Biology subjects

Schwartz, A. D.

Publications and source records attributed to Schwartz, A. D..

4 recordsLinked to original sources

bioRxiv2017

Anomalous Diffusion as a Descriptive Model of Cell Migration

Appropriately chosen descriptive models of cell migration in biomaterials will allow researchers to characterize and ultimately predict the movement of cells in engineered systems for a variety of applications in tissue engineering. The persistent random walk (PRW) model accurately describes cell migration on two-dimensional (2D) substrates. However, this model inherently cannot describe subdiffusive cell movement, i.e. migration paths in which the root mean square displacement increases more slowly than the square root of the time interval. Subdiffusivity is a common characteristic of cells moving in confined environments, such as three-dimensional (3D) porous scaffolds, hydrogel networks, and in vivo tissues. We demonstrate that a generalized anomalous diffusion (AD) model, which uses a simple power law to relate the mean square displacement (MSD) to time, more accurately captures individual cell migration paths across a range of engineered 2D and 3D environments than does the more commonly used PRW model. We used the AD model parameters to distinguish cell movement profiles on substrates with different chemokinetic factors, geometries (2D vs 3D), substrate adhesivities, and compliances. Although the two models performed with equal precision for superdiffusive cells, we suggest a simple AD model, in lieu of PRW, to describe cell trajectories in populations with a significant subdiffusive fraction, such as cells in confined, 3D environments.

bioengineering↗

bioRxiv2017

Fibroblasts from metastatic sites induce broad-spectrum drug desensitization via modulation of mitochondrial priming

Due to tumor heterogeneity, most believe that effective treatments should be tailored to the features of an individual tumor or tumor subclass. It is still unclear what information should be considered for optimal disease stratification, and most prior work focuses on tumor genomics. Here, we focus on the tumor micro-environment. Using a large-scale co-culture assay optimized to measure drug-induced cell death, we identify tumor-stroma interactions that modulate drug sensitivity. Our data show that the chemo-insensitivity typically associated with aggressive subtypes of breast cancer is not cell intrinsic, but rather a product of tumor-fibroblast interactions. Additionally, we find that fibroblast cells influence tumor drug response in two distinct and divergent manners, which were predicable based on the anatomical origin from which the fibroblasts were harvested. These divergent phenotypes result from modulation of \"mitochondrial priming\" of tumor cells, caused by secretion of inflammatory cytokines, such as IL6 and IL8, from stromal cells.

cancer biology↗

bioRxiv2017

A Biomaterial Screening Approach to Reveal Microenvironmental Mechanisms of Drug Resistance

TOC FigureDrug response screening, gene expression, and kinome signaling were combined across biomaterial platforms to combat adaptive resistance to sorafenib.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=158 SRC=\"FIGDIR/small/168039_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (60K):\norg.highwire.dtl.DTLVardef@a7af0eorg.highwire.dtl.DTLVardef@d5f2bborg.highwire.dtl.DTLVardef@330bd6org.highwire.dtl.DTLVardef@14e1f1d_HPS_FORMAT_FIGEXP M_FIG C_FIG Insight BoxWe combined biomaterial platforms, drug screening, and systems biology to identify mechanisms of extracellular matrix-mediated adaptive resistance to RTK-targeted cancer therapies. Drug response was significantly varied across biomaterials with altered stiffness, dimensionality, and cell-cell contacts, and kinome reprogramming was responsible for these differences in drug sensitivity. Screening across many platforms and applying a systems biology analysis were necessary to identify MEK phosphorylation as the key factor associated with variation in drug response. This method uncovered the combination therapy of sorafenib with a MEK inhibitor, which decreased viability on and within biomaterials in vitro, but was not captured by screening on tissue culture plastic alone. This combination therapy also reduced tumor burden in vivo, and revealed a promising approach for combating adaptive drug resistance.\n\nAbstractTraditional drug screening methods lack features of the tumor microenvironment that contribute to resistance. Most studies examine cell response in a single biomaterial platform in depth, leaving a gap in understanding how extracellular signals such as stiffness, dimensionality, and cell-cell contacts act independently or are integrated within a cell to affect either drug sensitivity or resistance. This is critically important, as adaptive resistance is mediated, at least in part, by the extracellular matrix (ECM) of the tumor microenvironment. We developed an approach to screen drug responses in cells cultured on 2D and in 3D biomaterial environments to explore how key features of ECM mediate drug response. This approach uncovered that cells on 2D hydrogels and spheroids encapsulated in 3D hydrogels were less responsive to receptor tyrosine kinase (RTK)-targeting drugs sorafenib and lapatinib, but not cytotoxic drugs, compared to single cells in hydrogels and cells on plastic. We found that transcriptomic differences between these in vitro models and tumor xenografts did not reveal mechanisms of ECM-mediated resistance to sorafenib. However, a systems biology analysis of phospho-kinome data uncovered that variation in MEK phosphorylation was associated with RTK-targeted drug resistance. Using sorafenib as a model drug, we found that co-administration with a MEK inhibitor decreased ECM-mediated resistance in vitro and reduced in vivo tumor burden compared to sorafenib alone. In sum, we provide a novel strategy for identifying and overcoming ECM-mediated resistance mechanisms by performing drug screening, phospho-kinome analysis, and systems biology across multiple biomaterial environments.

bioengineering↗

bioRxiv2017

Mechanosensing of Integrin α6 and EGFR Converges atCalpain 2

Introduction Introduction Materials and Methods Results Discussion Conclusions Author Contributions Conflict of Interest References Carcinoma progression is associated with deposition of ECM that stiffens the local microenvironment [1, 2]. This tissue stiffening results in deposition of additional matrix proteins, initiating a positive feedback loop between cells and the evolving stroma [3]. Cells sense and respond to the stiffness of their environment via RhoA GTPase activation, which feeds back to increase cell contractility via activation of myosin light chain kinase [4]. These ECM-driven changes in cytoskeletal tension regulate motility in a cell-type specific manner [5]. In vi ...

bioengineering↗