Tumor Invasion Research Articles

G‐Quadruplex RNA Based PROTAC Enables Targeted Degradation of RNA Binding Protein FMRP for Tumor Immunotherapy

AbstractFragile X mental retardation protein (FMRP), an RNA binding protein (RBP), is aberrantly hyper‐expressed in human tumors and plays an essential role in tumor invasion, metastasis and immune evasion. However, there is no small‐molecule inhibitor for FMRP so far. In this study, we developed the first FMRP‐targeting degrader based on PROteolysis TArgeting Chimera (PROTAC) technology and constructed a heterobifunctional PROTAC through linking a FMRP‐targeting G‐quadruplex RNA (sc1) to a von Hippel‐Lindau (VHL)‐targeting ligand peptide (named as sc1‐VHLL). Sc1‐VHLL specifically degraded endogenous FMRP via ubiquitination pathway in both mouse and human cancer cells. The FMRP degradation significantly changed the secretion pattern of cancer cells, resulting in higher expression of pro‐inflammatory cytokine and smaller amounts of immunomodulatory contents. Furthermore, sc1‐VHLL, when encapsulated into ionizable liposome nanoparticles (LNP), efficiently targeted tumor site and degraded FMRP in cancer cells. In CT26 tumor‐bearing mouse model, FMRP degradation within tumors substantially promoted the infiltration of lymphocytes and CD8 T cells and reduced the proportion of Treg cells, reshaping the proinflammatory tumor microenvironment and accordingly transforming cold tumor into hot tumor. When combined with immune checkpoint blockade (ICB) therapy, sc1‐VHLL based treatment remarkably inhibited the tumor growth.

G-Quadruplex RNA Based PROTAC Enables Targeted Degradation of RNA Binding Protein FMRP for Tumor Immunotherapy.

Fragile X mental retardation protein (FMRP), an RNA binding protein (RBP), is aberrantly hyper-expressed in human tumors and plays an essential role in tumor invasion, metastasis and immune evasion. However, there is no small-molecule inhibitor for FMRP so far. In this study, we developed the first FMRP-targeting degrader based on PROteolysis TArgeting Chimera (PROTAC) technology and constructed a heterobifunctional PROTAC through linking a FMRP-targeting G-quadruplex RNA (sc1) to a von Hippel-Lindau (VHL)-targeting ligand peptide (named as sc1-VHLL). Sc1-VHLL specifically degraded endogenous FMRP via ubiquitination pathway in both mouse and human cancer cells. The FMRP degradation significantly changed the secretion pattern of cancer cells, resulting in higher expression of pro-inflammatory cytokine and smaller amounts of immunomodulatory contents. Furthermore, sc1-VHLL, when encapsulated into ionizable liposome nanoparticles (LNP), efficiently targeted tumor site and degraded FMRP in cancer cells. In CT26 tumor-bearing mouse model, FMRP degradation within tumors substantially promoted the infiltration of lymphocytes and CD8 T cells and reduced the proportion of Treg cells, reshaping the proinflammatory tumor microenvironment and accordingly transforming cold tumor into hot tumor. When combined with immune checkpoint blockade (ICB) therapy, sc1-VHLL based treatment remarkably inhibited the tumor growth.

Linking Metastatic Potential and Viscoelastic Properties of Breast Cancer Spheroids via Dynamic Compression and Relaxation in Microfluidics.

The growth and invasion of solid tumors are associated with changes in their viscoelastic properties, influenced by both internal cellular factors and physical forces in the tumor microenvironment. Due to the lack of a comprehensive investigation of tumor tissue viscoelasticity, the relationship between such physical properties and cancer malignancy remains poorly understood. Here, the viscoelastic properties of breast cancer spheroids, 3D (in vitro) tumor models, are studied in relation to their metastatic potentials by imposing controlled, dynamic compression within a microfluidic constriction, and subsequently monitoring the relaxation of the imposed deformation. By adopting a modified Maxwell model to extract viscoelastic properties from the compression data, the benign (MCF-10A) spheroids are found to have higher bulk elastic modulus and viscosity compared to malignant spheroids (MCF-7 and MDA-MB-231). The relaxation is characterized by two timescales, captured by a double exponential fitting function, which reveals a similar fast rebound for MCF-7 and MCF-10A. Both the malignant spheroids exhibit similar long-term relaxation and display residual deformation. However, they differ significantly in morphology, particularly in intercellular movements. These differences between malignant spheroids are demonstrated to be linked to their cytoskeletal organization, by microscopic imaging of F-actin within the spheroids, together with cell-cell adhesion strength.

Alleviation of Tumor Invasion by the Development of Natural Polymerbased Low-risk Chemotherapeutic Systems - review on the Malignant Carcinoma Treatments.

The spread of tumors (48% in men and 51% in women), as well as the protection of malignant tumors by stromal cells and complex blood vessels, pose significant challenges to drug delivery to tumors. Modern chemotherapy, on the other hand, addresses tumor growth suppression by at least 60% through versatile formulation systems and numerous modifications to drug delivery systems. The renewable and naturally occurring polymers present invariably in all living cells form the fundamental foundation for most anticancer drug development. The review aims to discuss in detail the preparations of polysaccharide, lipid, and protein-based drug-loading vehicles for the targeted delivery of prominent anticancer drugs. It also provides an explanation of drug distribution in blood (cumulative releases of nearly 80% drug) and drug accumulation at tumor sites (1-5 mg/kg) due to enhanced permeability and retention (EPR). Specific delivery examples for treating colorectal and breast carcinomas have been presented to distinguish the varied drug administration, bioavailability, and tumor internalization mechanisms between sugar, fatty acid, and amino acid polymers. Current therapy possibilities based on cutting-edge literature are provided, along with drug delivery systems tailored to tumor location and invasive properties. The unique combinations of the three natural polymers provide unparalleled solutions to minimize the toxicity (<20% drug release) of the chemotherapeutic drugs on normal tissues. Moreover, the development of a consolidated drug delivery system has contributed to a substantial reduction (dose reduction from 10.43 μM to 1.9 μM) in the undesirable consequences of higher dosages of chemotherapeutic drugs. The review extensively covers safe chemotherapeutic systems with significant advantages (tumor volume shrinkage of 4T1 cells from 1000 mm3 to 200 mm3) in clinical applications of carcinoma treatments using natural polymers.

Evaluation of vascular invasion in pancreatic head tumors and its impact on radical surgical treatment

Objective. To evaluate the informativeness and sensitivity of radiological criteria for vascular invasion in pancreatic head tumors in comparison with intraoperative data and results of routine pathological examination. Materials and methods. The study included 98 patients with ductal adenocarcinoma of the pancreatic head with suspected venous invasion and spread of tumor growth along the vessels of the portomesenteric axis, who were operated on at the Department of Pancreatic and Bile Duct Surgery of the National Research Center of Surgery and Transplantation named after O. A. Shalimov in the period from 2019 to 2023. Group 1 included 51 (52.0%) patients who underwent radical surgery with resection of the superior mesenteric/hepatic portal vein and extended lymph and neurodissection, and group 2 included 47 (48.0%) patients who had positive vascular margins of pancreatic resection according to routine pathological examination. Diagnostic criteria for vascular alterations were developed. A comparative analysis of the informativeness of the developed criteria and the results of a routine pathological examination was performed. The edges of the pancreatic resection were evaluated, including the neck of the gland, common bile duct, duodenum/gastric duct, and the bed of the superior mesenteric/hepatic portal vein and superior mesenteric artery separately. R1 status was defined as the presence of tumor cells at a distance of less than 1 mm to the resection margin. Results. According to the criteria of the National Comprehensive Cancer Network (NCCN) 2023.2, 61 (62.2%) patients had a marginally resectable stage of ductal adenocarcinoma of the pancreatic head and tumor contact with the superior mesenteric/hepatic veins according to multislice computed tomography of the abdominal cavity. In group 1, there were 36 (70.6%) such patients, in group 2 – 25 (53.2%). According to the proposed radiologic criteria for vascular invasion, tumor contact with the superior mesenteric/hepatic portal veins was suspected in 76 (77.6%) patients, which is higher than in the standard approach. Determination of vascular alterations according to the results of our study is a more reliable method for diagnosing invasion of the superior mesenteric/hepatic portal vein (χ2 = 5.46, p = 0.019) and predicting the performance of radical surgery, including vascular resection. Conclusions. The proposed criteria for the radiological diagnosis of vascular invasion at the preoperative stage increased the sensitivity of this method from 62.2 to 77.6%. The most frequent radiological signs of vascular alteration are vascular wall irregularity (47.7%) and parapancreatic tissue density (62.5%). In the presence of any of the radiological signs of vascular alteration, resection of the affected area of the superior mesenteric/hepatic portal vein with extended lymph and neurodissection is indicated, which allows a statistically significant increase in the number of R0 resections.

The prognostic and immune significance of Rab11A in pan-cancer and its function and mechanism underlying estrogen receptor targeting in breast cancer.

Rab11A is an important molecule for recycling endosomes and is closely related to the proliferation, invasion, and metastasis of tumors. This study investigated the prognostic and immune significance of Rab11A and validated its potential function and mechanism in breast cancer (BRCA). RNA sequencing data for 33 tumors were downloaded from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression databases. Correlation analysis was used to evaluate the relationship between Rab11A expression and immune characteristics. Potential pathways were identified using the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analysis. Immunohistochemical analysis, colony formation assay, bromodeoxyuridine incorporation assay, immunofluorescence, and Western blot were used to explore potential function and mechanism. Analysis of the TCGA database showed significant upregulation of Rab11A expression in a variety of cancers. Rab11A was up-regulated in 82.4% of BRCA. High Rab11A expression is associated with poor survival in cancer patients and is a predictor of poor prognosis. CIBERSORT analysis showed that Rab11A was negatively associated with almost all immune cycle activity scores pan-cancer. The results of the TCGA-BRCA cohort were further confirmed by using pathological samples from clinical BRCA patients. The results showed that Rab11A expression was correlated with estrogen receptor (ER) and progesterone receptor expression in BRCA (p<0.05). Knockdown and overexpression of Rab11A affected the proliferation of BRCA cells. Further mechanistic studies revealed that down-regulation of ER alpha (ERα) and up-regulation of ER beta (ERβ) mediated Rab11A-induced inhibition of BRCA cell proliferation. Rab11A expression in pan-cancer is associated with poor prognosis and immune profile. In particular, in BRCA, Rab11A expression regulates cell proliferation by targeting ERα and ERβ. High Rab11A expression is tightly associated with immune characteristics, tumor microenvironment, and genetic mutations. These results provide a reference for exploring the role of Rab11A in pan-cancer and provide a new perspective for revealing potential therapeutic targets in BRCA.

Is Immunohistochemical Galectin-3 Expression Associated with the Epithelial-Mesenchymal Transition in High- and Low-Grade Invasive Urothelial Carcinomas of the Bladder?

Background/Objectives: Bladder cancer, predominantly urothelial carcinoma, is an important malignancy of the urinary system. Despite the same histologic grade and stage, some patients seem to have a worse prognosis. In this context, the epithelial-mesenchymal transition (EMT), characterized by the loss of E-cadherin and gain of vimentin expression, is an important process in tumor progression. Galectin-3, a lactose-binding protein involved in various cellular processes, has been associated with increased tumor cell migration, invasion, and treatment resistance. Methods: In this study, 223 bladder cancer cases were examined, and E-cadherin, vimentin, and galectin-3 expression was evaluated by immunohistochemical staining in tumor budding areas and invasive components. These markers were also correlated with clinicopathological parameters, including tumor grade and stage. Results: The results indicated a significant decrease in E-cadherin expression and an increase in vimentin staining in higher-grade and higher-stage tumors, supporting EMT involvement. Galectin-3 expression was notably higher in T1 high-grade tumors but decreased in T2 stage tumors. Despite this, no significant correlation was found between galectin-3 and E-cadherin or vimentin, suggesting a complex role of galectin-3 in EMT. Conclusions: High galectin-3 expression in T1 high-grade tumors highlights its potential role in early tumor progression and as a therapeutic target. However, the decrease in its expression in advanced stages underscores the need for further research to understand its multifaceted involvement in bladder cancer. These findings suggest that while galectin-3 may contribute to the EMT and early tumor progression, its exact role and potential as a therapeutic target require more detailed investigation.

DNA origami assembled spheroid for evaluating cytotoxicity and infiltration of chimeric antigen receptor macrophage (CAR-M)

Chimeric antigen receptor (CAR) T-cell therapies have shown remarkable results in patients with hematological malignancies. However, their success in treating solid tumors has been limited. As an alternative candidate for the CAR therapy, CAR-macrophages (CAR-M) have demonstrated activation and phagocytosis directed by tumor-associated antigen (TAA), showing promise in the treatment of solid tumors. Nevertheless, the mechanisms by which CARs direct tumor chemotaxis and invasion of CAR-M remain poorly understood. In this study, we aim to investigate the role of CARs in CAR-M attachment and infiltration using 3D tumor spheroids, which were created by utilizing a novel self-assembling nucleic acid nanostructure decorated living cells (NAC). Our results demonstrated that CAR-M exhibited higher invasion and killing capacity in 2D model and 3D tumor spheroids. In summary, the 3D NAC assembled tumor spheroid model provides a suitable platform for target screening and pharmacodynamic evaluation of CAR-M.

Strategies to Improve Clinical Outcomes and Patient Experience Undergoing Transurethral Resection of Bladder Tumor.

To describe patient experiences of transurethral resection of bladder tumor (TURBT) and review recent advances in enhancing clinical outcomes. High rates of recurrence and progression of non-muscle invasive bladder tumors expose patients to multiple TURBT procedures throughout their disease process. Understanding the impact of TURBT on quality of life and patient experiences is crucial for shared decision-making, thus enhanced recovery protocol trials are being explored to improve patient outcomes. The variability in TURBT practices worldwide contributes to differing bladder tumor recurrence rates, prompting efforts to standardize practices by evaluating the impact of patient, hospital, and surgeon factors. For select cases, less intensive surveillance regimens have reduced toxicities and costs without compromising oncologic outcomes. New innovative approaches such as en bloc- and stratified resection techniques may reduce perioperative complications and improve clinical outcomes. Finally, neoadjuvant and ablative treatments have shown to be promising alternatives to TURBT, necessitating further investigation in this setting. TURBT is essential for diagnosing and treating bladder cancer. Reducing associated morbidities and improving surgical outcomes involve multifaceted approaches, including standardizing surgical practices, exploring innovative techniques, and optimizing surveillance regimens, all while promoting patient quality of life. Neoadjuvant therapies as alternative treatments are on the horizon and may ultimately change the landscape of bladder cancer care.

Predictive value of prognostic nutritional index in patients undergoing gastrectomy for gastric cancer: A systematic review and meta-analysis.

The value of prognostic nutritional index (PNI) in gastrectomy remains controversial. This meta-analysis aimed to evaluate the predictive value of PNI in patients undergoing gastrectomy for malignancy. We retrieved studies from medical literature databases to analyze the endpoints of overall survival, cancer-specific survival, recurrence-free survival, and clinicopathologic features. The hazard ratio (HR) and 95% confidence interval (CI) were used to access the survival prognostic value of PNI in patients after gastrectomy. Odds ratio and mean difference were used to evaluate the relationship between the low PNI and clinicopathologic features. In total, we included 38 articles (39 trial comparisons) which contained 23,756 gastrectomy patients. The results showed that low PNI was associated with shorter overall survival (HR: 1.82, 95% CI 1.62-2.03), shorter cancer-specific survival (HR: 1.44, 95% CI 1.24-1.67), and shorter recurrence-free survival (HR: 2.52, 95% CI 1.41-4.47). Besides, patients with low PNI had a higher risk of postoperative complications compared with high PNI (HR: 1.65, 95% CI 1.30-2.09). And low PNI group was found to be related to older, lower BMI, larger tumor size, deeper tumor invasion, poorer differentiation, more advanced tumor stage, total gastrectomy, and the presence of lymph node metastasis, lymphatic invasion, and vessel invasion. PNI was significantly associated with survival and postoperative complications of gastric cancer patients undergoing gastrectomy. Therefore PNI has the potential to be a prognostic predictor for gastrectomy.

Clinicopathological Characteristics of Colorectal Cancer in the Anatomical Pathology Laboratory of Dr. M. Djamil Padang 2017-2020

Colorectal cancer is a malignant epithelial tumor originating from colorectal mucosa. Clinicopathology factors including age, gender, location, histopathological type, differentiation, depth of invasion, lymph node metastasis, and lymphovascular invasion are known affect the prognosis. This study aims to determine the clinicopathological characteristics of colorectal cancer at Anatomical Pathology Laboratory RSUP. Dr. M. Djamil Padang in 2017-2020 This study was descriptive observational with total sampling technique from medical records. Samples included all colorectal cancer patients in 2017-2020 who were fulfilled inclusion criteria, with total 251 samples. The results showed that the most patiens were female (52.2%), the age group were &gt; 50 years (66.1%), mostly located in the rectosigmoid (71.7%). Most of the histopathological types were adenocarcinoma (79.7%), with low grade differentiation (88.8%). More than a half of tumor invasion was at T3 (58.2%). Mainly metastatic status to lymph nodes was Nx (54.2%) and lymphovascular invasion were positive in 60% samples that included the lymphovascular invasion examination. The conclusion of this study is most of colorectal cancer in Anatomical Pathology Laboratory RSUP. Dr. M. Djamil Padang in 2017-2020 are in advanced stage, Early detection needs to be done so that colorectal cancer can be diagnosed at an early stage.

Single-Cell Transcriptomics Reveals Cellular Heterogeneity and Drivers in Serrated Pathway-Driven Colorectal Cancer Progression

Serrated lesions are common precancerous pathways in colorectal cancer (CRC), but the process by which they progress to malignancy remains unclear. We aimed to elucidate this progression through a single-cell RNA landscape. We conducted single-cell RNA sequencing on three normal colonic tissues and fifteen SLs (including HPs, SSLs, SSLD, and TSAs) and integrated these data with datasets containing tumor samples. We identified three invasive malignant epithelial cell subtypes related to CRC progression: SLC1, SLC2, and tumor cell. SLC1, specific to SSLs, is involved in cell proliferation and shows a continuum of malignancy in gene expression. TSA-specific SLC2 exhibited FOXQ1 upregulation and active EMT, indicating invasiveness. The trajectory analysis showed that HPs do not progress to cancer, and different SL types are linked to the MSI status of advanced CRCs. We validated molecular drivers in premalignant lesions and later carcinogenesis. In the tumor microenvironment, CAF and pre-CAF fibroblast subtypes associated with progression were identified. During the premalignant stage, SLC1 triggered CD8+ T cell responses, while at the advanced stage, CAFs promoted tumor invasion and metastasis via FN1-CD44, influencing tumor progression and the treatment response. Our findings highlight transcriptional changes across serrated pathway stages, aiding in early CRC diagnosis and treatment.

Hypoxia-related lncRNA correlates with prognosis and immune microenvironment in uveal melanoma

BackgroundHypoxia-related genes are linked to the prognosis of various solid malignant tumors. However, the role of hypoxia-related long non-coding RNAs (HRLs) in uveal melanoma (UVM) remains unclear. This study aimed to identify HRLs associated with UVM prognosis and develop a novel risk signature to predict patient outcomes.MethodsData from 80 UVM samples were obtained from The Cancer Genome Atlas. Prognostic HRLs were screened using Cox univariate and Pearson correlation analyses. HRL signature were constructed using Lasso analysis, and gene enrichment analysis was performed to explore the association between HRLs and immune features. Cell Counting Kit-8 assay was used to measure the propagation of human uveal melanoma (MuM2B) cells, while tumor invasion and migration were evaluated using Transwell and wound-healing experiments. Inflammatory factors and macrophage polarization were evaluated using quantitative PCR.ResultsIn total, 621 prognostic HRLs were screened and constructed in 12 HRLs. The risk score showed a significant correlation with the survival time of patients with UVM. Additionally, HRL correlated with diverse key immune checkpoints, revealing possible targets for immunotherapy. Immune-related pathways were highly enriched in the high-risk group. LINC02367, a protective HRL, was associated with the tumor microenvironment and survival time of patients with UVM. In vitro, LINC02367 significantly influenced MuM2B proliferation and migration. It also modulated macrophage polarization by regulating inflammatory factor levels, thereby affecting the immune microenvironment.ConclusionsWe developed a novel HRL signature to predict prognosis in patients with UVM. HRLs are potential biomarkers and therapeutic targets for the treatment of UVM.

A basement membrane-related signature for prognosis and immunotherapy benefit in bladder cancer based on machine learning

BackgroundBladder cancer has a poor clinical outcome because of its high aggressiveness. Basement membrane plays vital functions in tumor invasion and migration. Invasion and distant metastasis of cancer are facilitated by degradation of the basement membrane and extracellular matrix.MethodsTen machine learning methods were utilized to develop the basement membrane-related signature (MRS) using datasets from TCGA, GSE13507, GSE31684, GSE32984 and GSE48276. Three anti-PD1 or anti-CTLA4 datasets and several predicting scores were used to investigate the performance of MRS in predicting the immunotherapy benefits.ResultsA predicting model based on the Enet algorithm (alpha = 0.1) was chosen as the optimal MRS since it had the highest average C-index being 0.72. According to TCGA data, the MRS showed good performance in predicting bladder cancer patients' clinical outcomes, with area under curves of 0.744, 0.766 and 0.817 for 1, 3, and 5-year receiver operating characteristic curve, respectively. PD1 and CTLA4 immunophenoscopes were associated with a low MRS score, as well as a lower tumor immune dysfunction and exclusion score. As MRS score increased, immune-activated cells levels decreased, tumor immune dysfunction and exclusion score decreased, immune escape score decreased, intratumor heterogeneity score decreased, PD1&CTLA4 immunophenoscore increased, and tumor mutational burden score increased in bladder cancer, suggesting better immunotherapy benefits. Bladder cancer cases with high MRS score was correlated with higher cancer related hallmark scores, including NOTCH and glycolysis signaling.ConclusionA new MRS has been developed for bladder cancer, which could be used to predict prognosis and the success of immunotherapy.

Spatial Transcriptomics Unravel the Tissue Complexity of Oral Pathogenesis.

Spatial transcriptomics (ST) is a cutting-edge methodology that enables the simultaneous profiling of global gene expression and spatial information within histological tissue sections. Traditional transcriptomic methods lack the spatial resolution required to sufficiently examine the complex interrelationships between cellular regions in diseased and healthy tissue states. We review the general workflows for ST, from specimen processing to ST data analysis and interpretations of the ST dataset using visualizations and cell deconvolution approaches. We show how recent studies used ST to explore the development or pathogenesis of specific craniofacial regions, including the cranium, palate, salivary glands, tongue, floor of mouth, oropharynx, and periodontium. Analyses of cranial suture patency and palatal fusion during development using ST identified spatial patterns of bone morphogenetic protein in sutures and osteogenic differentiation pathways in the palate, in addition to the discovery of several genes expressed at critical locations during craniofacial development. ST of salivary glands from patients with Sjögren's disease revealed co-localization of autoimmune antigens with ductal cells and a subpopulation of acinar cells that was specifically depleted by the dysregulated autoimmune response. ST of head and neck lesions, such as premalignant leukoplakia progressing to established oral squamous cell carcinomas, oral cancers with perineural invasions, and oropharyngeal lesions associated with HPV infection spatially profiled the complex tumor microenvironment, showing functionally important gene signatures of tumor cell differentiation, invasion, and nontumor cell dysregulation within patient biopsies. ST also enabled the localization of periodontal disease-associated gene expression signatures within gingival tissues, including genes involved in inflammation, and the discovery of a fibroblast subtype mediating the transition between innate and adaptive immune responses in periodontitis. The increased use of ST, especially in conjunction with single-cell analyses, promises to improve our understandings of craniofacial development and pathogenesis at unprecedented tissue-level resolution in both space and time.

Substrate stiffness-dependent activation of Hippo pathway in cancer associated fibroblasts

The tumor microenvironment (TME) comprises a heterogenous cell population within a complex three-dimensional (3D) extracellular matrix (ECM). Stromal cells within this TME are altered by signaling cues from cancer cells to support uncontrolled tumor growth and invasion events. Moreover, the ECM also plays a fundamental role in tumor development through pathological remodeling, stiffening and interaction with TME cells. In healthy tissues, Hippo signaling pathway actively contributes to tissue growth, cell proliferation and apoptosis. However, in cancer, the Hippo signaling pathway is highly dysregulated, leading to nuclear translocation of the YAP/TAZ complex, which directly contributes to uncontrolled cell proliferation and tissue growth, and ECM remodeling and stiffening processes. Here, we compare the effect of increasing cell culture substrate stiffness, derived from tumor progression, upon the dysregulation of the Hippo signaling pathway in colorectal cancer-associated fibroblasts (CAFs) and normal colorectal fibroblasts (NFs). We correlate the dysregulation of Hippo pathway with the magnitude of the traction forces exerted by healthy and malignant stromal cells. We found that ECM stiffening is crucial in Hippo pathway dysregulation in CAFs, but not in normal fibroblasts.

Exploring the Bioactive Potential of Taraxacum officinale F.H. Wigg Aerial Parts on MDA Breast Cancer Cells: Insights into Phytochemical Composition, Antioxidant Efficacy, and Gelatinase Inhibition within 3D Cellular Models

In this work, aerial parts of Taraxacum officinale F.H. Wigg. produced in Umbria, Italy, were chemically investigated by solid-phase microextraction/gas chromatography–mass spectrometry (SPME/GC-MS) to describe their volatile profile. The results obtained showed the preponderant presence of monoterpenes, with limonene and 1,8-cineole as the main components. Further analyses by GC/MS after derivatization reaction were performed to characterize the non-volatile fraction highlighting the presence of fatty acids and di- and triterpenic compounds. T. officinale methanol and dichloromethane extracts, first analyzed by HRGC/MS, were investigated to evaluate the antioxidant activity, cytotoxicity, and antiproliferative properties of MDA cells on the breast cancer cell line and MCF 10A normal epithelial cells as well as the antioxidant activity by colorimetric assays. The impact on matrix metalloproteinases MMP-9 and MMP-2 was also explored in 3D cell systems to investigate the extracts’ efficacy in reducing cell invasiveness. The extracts tested showed no cytotoxic activity with EC50 &gt; 250 µg/mL on both cell lines. The DPPH assay revealed higher antioxidant activity in the MeOH extract compared with the DCM extract, while the FRAP assay showed a contrasting result, with the DCM extract exhibiting slightly greater antioxidant capacity. After treatment for 24 h with a non-cytotoxic concentration of 500 µg/mL of the tested extracts, gelatin zymography and Western blot analyses demonstrated that both MeOH and DCM extracts influenced the expression of MMP-9 and MMP-2 in MDA cells within the 3D cell model, leading to a significant decrease in the levels of these gelatinases, which are crucial markers of tumor invasiveness.

OSCC-derived EVs educate fibroblasts and remodel collagen landscape

Cancer-associated myofibroblasts (mCAFs) represent a significant component of the tumor microenvironment due to their contributions to extracellular matrix (ECM) remodeling. The pro-tumor mechanisms of extracellular vesicles (EVs) by regulating mCAFs and related collagens remain poorly understood in oral squamous cell carcinoma (OSCC). In this study, through analysis of single-cell sequencing data and immunofluorescence staining, we confirmed the increased presence of mCAFs and enrichment of specific collagen types in OSCC tissues. Furthermore, we demonstrated that OSCC-derived EVs promote the transformation of fibroblasts into mCAFs, leading to tumor invasion. Proteomic analysis identified the presence of TGF-β1 in EVs and revealed its role in inducing mCAFs via the TGF-β1/Smad3 signaling pathway. Experiments in vivo confirmed that EVs, particularly those carrying TGF-β1, trigger COL18high COL5high matrix deposition, thereby forming the pro-tumor ECM in OSCC. In summary, our investigation unveils the significant involvement of OSCC-derived EVs in orchestrating the differentiation of fibroblasts into mCAFs and modulating specific collagen types within the ECM. Therefore, this study provides a theoretical basis for targeting the EV-mediated TGF-β1 signaling pathway as a potential therapeutic strategy for OSCC.

Single cell analysis revealed SFRP2 cancer associated fibroblasts drive tumorigenesis in head and neck squamous cell carcinoma

Understanding the mechanisms of invasion and metastasis in head and neck squamous cell carcinoma (HNSCC) is crucial for effective treatment, particularly in metastatic cases. In this study, we analyzed multicenter bulk sequencing and comprehensive single-cell data from 702,446 cells, leading to the identification of a novel subtype of cancer-associated fibroblasts (CAFs), termed Secreted Frizzled-Related Protein2 CAFs (SFRP2_CAFs). These cells, originating from smooth muscle cells, display unique characteristics resembling both myofibroblastic CAFs and inflammatory CAFs, and are linked to poorer survival outcomes in HNSCC patients. Our findings reveal significant interactions between SFRP2_CAFs and SPP1 tumor-associated macrophages, which facilitate tumor invasion and metastasis. Moreover, our research identifies Nuclear factor I/X (NFIX) as a key transcription factor regulating SFRP2_CAFs behavior, confirmed through gene regulatory network analysis and simulation perturbation.

"Enhancing post-craniotomy recovery: leveraging AI and network analysis for improved outcomes".

This letter addresses the importance of enhancing post-craniotomy care for primary brain tumor patients by leveraging insights from Rongqing Li et al.'s study on symptom networks. The study identified key central and bridge symptoms, such as sadness and difficulty understanding, which influence post-surgical recovery and quality of life. It also highlighted that patients with noninvasive tumors showed more cohesive symptom networks compared to those with invasive tumors. However, the study had limitations, including a short observation period and reliance on self-reported data, which restricted the depth of the findings.To optimize recovery, integrating artificial intelligence (AI) and machine learning (ML) could revolutionize post-craniotomy care. AI can assist with surgical planning, predict complications, and monitor recovery through wearable devices and real-time alerts. Natural Language Processing (NLP) can improve symptom detection from electronic health records, enhancing clinical decision-making. Despite the potential of these technologies, ethical concerns regarding data privacy and AI-generated report accuracy must be addressed. Future research should focus on long-term outcomes and refining AI applications to improve post-craniotomy symptom management and overall patient outcomes.