SASP contributes to the tumor environment by promoting inflammation, matrix remodeling, and tumor cell invasion. The paradox of tumor prevention/promotion is particularly relevant to the bone niche tumor microenvironment, where longer-lasting, chronic inflammation promotes tumor formation. Insights into a mechanistic understanding of cellular senescence and SASP provide the basis for targeted therapies, such as senolytics, which aim to eliminate senescent cells, or SASP inhibitors, which would eliminate the tumor-promoting effects of senescence. These therapeutic interventions offer significant clinical implications for treating cancer and healthy aging.

ALB inhibits tumor cell proliferation and invasion by regulating immune microenvironment and endoplasmic reticulum stress in clear cell renal cell carcinoma.

The aim of this work is to identify putative hub genes for the advancement of clear cell renal cell carcinoma (ccRCC) and determine the fundamental mechanisms. We employed multiple bioinformatics techniques to screen hub genes. Key hub gene expression levels in ccRCC were assessed. A plethora of functional experiments were carried out to explore the biological role of hub gene. Based on genome-wide association studies, a Mendelian randomization research was conducted to ascertain the causative relationship between albumin (ALB) and ccRCC. ALB was low expression in ccRCC tissues and cell lines. It was an independent predictor of progression-free survival following treatment and the overall survival of ccRCC patients. ALB overexpression exhibited the reverse effects of ALB knockdown, which increased cell proliferation, migration, and invasion while inhibiting cell death. Similarly, ALB overexpression inhibited the growth of ccRCC tumors in vivo. Consistent with functional enrichment analysis, ALB overexpression activates the endoplasmic reticulum stress (ERS) in vitro and vivo. The Mendelian randomization showed ALB was associated with the risk of ccRCC. Additionally, ALB was causally associated with γδT cells infiltrates in ccRCC. ALB plays an important effect in ccRCC via activation of the ERS and regulating immune microenvironment.

Glut-1 exerts anti-tumor activity in glioma by regulating AKT / mTOR signaling pathway

Objective Glioma is a common tumor in neurosurgery. Glut-1 is the main carrier of glucose uptake by cells and can provide energy through the glycolytic pathway. However, the role and related mechanisms of Glut-1 in glioma have not yet been elucidated. Methods Real time PCR and Western blot were done to assess Glut-1 level in glioma tumor tissues and adjacent tissues. Glioma U87 cells were separated into control group; Glut-1 negative control (NC group); and Glut-1 siRNA group followed by analysis of Glut-1 expression, cell proliferation by MTT assay, cell invasion, cell apoptosis and cycle by flow cytometry and AKT / mTOR signaling proteins level by Western blot. Results Glut-1 expression was significantly increased in the tissues of glioma patients (P < 0.05) compared to adjacent tissues and its level was related to tumor size, pathological grade and survival. Down-regulating the expression of Glut-1 can significantly inhibit tumor cell proliferation and invasion, increase apoptosis and induce G0 phase of cell cycle arrest, and inhibit the expression of AKT / mTOR signaling proteins phosphorylation (P < 0.05). Conclusions Glut-1 level in glioma tissues is significantly increased, which is related to the pathological features. Down-regulating Glut-1 can inhibit glioma by regulating the AKT / mTOR signaling pathway.

MARVELD1 Promotes the Invasiveness in Pancreatic Adenocarcinoma through the Activation of Epithelial-to-Mesenchymal Transition.

MARVEL domain-containing 1 (MARVELD1) has been implicated in the progression of several cancers, but its role in pancreatic adenocarcinoma (PAAD) remains poorly understood. RNA-seq data from the TCGA-PAAD and GTEx-Pancreas cohorts were analyzed to assess MARVELD1 expression. Stable MARVELD1 knockdown and overexpression were conducted in BxPC3 and PANC-1 cells. Cell viability, proliferation, migration, and invasion were evaluated using functional assays, and western blotting was employed to examine EMT-associated protein levels, including Vimentin, MMP2, MMP9, and E-cadherin. Differentially expressed genes (DEGs) between MARVELD1-high and MARVELD1-low groups were identified, and pathway enrichment analyses were performed. We observed a significant increase of MARVELD1 in PAAD patient samples, with elevated MARVELD1 levels correlating with poor clinical survival. Knockdown of MARVELD1 in PAAD cells remarkably decreased cell proliferation and colony formation, while overexpression of MARVELD1 enhanced these properties. Moreover, simulated cell invasion and migration assay further suggested that MARVELD1 might contribute to PAAD cell aggressiveness. Mechanistically, MARVELD1 promoted tumor cell migration and invasion through the activation of Vimentin, MMP2, and MMP9 protein while suppressing E-cadherin. Bioinformatics analysis revealed that MARVELD1-high samples were enriched in EMT-related pathways, including TGF-β receptor signaling, actin cytoskeleton regulation, and cell adhesion. Taken together, our study highlights the roles of MARVELD1 in promoting tumor cell proliferation and invasion, suggesting its potential application as a prognostic and diagnostic biomarker for PAAD in the clinical context.

A Novel 167-Amino Acid Protein Encoded by CircPCSK6 Inhibits Intrahepatic Cholangiocarcinoma Progression via IKBα Ubiquitination.

Intrahepatic cholangiocarcinoma (ICC), a formidable challenge in oncology, demands innovative biomarkers and therapeutic targets. This research highlights the importance of the circular RNA (circRNA) circPCSK6 and its peptide derivative circPCSK6-167aa in ICC. CircPCSK6 is significantly downregulated in both ICC patients and mouse primary ICC models, and its lower expression is linked to adverse prognosis, highlighting its pivotal role in ICC pathogenesis. Functionally, this study elucidates the regulatory effect of circPCSK6-167aa on IκBα ubiquitination within the NF-κB pathway, which is mediated by its competitive binding to the E3 ligase RBBP6. This complex interaction leads to reduced activation of the NF-κB pathway, thereby curbing tumor cell proliferation, migration, invasion, stemness, and hepatic-lung metastasis in vivo. This groundbreaking discovery expands the understanding of circRNA-driven tumorigenesis through atypical signaling pathways. Additionally, this investigation identified EIF4A3 as a detrimental regulator of circPCSK6, exacerbating ICC malignancy. Importantly, by leveraging patient-derived xenograft (PDX), organoids, and organoid-derived PDX models, higher levels of circPCSK6-167aa enhance sensitivity to gemcitabine, indicating its potential to improve the effectiveness of chemotherapy. These insights emphasize the therapeutic promise of targeting circPCSK6-167aa, offering vital biological insights and clinical directions for developing cutting-edge therapeutic approaches, thus revealing innovative strategies and targets for future treatments.

Microenvironment Mechanical Torque from ZnFe2O4 (ZFO) Micromotors Inhibiting Tumor Migration.

Mechanical force attracts booming attention with the potential to tune the tumor cell behavior, especially in cell migration. However, the current approach for introducing mechanical input is difficult to apply in vivo. How the mechanical force affects cell behavior in situ also remains unclear. In this work, an intelligent miniaturized platform is constructed with magnetic ZnFe2O4 (ZFO) micromotors. The wireless ZFO can self-assemble in situ and rotate to generate mechanical torque of biologically relevant piconewton-scale at the target tumor site. It is observed unexpectedly that enhanced in situ mechanical rotating torque from ZFO micromotors and the active fluid inhibit the migration of highly invasive A549 tumor cells. The down-regulation of the Piezo1 channel and the suppressed signaling of ROCK1 in mechano-adaptive tumor cells is found to be related to the inhibition effect. With effectiveness confirmed with the zebrafish xenograft model, this platform provides a valuable toolkit for mechanobiology and force-associated non-invasive tumor therapy.

Targeting glycolysis: exploring a new frontier in glioblastoma therapy.

Glioblastoma(GBM) is a highly malignant primary central nervous system tumor that poses a significant threat to patient survival due to its treatment resistance and rapid recurrence.Current treatment options, including maximal safe surgical resection, radiotherapy, and temozolomide (TMZ) chemotherapy, have limited efficacy.In recent years, the role of glycolytic metabolic reprogramming in GBM has garnered increasing attention. This review delves into the pivotal role of glycolytic metabolic reprogramming in GBM, with a particular focus on the multifaceted roles of lactate, a key metabolic product, within the tumor microenvironment (TME). Lactate has been implicated in promoting tumor cell proliferation, invasion, and immune evasion. Additionally, this review systematically analyzes potential therapeutic strategies targeting key molecules within the glycolytic pathway, such as Glucose Transporters (GLUTs), Monocarboxylate Transporters(MCTs), Hexokinase 2 (HK2), 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3 (PFKFB3), Pyruvate Kinase Isozyme Type M2 (PKM2), and the Lactate Dehydrogenase A (LDHA). These studies provide a novel perspective for GBM treatment. Despite progress made in existing research, challenges remain, including drug penetration across the blood-brain barrier, side effects, and resistance. Future research will aim to address these challenges by improving drug delivery, minimizing side effects, and exploring combination therapies with radiotherapy, chemotherapy, and immunotherapy to develop more precise and effective personalized treatment strategies for GBM.

Molecular mechanisms of transcription factor KLF4-mediated immune infiltration influencing lung adenocarcinoma invasion.

Lung adenocarcinoma (LUAD) is associated with an increasing incidence and mortality rate while existing treatment strategies continue to exhibit considerable limitation. Studies have demonstrated that upregulation of KLF4 gene inhibits LUAD progression, but its underlying mechanisms remain elusive. The present research explored roles and mechanisms of KLF4 and the NF-κB pathway in LUAD. Lentiviral vectors encoding KLF4 were constructed and transduced into H1299 and A549 cells to generate stable cell lines. These stable cell lines were then injected into BALB/c mice to establish a LUAD model. Subsequently, RNA sequencing, HE staining, immunohistochemistry, ELISA, Western blotting, and flow cytometry were employed to investigate the effects of KLF4 on tumor growth, invasion, immune cell infiltration, and related signaling pathways. Finally, dual-luciferase and in vivo mouse experiments were conducted to validate the molecular mechanisms. KLF4 significantly reduced tumor cell invasion while promoted tumor cell necrosis. Transcriptomic sequencing identified CXCR2 as a target gene and the NF-κB signaling pathway associated with immune infiltration regulation. KLF4 downregulated NF-κB2 and CXCR2 expression, concomitantly decreasing tumor cell invasiveness but increasing levels of CD4+ and CD8+ T cells and macrophages. NF-κB and CXCR2 play an important role in KLF4-mediated immune infiltration, thereby inhibiting tumor invasion and promoting tumor cell apoptosis in mice.

An integrated single-cell and spatial transcriptomic atlas of thyroid cancer progression identifies prognostic fibroblast subpopulations.

Thyroid cancer progression from curable well-differentiated thyroid carcinoma to highly lethal anaplastic thyroid carcinoma is distinguished by tumor cell de-differentiation and recruitment of a robust stromal infiltrate. Combining an integrated thyroid cancer single-cell sequencing atlas with spatial transcriptomics and bulk RNA-sequencing, we define stromal cell subpopulations and tumor-stromal cross-talk occurring across the histologic and mutational spectrum of thyroid cancer. We identify distinct inflammatory and myofibroblastic cancer-associated fibroblast (iCAF and myCAF) populations and perivascular-like populations. The myCAF population is only found in malignant samples and is associated with tumor cell invasion, BRAF V600E mutation, lymph node metastasis, and disease progression. Tumor-adjacent myCAFs abut invasive tumor cells with a partial epithelial-to-mesenchymal phenotype. Tumor-distant iCAFs infiltrate inflammatory autoimmune thyroid lesions and anaplastic tumors. In summary, our study provides an integrated atlas of thyroid cancer fibroblast subtypes and spatial characterization at sites of tumor invasion and de-differentiation, defining the stromal reorganization central to disease progression.

Clinical implications of epithelial-to-mesenchymal transition in cancers which potentially spread to peritoneum.

Epithelial-to-mesenchymal transition (EMT) is a biological process by which epithelial cells increase their motility and acquire invasive capacity. It represents a crucial driver of cancer metastasis and peritoneal dissemination. EMT plasticity, with cells exhibiting hybrid epithelial/mesenchymal states, and its reverse process, mesenchymal-to-epithelial transition (MET), allows them to adapt to different microenvironments and evade therapeutic intervention. Resistance to conventional treatments, including chemotherapy, is a major problem. Therapies targeting EMT may inhibit tumour cell migration and invasion, while affecting normal cells and repair mechanisms, resulting in potential side effects. This paper addresses the question of the impact of EMT status on cancers with potential spread to the peritoneum, which has remained unclear in literature. Relevant studies were selected from 2000 to 2024. Three macrosections were analysed: (i) pathological characteristics, (ii) surgical implications and (iii) oncological therapies. The focus was on survival and peritoneal recurrence time in patients who underwent surgical treatment.

Selenium-Chondroitin Sulfate Nanoparticles Inhibit Angiogenesis by Regulating the VEGFR2-Mediated PI3K/Akt Pathway.

Chondroitin sulfate (CS), a class of glycosaminoglycans covalently attached to proteins to form proteoglycans, is widely distributed in the extracellular matrix and cell surface of animal tissues. In our previous study, CS was used as a template for the synthesis of seleno-chondroitin sulfate (SeCS) through the redox reaction of ascorbic acid (Vc) and sodium selenite (Na2SeO3) and we found that SeCS could inhibit tumor cell proliferation and invasion. However, its effect on angiogenesis and its underlying mechanism are unknown. In this study, we analyzed the effect of SeCS on tube formation in vitro, based on the inhibition of tube formation and migration of human umbilical vein endothelial cells (HUVECs), and evaluated the in vivo angiogenic effect of SeCS using the chick embryo chorioallantoic membrane (CAM) assay. The results showed that SeCS significantly inhibited the angiogenesis of chicken embryo urothelium. Further mechanism analysis showed that SeCS had a strong inhibitory effect on VEGFR2 expression and its downstream PI3K/Akt signaling pathway, which contributed to its anti-angiogenic effects. In summary, SeCS showed good anti-angiogenic effects in an HUVEC cell model and a CAM model, suggesting that it may be a potential angiogenesis inhibitor.

MIRO2 promotes cancer invasion and metastasis via MYO9B suppression of RhoA activity.

Metastasis to vital organs remains the leading cause of cancer-related deaths, emphasizing an urgent need for actionable targets in advanced-stage cancer. The role of mitochondrial Rho GTPase 2 (MIRO2) in prostate cancer growth was recently reported; however, whether MIRO2 is important for additional steps in the metastatic cascade is unknown. Here, we show that knockdown of MIRO2 ubiquitously reduces tumor cell invasion invitro and suppresses metastatic burden in prostate and breast cancer mouse models. Mechanistically, depletion of MIRO2's binding partner-unconventional myosin 9B (MYO9B)-reduces tumor cell invasion and phenocopies MIRO2 depletion, which in turn results in increased active RhoA. Furthermore, dual ablation of MIRO2 and RhoA fully rescues tumor cell invasion, and MIRO2 is required for MYO9B-driven invasion. Taken together, we show that MIRO2 supports invasion and metastasis through cooperation with MYO9B, underscoring a potential targetable pathway for patients with advanced disease.