Inherent Interfacial Mechanical Gradients in 3D Hydrogels Influence Tumor Cell Behaviors

Rao, Shreya; Bentil, Sarah A.; DeJesus, Jessica; Larison, John; Hissong, Alex; Dupaix, Rebecca B.; Sarkar, Atom; Winter, Jessica O.

doi:10.1371/journal.pone.0035852

Cited by 57 publications

(59 citation statements)

References 37 publications

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“…It is well documented that cells behave very differently in 3D microenvironments than on 2D surfaces, and even embedded within a 3D matrix, cells behave differently when in proximity to a glass coverslip or other stiff surfaces (Ma et al, 2013; Provenzano et al, 2009; Rao et al, 2012; Wang et al, 2014). To enable the controlled study of the effects of matrix mechanical properties on cell function (Rao et al, 2012), we therefore designed meSPIM to image cells in microenvironments free of hard surfaces near the sample (Figures 1L and 1M).…”

Section: Designmentioning

confidence: 99%

Quantitative Multiscale Cell Imaging in Controlled 3D Microenvironments

et al. 2016

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The microenvironment determines cell behavior, but the underlying molecular mechanisms are poorly understood because quantitative studies of cell signaling and behavior have been challenging due to insufficient spatial and/or temporal resolution and limitations on microenvironmental control. Here we introduce microenvironmental selective plane illumination microscopy (meSPIM) for imaging and quantification of intracellular signaling and submicrometer cellular structures as well as large-scale cell morphological and environmental features. We demonstrate the utility of this approach by showing that the mechanical properties of the microenvironment regulate the transition of melanoma cells from actin-driven protrusion to blebbing, and we present tools to quantify how cells manipulate individual collagen fibers. We leverage the nearly isotropic resolution of meSPIM to quantify the local concentration of actin and phosphatidylinositol 3-kinase signaling on the surfaces of cells deep within 3D collagen matrices and track the many small membrane protrusions that appear in these more physiologically relevant environments.

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Section: Designmentioning

confidence: 99%

Quantitative Multiscale Cell Imaging in Controlled 3D Microenvironments

et al. 2016

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“…[45][46][47][48][49][50] In addition, they are biocompatible and can be functionalized with cell-adhesive ligands. 51 Hydrogels can be assembled from a single ECM protein, their mixtures such as MatrigelÔ, 48,[52][53][54][55][56][57] or from synthetic materials such as polyethylene glycol (PEG) and other polymers.…”

Section: Hydrogelsmentioning

confidence: 99%

Cell Migration on Planar and Three-Dimensional Matrices: A Hydrogel-Based Perspective

Jain

Veres

et al. 2015

Tissue Engineering Part B: Reviews

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The migration of cells is a complex process that is dependent on the properties of the surrounding environment. In vivo, the extracellular environment is complex with a wide range of physical features, topographies, and protein compositions. There have been a number of approaches to design substrates that can recapitulate the complex architecture in vivo. Two-dimensional (2D) substrates have been widely used to study the effect of material properties on cell migration. However, such substrates do not capture the intricate structure of the extracellular environment. Recent advances in hydrogel assembly and patterning techniques have enabled the design of new three-dimensional (3D) scaffolds and microenvironments. Investigations conducted on these matrices provide growing evidence that several established migratory trends obtained from studies on 2D substrates could be significantly different when conducted in a 3D environment. Since cell migration is closely linked to a wide range of physiological functions, there is a critical need to examine migratory trends on 3D matrices. In this review, our goal is to highlight recent experimental studies on cell migration within engineered 3D hydrogel environments and how they differ from planar substrates. We provide a detailed examination of the changes in cellular characteristics such as morphology, speed, directionality, and protein expression in 3D hydrogel environments. This growing field of research will have a significant impact on tissue engineering, regenerative medicine, and in the design of biomaterials.

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“…However, the inability of 2D culture to accurately predict therapeutic response and the complexity of animal models has paved the way for the development of 3D in vitro models, which utilize materials such as hydrogels to recapitulate elements of the tumor microenvironment [21][22][23]. To date, 3D in vitro models for GBM primarily incorporate only tumor cells, despite the demonstrated contributions of additional cell types to in vivo GBM behavior [6,[24][25][26][27][28][29][30]. A few studies have examined the interactions between GBM cells, perivascular niche cells, and macrophages within 3D in vitro platforms, but these models feature spatial segregation between the different cell types that is not reminiscent of the in vivo microenvironment [20,[31][32][33][34].…”

Section: Introductionmentioning

confidence: 99%

Perivascular signals alter global gene expression profile of glioblastoma and response to temozolomide in a gelatin hydrogel

Harley

Ngo

2018

Preprint

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Glioblastoma (GBM) is the most common primary malignant brain tumor, with patients exhibiting poor survival (median survival time: 15 months). Difficulties in treating GBM include not only the inability to resect the diffusively-invading tumor cells but also therapeutic resistance. The perivascular niche within the GBM tumor microenvironment contributes significantly to tumor cell invasion, cancer stem cell maintenance, and has been shown to protect tumor cells from radiation and chemotherapy. In this study, we describe the development of an in vitro artificial perivascular niche (PVN), culturing endothelial and stromal cells along with GBM cells within a methacrylamide-functionalized gelatin hydrogel, in order to examine howthe presence of the PVN alters global genomic expression profiles. Using RNA-seq, we demonstrate that the inclusion of perivascular niche cells with GBM cells upregulates genes related to angiogenesis and remodeling, while downregulated genes are related to cell cycle and DNA damage repair.Signaling pathways and genes commonly implicated in GBM malignancy, such as MGMT, EGFR, PI3K-Akt signaling, and Ras/MAPK signaling are also upregulated in the presence of perivascular niche cells. We describe the kinetics of gene expression within the PVN hydrogels over a course of 14 days, observing the patterns associated with previously-observed GBMmediated endothelial network co-option and regression that are altered in the presence of covalently-bound hyaluronic acid. We finally examine the effect of PVN culture on GBM cell responsiveness to temozolomide, a frontline chemotherapy used clinically against GBM.Notably, the presence of a PVN leads to significantly increased TMZ resistance compared to hydrogels containing only GBM cells. Overall, these results demonstrate that inclusion of cellular and matrix-associated elements of the PVN within in vitro models of GBM provide critical signals to regulate the phenotype and therapeutic responsiveness of GBM cells.

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Inherent Interfacial Mechanical Gradients in 3D Hydrogels Influence Tumor Cell Behaviors

Cited by 57 publications

References 37 publications

Quantitative Multiscale Cell Imaging in Controlled 3D Microenvironments

Quantitative Multiscale Cell Imaging in Controlled 3D Microenvironments

Cell Migration on Planar and Three-Dimensional Matrices: A Hydrogel-Based Perspective

Perivascular signals alter global gene expression profile of glioblastoma and response to temozolomide in a gelatin hydrogel

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