Biology subjects

Fowlkes, N.

Publications and source records attributed to Fowlkes, N..

6 recordsLinked to original sources

bioRxiv2025

Soluble E-cadherin Drives Brain Metastasis in Inflammatory Breast Cancer

The brain is a common site of relapse in inflammatory breast cancer (IBC), an E-cadherin positive, aggressive form of breast cancer. We found that elevated serum levels of soluble E-cadherin (sEcad), an 80-kDa fragment of E-cadherin, in patients with metastatic IBC correlated with poorer outcomes and increased rates of brain metastases. In our effort to understand the underlying mechanism, we discovered that sEcad binds to XIAP, an inhibitor of cell death, activating the pro-survival NF-k{beta} signaling in tumor cells. We also discovered that sEcad affects the tumor cell microenvironment by enhancing cancer cell adhesion to endothelial cells and inducing reactive astrocytosis in the brain. In addition, we found that sEcad-mediated reactive astrocytosis relies on the CXCL1/CXCL8-CXCR2 axis and treatment with a brain-permeable CXCR2 antagonist reduced brain metastatic burden and prolonged survival. These findings implicate sEcad in brain metastasis and provide new insights into potential therapeutic targets for IBC. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=148 SRC="FIGDIR/small/660428v1_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@10a7c47org.highwire.dtl.DTLVardef@1653278org.highwire.dtl.DTLVardef@d4787corg.highwire.dtl.DTLVardef@132489b_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIHigh serum sEcad levels correlate clinically with poor survival outcomes and development of brain metastasis C_LIO_LIsEcad drives IBC brain metastasis growth in mouse models C_LIO_LIsEcad binds XIAP to activate NFkB and promote anoikis resistance and invasion of IBC cells C_LIO_LIsEcad activates reactive astrocytes and induces CXCR2 expression on tumor cells in vitro and in vivo C_LIO_LICXCR2-IN-1, a brain-permeable CXCR2 antagonist, reduces metastasis and improves survival in IBC brain metastasis models C_LI

cancer biology↗

bioRxiv2025

Adaptive Plasticity Tumor Cells Modulate MAPK-Targeting Therapy Response in Colorectal Cancer

MAPK pathway inhibitors (MAPKi) are increasingly used in the treatment of advanced colorectal cancer, but often produce short-lived responses in patients. Although acquired resistance by de novo mutations in tumors have been found to reduce response in some patients, additional mechanisms underlying the limited response durability of MAPK targeting therapy remain unknown. Here, we denote new contributory tumor biology and provide insight on the impact of tumor plasticity on therapy response. Analysis of MAPKi treated patients revealed activation of stemness programs and increased ASCL2 expression, which are associated with poor outcomes. Greater ASCL2 with MAPKi treatment was also seen in patient-derived CRC models, independent of driver mutations. We find ASCL2 denotes a distinct cell population, arising from phenotypic plasticity, with a proliferative, stem-like phenotype, and decreased sensitivity to MAPKi therapy, which were named adaptive plasticity tumor (APT) cells. MAPK pathway suppression induces the APT phenotype in cells, resulting in APT cell enrichment in tumors and limiting therapy response in preclinical and clinical data. APT cell depletion improved MAPKi treatment efficacy and extended MAPKi response durability in mice. These findings uncover a cellular program that mitigates the impact of MAPKi therapies and highlights the importance of addressing tumor plasticity to improve clinical outcomes.

cancer biology↗

bioRxiv2023

Image-guided deployment and monitoring of a novel tungsten nanoparticle-infused radiopaque absorbable inferior vena cava filter in pig

The use of absorbable inferior vena cava filters (IVCFs) constructed with poly-p-dioxanone (PPDO) eliminates risks and complications associated with the use of retrievable metallic filters. Radiopacity of radiolucent PPDO IVCFs can be improved with the incorporation of nanoparticles (NPs) made of high-atomic number materials such as gold and bismuth. In this study, we focused on incorporating tungsten NPs (WNPs), along with polyhydroxybutyrate (PHB), polycaprolactone (PCL), and polyvinylpyrrolidone (PVP) polymers to increase the surface adsorption of the WNPs. We compared the imaging properties of WNPs with single-polymer PHB (W-P) and WNPs with polymer blends consisting of PHB, PCL, and PVP (W-PB). Our in vitro analyses using PPDO sutures showed enhanced radiopacity with either W-P or W-PB coating, without compromising the inherent physico-mechanical properties of the PPDO sutures. We observed a more sustained release of WNPs from W-PB-coated sutures than W-P-coated sutures. We successfully deployed W-P- and W-PB-coated IVCFs into the inferior vena cava of pig models, with monitoring by fluoroscopy. At the time of deployment, W-PB-coated IVCFs showed a 2-fold increase in radiopacity compared to W-P-coated IVCFs. Longitudinal monitoring of in vivo IVCFs over a 12-week period showed a drastic decrease in radiopacity at week 3 for both filters. Results of this study highlight the utility of NPs and polymers for enhancing radiopacity of medical devices; however, different methods of incorporating NPs and polymers can still be explored to improve the efficacy, safety, and quality of absorbable IVCFs.

bioengineering↗

bioRxiv2023

Gold Nanoparticles for Monitoring of Mesenchymal Stem Cell-Loaded Bioresorbable Polymeric Wraps for Arteriovenous Fistulas

BackgroundTo address high rates of arteriovenous fistula (AVF) failure, a mesenchymal stem cell (MSC)-seeded polymeric perivascular wrap has been developed to reduce neointimal hyperplasia (NIH) and enhance AVF maturation in a rat model. However, the wraps radiolucency makes its placement and integrity difficult to monitor. PurposeIn this study, we infused gold nanoparticles (AuNPs) into the polymeric perivascular wrap to improve its radiopacity and tested the effect of infusion on the previously reported beneficial effects of the polymeric wrap on the AVF outflow vein. Materials and MethodsWe fabricated a polymeric perivascular wrap made of polycaprolactone (PCL) infused with AuNPs via electrospinning. Sprague-Dawley rat mesenchymal stem cells (MSCs) were seeded on the surface of the wraps. We then compared the effect of five AVF treatments--no perivascular wrap (i.e., control), PCL wrap, PCL+MSC wrap, PCL-Au wrap, and PCL-Au+MSC wrap--on AVF maturation in a Sprague-Dawley rat model of chronic kidney disease (n=3 per group). Statistical significance was defined as p<.05, and one-way analysis of variance was performed using GraphPad Prism software. ResultsOn micro-CT, AuNP-infused wraps demonstrated significantly higher radiopacity compared to wraps without AuNPs. On ultrasonography, wraps with and without AuNPs equally reduced the wall-to-lumen ratio of the outflow vein, a marker of vascular stenosis. On histomorphometric analysis, wraps with and without AuNPs equally reduced the neointima-to- lumen ratio of the outflow vein, a measure of NIH. On immunofluorescence analysis, representative MSC-seeded wraps demonstrated reduced neointimal staining for markers of smooth muscle cells (-SMA), inflammatory cells (CD45), and fibroblasts (vimentin) infiltration when compared to control and wraps without MSCs. ConclusionGold nanoparticle infusion allows the in vivo monitoring via micro-CT of a mesenchymal stem cell-seeded polymeric wrap over time without compromising the benefits of the wrap on arteriovenous fistula maturation. Summary StatementGold nanoparticle infusion enables in vivo monitoring via micro-CT of the placement and integrity over time of mesenchymal stem cell-seeded polymeric wrap supporting arteriovenous fistula maturation. Key ResultsO_LIGold nanoparticle (AuNP)-infused perivascular wraps demonstrated higher radiopacity on micro-CT compared with wraps without AuNPs after 8 weeks. C_LIO_LIAuNP-infused perivascular wraps equally improved the wall-to-lumen ratio of the outflow vein (a marker of vascular stenosis) when compared with wraps without AuNPs, as seen on US. C_LIO_LIAuNP-infused perivascular wraps equally reduced the neointima-to-lumen ratio of the outflow vein (a measure of neointimal hyperplasia) when compared with wraps without AuNPs, as seen on histomorphometry. C_LI

bioengineering↗

bioRxiv2023

Rosuvastatin-Eluting Gold Nanoparticle-Loaded Perivascular Implantable Wrap for Enhanced Arteriovenous Fistula Maturation in a Murine Model

BackgroundArteriovenous fistulas (AVFs) are a vital intervention for patients requiring hemodialysis, but they also contribute to overall mortality due to access malfunction. The most common cause of both AVF non-maturation and secondary failure is neointimal hyperplasia (NIH). Absorbable polycaprolactone (PCL) perivascular wraps can address these complications by incorporating drugs to attenuate NIH, such as rosuvastatin (ROSU), and metallic nanoparticles for visualization and device monitoring. ObjectivesThis study aimed to assess the impacts of gold nanoparticle (AuNP) and ROSU-loaded perivascular wraps on vasculature NIH and AVF maturation and patency in a chronic kidney disease rat model. MethodsElectrospun wraps containing combinations of PCL, AuNP, and ROSU were monitored for in vitro drug elution, nanoparticle release, tensile strength, and cell viability. Perivascular wraps were implanted in chronic kidney disease rats for in vivo ultrasound (US) and micro-computed tomography (mCT) imaging. AVF specimens were collected for histological analyses. ResultsNo difference in cell line viability was observed in ROSU-containing grafts. In vitro release studies of ROSU and AuNPs correlated with decreasing radiopacity over time on in vivo mCT analysis. The mCT study also demonstrated increased radiopacity in AuNP-loaded wraps compared with PCL and control. The addition of ROSU demonstrated decreased US and histologic measurements of NIH. ConclusionsThe reduced NIH seen with ROSU-loading of perivascular wraps suggests a synergistic effect between mechanical support and anti-hyperplasia medication. Furthermore, the addition of AuNPs increased wrap radiopacity. Together, our results show that radiopaque, AuNP-, and ROSU-loaded PCL grafts induce AVF maturation and suppress NIH while facilitating optimal implanted device visualization.

bioengineering↗

bioRxiv2022

Bioresorbable mesenchymal stem cell-loaded electrospun polymeric scaffold inhibits neointimal hyperplasia following arteriovenous fistula formation in a rat model of chronic kidney disease

In the setting of chronic kidney disease (CKD), the periadventitial injection of mesenchymal stem cells (MSCs) has shown significant potential in improving arteriovenous fistula (AVF) maturation by inhibiting neointimal hyperplasia (NIH). However, the rapid clearance of MSCs remains a challenge. Hence, we fabricated an electrospun perivascular scaffold from polycaprolactone (PCL) to support MSC attachment and allow gradual MSC elution at the outflow vein, the AVF site most prone to NIH. We performed a 5/6th nephrectomy to induce CKD in Sprague-Dawley rats, followed by direct AVF formation and perivascular scaffold application. We then compared the following groups of CKD rats: no perivascular scaffold (i.e., control), PCL scaffold, and PCL+MSC scaffold. On ultrasonography, the PCL and PCL+MSC groups showed significantly reduced wall thickness and wall-to-lumen ratio and increased luminal diameter and flow rate. Of note, the PCL+MSC group showed greater improvement in luminal diameter and flow rate compared to PCL alone. Moreover, 18F-fluorodeoxyglucose positron emission tomography showed that only PCL+MSC resulted in a significant reduction in uptake. On histology, the PCL and PCL+MSC groups showed significantly reduced neointima-to-lumen and neointima-to-media ratios and reduced neointimal CD45, -SMA, and vimentin fluorescence staining compared to the control. Although the two scaffold treatments did not differ significantly in histology, in vivo imaging suggested that the addition of MSCs promoted greater luminal expansion and blood flow and reduced the inflammatory process underlying NIH. Our results demonstrate the utility of mechanical support loaded with MSCs at the outflow vein immediately after AVF formation to support maturation by minimizing NIH.

bioengineering↗