Biology subjects

Rosenzweig, D. H.

Publications and source records attributed to Rosenzweig, D. H..

7 recordsLinked to original sources

bioRxiv2025

Targeting breast cancer senescence in 3D models of bone metastasis

Chemotherapeutic treatment of breast cancer with Doxorubicin can induce tumor and stromal cell senescence leading to therapy-resistance. Senescence-associated secretory phenotype (SASP) promotes secretion of pro-inflammatory and tumorigenic factors causing systemic inflammation. Combined, this can result in immune suppression, tumor growth and secondary spread of cancer. Targeting and removing senescent and cancerous cells using a combination of chemotherapeutic and senolytic drugs may reduce systemic inflammation, improve therapeutic efficacy, and prevent metastasis. Treatment of both triple-negative breast cancer (MDA-MB-231) cells, and primary spine osteoblasts 0.25 {micro}M Doxorubicin showed significant induction of senescence indicated by p21 positive cells. Doxorubicin and senolytics (RG-7112, o-Vanillin) treatment of mono-culture and co-culture spheroids showed a significant additive effect on decreased tumor sphere viability and growth. This was correlated with decreased p21 and Ki67 proliferation marker in both the breast cancer and osteoblast cells. In all cases, combined Doxorubicin and senolytics significantly reduced sphere size and cancer cell outgrowth, indicating reduced metastatic potential. Future chemotherapeutic treatment of breast cancer patients may be optimized by adding senolytic drugs to more effectively clear tumors and help regenerate surrounding stroma tissue such as in the bone metastatic environment.

cancer biology↗

bioRxiv2024

Cold Atmospheric Plasma Selectively Disrupts Breast Cancer Growth in a Bioprinted 3D Tumor Microenvironment Model

Spine metastases are the most common bone site for breast cancer, with evolving surgery and multidisciplinary care improving outcomes. Current treatments, including chemotherapy and invasive surgery, may damage healthy tissue and may leave residual tumors that lead to recurrence. Cold atmospheric plasma (CAP) offers a non-invasive alternative by delivering reactive oxygen and nitrogen species (RONS) locally to tumor sites, selectively targeting cancer cells while sparing healthy tissue. To assess the impact and selectivity toward tumor cells adjacent to bone-like tissue, we develop a 3D bioprinted tumor-stroma model using a 1% alginate and 7% gelatin cell-laden hydrogel to mimic a bone-like microenvironment. The model co-cultures triple-negative MDA-MB-231 human breast cancer cells with primary human bone marrow mesenchymal stromal cells to simulate tumor-stroma interactions. The effects of CAP treatments are assessed through metabolic activity and viability assays over three days. Results show significant selectivity for cancer cells in both 2D and 3D cultures. CAP minimizes damage to healthy cells, offering the potential for localized treatment over systemic chemotherapies such as doxorubicin. Our novel bioprinted model, combined with a plasma source controlling RONS composition, enables detailed studies of redox-based cancer cell inactivation and highlights CAP as a personalized, non-invasive treatment for bone metastases.

bioengineering↗

bioRxiv2024

Directed biomechanical compressive forces enhance fusion efficiency in model placental trophoblast cultures

The syncytiotrophoblast is a multinucleated structure that arises from fusion of mononucleated cytotrophoblasts, to sheath the placental villi and regulate transport across the maternal-fetal interface. Here, we ask whether the dynamic mechanical forces that must arise during villous development might influence fusion, and explore this question using in vitro choriocarcinoma trophoblast models. We demonstrate that mechanical stress patterns arise around sites of localized fusion in cell monolayers, in patterns that match computational predictions of villous morphogenesis. We then externally apply these mechanical stress patterns to cell monolayers and demonstrate that equibiaxial compressive stresses (but not uniaxial or equibiaxial tensile stresses) enhance expression of the syndecan-1 marker of fusion. These findings suggest that the mechanical stresses that contribute towards sculpting the placental villi may also impact fusion in the developing tissue. We then extend this concept towards 3D cultures and demonstrate that fusion can be enhanced by applying low isometric compressive stresses to spheroid models, even in the absence of an inducing agent. These results indicate that mechanical stimulation is a potent activator of cellular fusion, suggesting novel avenues to improve experimental reproductive modelling, placental tissue engineering, and understanding disorders of pregnancy development.

biophysics↗

bioRxiv2023

Nanoparticle-Functionalized Acrylic Bone Cement for Local Therapeutic Delivery to Spinal Metastases

Polymethylmethacrylate bone cement is often used to reconstruct critical-sized defects generated by surgical resection of spinal metastases. Residual tumor cells after a resection can drive recurrence and destabilization. Doxorubicin (DOX) is a common chemotherapeutic drug with unwanted side-effects when administered systemically. Mesoporous silica nanoparticles are gaining attention for targeted drug delivery to bypass the negative side effects associated with systemic drug administration. We developed a nanoparticle-functionalized cement for the local release of DOX and tested its ability to suppress cancer cells. DOX was loaded onto nanoparticles which were then mixed into the cement. Drug release profiles were obtained over a period of 4 weeks. Cement constructs were incubated with 2D and 3D cultures of breast and prostate cancer cell lines, and cell metabolic activity and viability were evaluated. Cell migration and spheroid growth were assessed in collagen-coated spheroid cultures. Nanoparticles were homogenously dispersed and did not alter cement mechanical strength. A sustained DOX release profile was achieved with the addition of nanoparticles to the bone cement. The release profile of DOX from nanoparticle cement may be modified by varying the amount of the drug loaded onto the nanoparticles and the proportion of nanoparticles in the cement. Cells treated with the cement constructs showed a dose- and time-dependent inhibition. Cell migration and spheroid growth were impaired in 3D culture. We show that nanoparticles are essential for sustained DOX release from bone cement. DOX-loaded nanoparticle cement can inhibit cancer cells and impair their migration, with strong potential for in vivo translation studies.

bioengineering↗

bioRxiv2021

Mechanical activation drives tenogenic differentiation of human mesenchymal stem cells in aligned dense collagen hydrogels

Tendons are force transmitting mechanosensitive tissues predominantly comprised of highly aligned collagen type I fibres. In this study, the recently introduced gel aspiration-ejection method was used to rapidly fabricate aligned dense collagen (ADC) hydrogel scaffolds. ADCs provide a biomimetic environment compared to traditional collagen hydrogels that are mechanically unstable and comprised of randomly oriented fibrils. The ADC scaffolds were shown to be anisotropic with comparable stiffness to immature tendons. Furthermore, the application of static and cyclic uniaxial loading, short-term (48 h) and high-strain (20%), resulted in a 3-fold increase in both the ultimate tensile strength and modulus of ADCs. Similar mechanical activation of human mesenchymal stem cell (MSC) seeded ADCs in serum- and growth factor-free medium induced their tenogenic differentiation. Both static and cyclic loading profiles resulted in a greater than 12-fold increase in scleraxis gene expression and either suppressed or maintained osteogenic and chondrogenic expressions. Following the 48 h mechanoactivation period, the MSC-seeded scaffolds were matured by tethering in basal medium without further external mechanical stimulation for 19 days, altogether making up 21 days of culture. Extensive cell-induced matrix remodeling and deposition of collagens type I and III, tenascin-C and tenomodulin were observed, where initial cyclic loading induced significantly higher tenomodulin protein content. Moreover, the initial short-term mechanical stimulation elongated and polarized seeded MSCs and overall cell alignment was significantly increased in those under static loading. These findings indicate the regenerative potential of the ADC scaffolds for short-term mechanoactivated tenogenic differentiation, which were achieved even in the absence of serum and growth factors that may potentially increase clinical translatability. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/470026v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1d52807org.highwire.dtl.DTLVardef@13716c5org.highwire.dtl.DTLVardef@1b7ffeforg.highwire.dtl.DTLVardef@103c183_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2021

A Novel 3D Co-culture Platform for Integrating Tissue Interfaces for Tumor Growth, Migration and Therapeutic Sensitivity: PP-3D-S

Metastatic cancers can be highly heterogeneous, show large patient variability and are typically hard to treat due to chemoresistance. Personalized therapies are therefore needed to suppress tumor growth and enhance patients quality of life. Identifying appropriate patient-specific therapies remains a challenge though, due mainly to non-physiological in vitro culture systems. Therefore, more complex and physiological in vitro human cancer microenvironment tools could drastically aid in development of new therapies. We developed a plasma-modified, electro-spun 3D scaffold (PP-3D-S) that can mimic the human cancer microenvironment for customized-cancer therapeutic screening. The PP-3D-S were characterized for optimal plasma-modifying treatment and scaffolds morphology including fiber diameter and pore size. PP-3D-S was then seeded with human fibroblasts to mimic a stromal tissue layer; cell adhesion on plasma-modified poly (lactic acid), PLA, electrospun mats vastly exceeded that on untreated controls. The cell-seeded scaffolds were then overlaid with alginate/gelatin-based hydrogel embedded with MDA-MB231 human breast cancer cells, representing a tumor-tissue interface. Among three different plasma treatments, we found that NH3 plasma promoted the most tumor cell migration to the scaffold surfaces after 7 days of culture. For all treated and non-treated mats, we observed a significant difference in tumor cell migration between small-sized and either medium- or large-sized scaffolds. In addition, we found that the PP-3D-S was highly comparable to the standard Matrigel(R) migration assays in two different sets of doxorubicin screening experiments, where 75% reduction in migration was achieved with 0.5M doxorubicin for both systems. Taken together, our data indicate that PP-3D-S is an effective, low-cost, and easy-to-use alternate 3D tumor migration model which may be suitable as a physiological drug screening tool for personalized medicine against metastatic cancers.

bioengineering↗

bioRxiv2020

Actuation Enhances Patterning in Human Neural Tube Organoids

Tissues achieve their complex spatial organization through an interplay between gene regulatory networks, cell-cell communication, and physical interactions mediated by mechanical forces. Current strategies to generate in-vitro tissues have largely failed to implement such active, dynamically coordinated mechanical manipulations, relying instead on extracellular matrices which respond to, rather than impose mechanical forces. Here we develop devices that enable the actuation of organoids. We show that active mechanical forces increase growth and lead to enhanced patterning in an organoid model of the neural tube derived from single human pluripotent stem cells (hPSC). Using a combination of single-cell transcriptomics and immunohistochemistry, we demonstrate that organoid mechanoregulation due to actuation operates in a temporally restricted competence window, and that organoid response to stretch is mediated extracellularly by matrix stiffness and intracellularly by cytoskeleton contractility and planar cell polarity. Exerting active mechanical forces on organoids using the approaches developed here is widely applicable and should enable the generation of more reproducible, programmable organoid shape, identity and patterns, opening avenues for the use of these tools in regenerative medicine and disease modelling applications.

bioengineering↗