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Engineered hydrogel reveals contribution of matrix mechanics to esophageal adenocarcinoma and identifies matrix-activated therapeutic targets [WES]

ABSTRACT: Increased extracellular matrix (ECM) stiffness has been implicated in esophageal adenocarcinoma (EAC) progression, metastasis, and resistance to therapy. However, the underlying pro-tumorigenic pathways are yet to be defined. Additional work is needed to develop physiologically relevant in vitro 3D culture models that better recapitulate the human tumor microenvironment and can be used to dissect the contributions of matrix stiffness to EAC pathogenesis. Here, we describe a modular, tumor ECM-mimetic hydrogel platform with tunable mechanical properties, defined presentation of cell-adhesive ligands, and protease-dependent degradation that supports robust in vitro growth and expansion of patient-derived EAC 3D organoids (EAC PDOs). Hydrogel mechanical properties control EAC PDO formation, growth, proliferation, and activation of tumor-associated pathways that elicit stem-like properties in the cancer cells, as highlighted through in vitro and in vivo environments.

ORGANISM(S): Homo sapiens

PROVIDER: GSE240917 | GEO | 2023/10/27

REPOSITORIES: GEO

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Engineered hydrogel reveals contribution of matrix mechanics to esophageal adenocarcinoma and identifies matrix-activated therapeutic targets [RNA-seq]

Project description:Increased extracellular matrix (ECM) stiffness has been implicated in esophageal adenocarcinoma (EAC) progression, metastasis, and resistance to therapy. However, the underlying pro-tumorigenic pathways are yet to be defined. Additional work is needed to develop physiologically relevant in vitro 3D culture models that better recapitulate the human tumor microenvironment and can be used to dissect the contributions of matrix stiffness to EAC pathogenesis. Here, we describe a modular, tumor ECM-mimetic hydrogel platform with tunable mechanical properties, defined presentation of cell-adhesive ligands, and protease-dependent degradation that supports robust in vitro growth and expansion of patient-derived EAC 3D organoids (EAC PDOs). Hydrogel mechanical properties control EAC PDO formation, growth, proliferation, and activation of tumor-associated pathways that elicit stem-like properties in the cancer cells, as highlighted through in vitro and in vivo environments. We also demonstrate that the engineered hydrogel serves as a platform to identify potential therapeutic targets to disrupt the contribution of pro-tumorigenic matrix mechanics in EAC. Together, these studies show that an engineered PDO culture platform can be used to elucidate underlying matrix-mediated mechanisms of EAC, and inform the development of therapeutics that target ECM stiffness in EAC.

2023-10-27 | GSE230383 | GEO

Expression data from pulmonary arterial endothelial cells treated with siRNA control or siGLS in stiff or soft matrix

Project description:Dysregulation of vascular stiffness and cellular metabolism occur early in pulmonary hypertension (PH). Yet, the mechanisms by which biophysical properties of extracellular matrix relate to metabolic processes and downstream PH phenotypes remain undefined. In cultured endothelial and smooth muscle cells and confirmed in PH-diseased human samples, we found that ECM stiffening activates the mechanosensitive factors YAP/TAZ to increase glycolysis and induce glutaminase (GLS) expression and glutaminolysis. Glutaminolysis replenishes aspartate for anabolic biosynthesis, thus sustaining proliferation and migration within stiff ECM. In vitro GLS inhibition blocks aspartate production, consequently reprogramming entire cellular proliferative pathways, while aspartate restores proliferation. In a rat model in vivo, GLS inhibition prevents hemodynamic and histologic manifestations of PH. Thus, mechanical ECM stiffening sustains vascular cell growth and migration through YAP/TAZ-dependent glutaminolysis â a paradigm that advances our understanding of the connections of mechanical stimuli with dysregulated vascular metabolism and identifies new metabolic drug targets in PH. We used microarrays to decipher the global program of gene expression involved in response to matrix stiffening and determined the implication of glutaminolysis (GLS) in these process PAECs were transfected with an siRNA control (siNC) or a siRNA against GLS (siGLS) and cultivated on soft hydrogel (1kPa) or stiff hydrogel (50kPa). After 48h of transfection cells were lysate and RNA extract for hybridization on Affymetrix microarrays.

2016-09-01 | E-GEOD-75793 | biostudies-arrayexpress

Tumor decellularization reveals proteomic and mechanical characteristics of the extracellular matrix of primary liver cancer

Project description:Tumor initiation and progression are critically dependent on interaction of cancer cells with their cellular and extracellular microenvironment. Alterations in the composition, integrity, and mechanical properties of the extracellular matrix (ECM) dictate tumor processes including proliferation, migration, and invasion. Also in primary liver cancers, consisting of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), the dysregulation of the extracellular environment by liver fibrosis and tumor desmoplasia is pertinent. Yet, in-depth characterization of liver cancer ECM and underlying tumor-promoting mechanisms remain largely unknown. Herein, we used an integrative molecular and mechanical approach to extensively characterize the ECM of HCC and CCA tumors by utilizing decellularization techniques. We identified a myriad of ECM-related proteins in both tumor and adjacent liver tissue, highlighting the complexity of the primary liver cancer matrisome. The differences in ECM protein abundance result in divergent mechanical properties on a macro- and micro-scale that is tumor-type specific. Furthermore, we employed the decellularized tumor ECM to create a tumor-specific hydrogel that support patient-derived tumor organoids. This provides a new avenue for personalized medicine by combining patient-derived tumor ECM and cancer cells. Taken together, this study provides better understanding of alterations to key aspects of the ECM that occur during primary liver cancer development.

2023-03-28 | PXD035261 | Pride

Mechanical forces direct the cell fate of inner ear organoids in a stage-dependent manner

Project description:During the development, mechanical force plays an important role in shaping the inner ear and establishing regular cellular patterns, however, the effects of ubiquitous mechanical cues on cellular fate determination are not clear. Here we developed stiffness adjustable hydrogels for three-dimensional (3D) cochlear organoid culture, which could precisely simulate the mechanical force from the extracellular matrix (ECM) during the expansion of cochlear progenitor cells (CPCs) and organoid formation. Within a certain range, suitable stiffness can stimulate CPC proliferation through a mechanism requiring integrin/cytoskeleton/YAP signaling. Surprisingly, increasing stiffness could inhibit the proliferation of CPCs and induce the differentiation of organoids, which was mediated by the increased intracellular Ca2+ signaling in CPCs, and further activated Klf2 to promote the differentiation of HCs with bundles. Furthermore, this chemical-defined hydrogel is also suitable for 3D bioprinting, and we printed the spiral-like structure with CPCs and HCs, which provided a promising way for cochlear organoids to further improve our understanding of the organization of the inner ear and contribute to developing new therapeutic approaches for HCs regeneration.

2023-10-26 | GSE202640 | GEO

Three-Dimensional Matrix Stiffness Modulates Mechanosensitive and Phenotypic Alterations in Oral Squamous Cell Carcinoma Spheroids

Project description:Extracellular biophysical cues such as matrix stiffness are key stimuli tuning cell fate and affecting tumor progression in vivo. However, it remains unclear how spheroids in a 3D microenvironment perceive matrix mechanical stiffness stimuli and translate them into intracellular signals driving cancer. Mechanosensitive Piezo1 and TRPV4 ion channels, upregulated in many malignancies, are major transducers of such physical stimuli into biochemical responses. Most mechanotransduction studies probing the reception of changing stiffness cues by cells are, however, still limited to 2D culture systems or cell-extracellular matrix models which lack the major cell-cell interactions prevalent in 3D cancer tumors. Here, we engineered a 3D spheroid culture environment with varying mechanobiological properties to study the effect of static matrix stiffness stimuli on mechanosensitive and malignant phenotypes in oral squamous cell carcinoma spheroids. We find that spheroid growth is enhanced when cultured in stiff extracellular matrix. Using flow cytometry, we show that the expression of mechanoreceptor Piezo1 and stemness marker CD44 is upregulated in stiff matrix. We also report the upregulation of a selection of genes with associations to mechanoreception, ion channel transport, extracellular matrix organization, and tumorigenic phenotypes in stiff matrix spheroids. Together, our results indicate that cancer cells in 3D spheroids utilize mechanosensitive ion channels Piezo1 and TRPV4 to sense changes in static extracellular matrix stiffness and that stiffness drives pro-tumorigenic phenotypes in oral squamous cell carcinoma.

2024-03-28 | GSE262142 | GEO

Breast tumor stiffness instructs bone metastasis via mechanical memory

Project description:The mechanical microenvironment of primary breast tumors plays a substantial role in promoting tumor progression. While the transitory response of cancer cells to pathological stiffness in their native microenvironment has been well described, it is unclear whether mechanical stimuli in the primary tumor influence distant, late-stage metastatic phenotypes in absentia. Here, we show that primary tumor stiffness promotes stable yet non-genetically heritable phenotypes in breast cancer cells. This “mechanical memory” instructs cancer cells to adopt and maintain increased cytoskeletal dynamics, traction force, and 3D invasion in vitro, in addition to promoting osteolytic bone metastasis in vivo. We established a “mechanical conditioning score” comprised of mechanically-regulated genes as a proxy measurement of tumor stiffness response, and we show that it is associated with bone metastasis in patients. Using a discovery approach, we mechanistically traced mechanical memory in part to ERK-mediated mechanotransductive activation of RUNX2, an osteogenic gene bookmarker and bone metastasis driver. This combination of traits allows for the stable transactivation of osteolytic target genes which persists after cancer cells disseminate from their activating microenvironment. Using genetic, epigenetic, and functional approaches, RUNX2-mediated mechanical memory can be stimulated, repressed, selected, or extended. In concert with previous studies detailing how biochemical properties of the primary tumor stroma influence distinct metastatic phenotypes, the impact of local biomechanical properties we present here support a generalized model of cancer progression in which the integrated properties of the primary tumor microenvironment govern cell behavior in the metastatic microenvironment.

2021-07-01 | GSE127887 | GEO

Porcine breast extracellular matrix hydrogel for spatial tissue culture

Project description:Porcine mammary fatty tissues represent an abundant source of biomaterial for generation of breast-specific extracellular matrix (ECM). Here we report the extraction of total ECM proteins from pig breast fatty tissues, the fabrication of hydrogel scaffolds from the extracted ECM proteins, the structural properties of the scaffolds, and the applications of the hydrogel in human mammary epithelial cell spatial cultures for cell surface receptor expression, metabolomics characterization, acini formation, proliferation, migration between different scaffolding compartments, and in vivo tumor formation. This model system provides an additional option for studying human breast diseases such as breast cancer.

2019-11-12 | PXD010960 | Pride

Expression data from pulmonary arterial endothelial cells treated with siRNA control or siGLS in stiff or soft matrix

Project description:Dysregulation of vascular stiffness and cellular metabolism occur early in pulmonary hypertension (PH). Yet, the mechanisms by which biophysical properties of extracellular matrix relate to metabolic processes and downstream PH phenotypes remain undefined. In cultured endothelial and smooth muscle cells and confirmed in PH-diseased human samples, we found that ECM stiffening activates the mechanosensitive factors YAP/TAZ to increase glycolysis and induce glutaminase (GLS) expression and glutaminolysis. Glutaminolysis replenishes aspartate for anabolic biosynthesis, thus sustaining proliferation and migration within stiff ECM. In vitro GLS inhibition blocks aspartate production, consequently reprogramming entire cellular proliferative pathways, while aspartate restores proliferation. In a rat model in vivo, GLS inhibition prevents hemodynamic and histologic manifestations of PH. Thus, mechanical ECM stiffening sustains vascular cell growth and migration through YAP/TAZ-dependent glutaminolysis – a paradigm that advances our understanding of the connections of mechanical stimuli with dysregulated vascular metabolism and identifies new metabolic drug targets in PH. We used microarrays to decipher the global program of gene expression involved in response to matrix stiffening and determined the implication of glutaminolysis (GLS) in these process

2016-09-01 | GSE75793 | GEO

Development of a Novel Air-Liquid Interface Airway Tissue Equivalent Model for In Vitro Respiratory Modeling Studies

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2022-07-14 | GSE207931 | GEO

Modulation of TGF-B1 mediated fibroblast activation in human vocal fold fibroblast cells by Porcine-Derived Lamina Propria Extracellular Matrix Hydrogel

Project description:Vocal folds (VFs) are exposed to external and internal stimuli that may cause damage leading to structural alterations and compromised function. Extracellular matrix (ECM)-based biomaterials have been explored as bioactive scaffolds to tissue repair. An injectable form of the VF-ECM scaffold would be an ideal biomaterial for minimally invasive delivery to injured VFs. The goal of this study was to develop a hydrogel form of VF lamina propria ECM (VFLP-ECM) and to characterize its properties and in vitro cellular response.

2021-05-25 | GSE125463 | GEO

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