Tunable hydrogels for controlling phenotypic cancer cell states to model breast cancer dormancy and reactivation

Pradhan, Shantanu; Slater, John H.

doi:10.1016/j.biomaterials.2019.04.022

Cited by 55 publications

(129 citation statements)

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“…[30] Recently, synthetic PEG-based hydrogels formed by free radical chain growth polymerization have been used for the 3D culture of TN breast cancer cells associated with early recurrence, where the presence and concentration of the integrin-binding ligand RGDS was observed to influence dormancy versus growth. [33] Cumulatively, these studies demonstrate the relevance of well-defined synthetic matrices for the study of breast cancer and present an opportunity for probing cell-matrix interactions in breast cancer dormancy. The application of soft synthetic ECMs to the study of ER+ breast cancer dormancy has the potential to provide new insights into late recurrence and improved 3D model systems for a range of investigations into this intractable disease.…”

Section: Here a Robust Bioinspired 3d Er+ Dormancy Culture Model Ismentioning

confidence: 80%

Understanding ER+ Breast Cancer Dormancy Using Bioinspired Synthetic Matrices for Long‐Term 3D Culture and Insights into Late Recurrence

et al. 2020

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Late recurrences of breast cancer are hypothesized to originate from disseminated tumor cells that re‐activate after a long period of dormancy, ≥5 years for estrogen‐receptor positive (ER+) tumors. An outstanding question remains as to what the key microenvironment interactions are that regulate this complex process, and well‐defined human model systems are needed for probing this. Here, a robust, bioinspired 3D ER+ dormancy culture model is established and utilized to probe the effects of matrix properties for common sites of late recurrence on breast cancer cell dormancy. Formation of dormant micrometastases over several weeks is examined for ER+ cells (T47D, BT474), where the timing of entry into dormancy versus persistent growth depends on matrix composition and cell type. In contrast, triple negative cells (MDA‐MB‐231), associated with early recurrence, are not observed to undergo long‐term dormancy. Bioinformatic analyses quantitatively support an increased “dormancy score” gene signature for ER+ cells (T47D) and reveal differential expression of genes associated with different biological processes based on matrix composition. Further, these analyses support a link between dormancy and autophagy, a potential survival mechanism. This robust model system will allow systematic investigations of other cell‐microenvironment interactions in dormancy and evaluation of therapeutics for preventing late recurrence.

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Section: Here a Robust Bioinspired 3d Er+ Dormancy Culture Model Ismentioning

confidence: 80%

Understanding ER+ Breast Cancer Dormancy Using Bioinspired Synthetic Matrices for Long‐Term 3D Culture and Insights into Late Recurrence

et al. 2020

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“…Sixteen different hydrogel formulations are used to quantify the temporal response of metastatic breast cancer cells, which extensively analyze the influences of ECM biochemical (ligand (RGDS) density and degradability) and biophysical properties (stiffness and mesh size) on breast cancer cell dormancy, such as viability, apoptotic death, proliferation, metabolic activity, invasiveness, and cell clusters formation over 15 d culture. [ 8 ] Among these synthetic polymer hydrogels, relatively few are successfully translated into the approved devices and therapeutics, as synthetic polymer hydrogels are simply not made of well‐defined compositions. To achieve an in vivo‐like ECM structure, with the essential microenvironmental cues, is a complex and challenging issue for official approval and commercialization.…”

Section: Common Hydrogel Products and Biomedical Featuresmentioning

confidence: 99%

“…Except of designer peptide hydrogels described above, some bioengineering synthetic polymer hydrogels are developed to fabricate the regenerative microenvironments in the personalized human microtissue models in vitro. The reader may refer to outside literatures for details, [ 6–8,18 ] Exactly, in 3D context, adhesion‐mediated signaling is affected not only by the chemical and biophysical nature of substrate scaffolds but also by the topographical features in substrate scaffolds, including the spatial patterning and alignment of the adhesive epitopes available for cell binding, the mechanical cues in the rigidity or stiffness. [ 57,134b,143b ] In 3D TMEs in vivo, where malignant cells reach protective niches in the body, cell motility and adhesion are apparently critical steps in invasive metastatic processes.…”

Section: Instructive Cell Constructs In Tissue Engineering and Precismentioning

confidence: 99%

“…In the contrary, synthetic biomaterials can be artificially designed, accurately tuned, and overly modified to mimic the native cell microenvironments and the key factors in ECM components, [ 4b,5 ] For example, a biomimetic type of synthetic hydrogel composed of hyaluronic acid (HA) is rationally designed to mimic the ECM of the diseased lung and reconstruct the complex mechanisms of cell invasion and cell viability in 3D context, where the HA polymer backbone is modified with furan motifs to form tissue‐specific ECMs. [ 7a ] A set of PEG‐based synthetic hydrogels are composed of PEG‐macromer containing the enzymatically degradable peptide sequence, GGGPQGIWGQGK, with varying concentrations of the integrin ligating peptide, RGDS (0–10 × 10 −3 m ), which may elucidate the influence of these matrix properties (stiffness, degradability, mesh size, adhesivity) and their independent control on the cancer cell's quiescence and dormancy, [ 8 ] which is completely distinct from the natural type of hydrogels. As a rapidly growing research field in biomaterials, when well‐designed, synthetic hydrogels may be developed to be ideal functional biomaterials to use as 3D cell culture scaffolds and the popularly utilized tools for tissue‐specific mimicry.…”

Section: Introductionmentioning

confidence: 99%

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Designer Self‐Assembling Peptide Hydrogels to Engineer 3D Cell Microenvironments for Cell Constructs Formation and Precise Oncology Remodeling in Ovarian Cancer

Yang

Zhao

2020

Advanced Science

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mouse intestinal stem cells and primary colorectal cancer cells can be propagated in vitro long term, [1] there is an urgent need to develop more physiologically relevant, efficient, and robust precise oncology models that closely recapitulate the genetic and morphological heterogeneous composition and mimic the arrangement pattern of cancer cells in the original tumor. [2] To our knowledge in biomedical research, hydrogel is the best tool to reconstruct precise oncology models in vitro, especially tumor organoid, which not only recapitulates in vivo biology and microenvironmental factors, but also at large extent allows side-by-side comparison to evaluate the translational potential of 3D model systems to the patients. [2a,3] Generally, hydrogels are mainly composed of hydrophilic polymeric scaffolds that absorb large amounts of water, so the hydrogel matrix better mimics elastic and viscoelastic properties in ECM and microscale topographies of cell matrices, which controls proper cell morphology, directs viable cell behaviors, and drives in vivo fundamental cell-cell or cell-ECM interactions. [4] To recapitulate pathophysiological features of human tumors and imitate various aspects of human tumorigenesis in vivo, hydrogels can provide a realistic platform to establish a useful bridge between in vitro assays and in vivo cell microenvironments. In current biomedical applications, there are many kinds of hydrogels to be developed to mimic the biological properties of ECM, such Designer self-assembling peptides form the entangled nanofiber networks in hydrogels by ionic-complementary self-assembly. This type of hydrogel has realistic biological and physiochemical properties to serve as biomimetic extracellular matrix (ECM) for biomedical applications. The advantages and benefits are distinct from natural hydrogels and other synthetic or semisynthetic hydrogels. Designer peptides provide diverse alternatives of main building blocks to form various functional nanostructures. The entangled nanofiber networks permit essential compositional complexity and heterogeneity of engineering cell microenvironments in comparison with other hydrogels, which may reconstruct the tumor microenvironments (TMEs) in 3D cell cultures and tissue-specific modeling in vitro. Either ovarian cancer progression or recurrence and relapse are involved in the multifaceted TMEs in addition to mesothelial cells, fibroblasts, endothelial cells, pericytes, immune cells, adipocytes, and the ECM. Based on the progress in common hydrogel products, this work focuses on the diverse designer self-assembling peptide hydrogels for instructive cell constructs in tissue-specific modeling and the precise oncology remodeling for ovarian cancer, which are issued by several research aspects in a 3D context. The advantages and significance of designer peptide hydrogels are discussed, and some common approaches and coming challenges are also addressed in current complex tumor diseases.

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“…Interestingly, while the effect of matrix stiffness is extensively studied in the context of tumor progression [15,16], stem cell differentiation [17][18][19] and aging [6], few studies have focused on the role of mechanical stresses [20]. This field of research remains underdeveloped due to lack of standard in vitro assays enabling quantification of phenotypic and genotypic modifications of cells upon extended mechanical stimulation.…”

Section: Introductionmentioning

confidence: 99%

Development of a soft cell confiner to decipher the impact of mechanical stimuli on cells

Prunet

Lefort

Delanoë-Ayari

et al. 2020

Preprint

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Emerging evidence suggests the importance of mechanical stimuli in normal and pathological situations for the control of many critical cellular functions. While the effect of matrix stiffness has been and is still extensively studied, few studies have focused on the role of mechanical stresses. The main limitation of such analyses is the lack of standard in vitro assays enabling extended mechanical stimulation compatible with dynamic biological and biophysical cell characterization. We have developed an agarose-based microsystem, the soft cell confiner, which enables the precise control of confinement for single or mixed cell populations. The rigidity of the confiner matches physiological conditions and enables passive medium renewal. It is compatible with time-lapse microscopy, in situ immunostaining, and standard molecular analyses, and can be used with both adherent and nonadherent cell lines. Cell proliferation of various cell lines (hematopoietic cells, MCF10A epithelial breast cells and HS27A stromal cells) was followed for several days up to confluence using video-microscopy and further documented by Western blot and immunostaining. Interestingly, even though the nuclear projected area was much larger upon confinement, with many highly deformed nuclei (non-circular shape), cell viability, assessed by live and dead cell staining, was unaffected for up to 8 days in the confiner. However, there was a decrease in cell proliferation upon confinement for all tested cell lines. The soft cell confiner is thus a valuable tool to decipher the effect of long-term confinement and deformation on the biology of cell populations. This tool will be instrumental in deciphering the impact of nuclear and cytoskeletal mechanosensitivity in normal and pathological conditions involving highly confined situations, such as those reported upon aging with fibrosis or during cancer. Highlights-We have developed a flexible hydrogel-based microsystem that precisely confines cells for extended periods of time with controlled nutrient levels.-The soft confiner system was validated for both adherent and non-adherent cells and allows the simultaneous in situ follow-up or ex situ analysis of multiple subpopulations.-A unique tool to analyze the role of long-term effect of mechanical confinement in normal and pathological conditions. Graphical abstract3/27

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Tunable hydrogels for controlling phenotypic cancer cell states to model breast cancer dormancy and reactivation

Cited by 55 publications

References 55 publications

Understanding ER+ Breast Cancer Dormancy Using Bioinspired Synthetic Matrices for Long‐Term 3D Culture and Insights into Late Recurrence

Understanding ER+ Breast Cancer Dormancy Using Bioinspired Synthetic Matrices for Long‐Term 3D Culture and Insights into Late Recurrence

Designer Self‐Assembling Peptide Hydrogels to Engineer 3D Cell Microenvironments for Cell Constructs Formation and Precise Oncology Remodeling in Ovarian Cancer

Development of a soft cell confiner to decipher the impact of mechanical stimuli on cells

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