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RNA-seq of CAF05s grown on different substrates

ABSTRACT: Almost all solid tumors become stiff with progression of cancer. Cancer Associated Fibroblasts (CAFs), most abundant stromal cells in the tumor microenvironment (TME), are known to mediate the stiffening. While the biochemical crosstalk between CAFs and cancer cells have been widely investigated, it is yet not clear whether CAFs in stiffer TME promote metastatic progression, and if so, how. To address this question, here we explore the role of mechanical stiffness and cell traction force in regulating human colorectal CAF (CAF05 cell line) gene expressions that are relevant to metastatic progression. We cultured CAFs on 2D polyacrylamide hydrogels with increasing elastic modulus (E) of 1, 10 and 40 kPa, and quantified corresponding cell spreading area and cytoskeletal force. We performed genome-wide transcriptome analyses in these cells to identify differentially expressed genes on 40 KPa compared to those on 1 kPa substrate. The latter represents normal tissue stiffness of colon.

ORGANISM(S): Homo sapiens

PROVIDER: GSE229742 | GEO | 2023/04/18

REPOSITORIES: GEO

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RNA-seq of CAFs grown on different substrates

Project description:Almost all solid tumors become stiff with progression of cancer. Cancer Associated Fibroblasts (CAFs), most abundant stromal cells in the tumor microenvironment (TME), are known to mediate the stiffening. While the biochemical crosstalk between CAFs and cancer cells have been widely investigated, it is yet not clear whether CAFs in stiffer TME promote metastatic progression, and if so, how. To address this question, here we explore the role of mechanical stiffness and cell traction force in regulating human colorectal CAF (CAF05 cell line) gene expressions that are relevant to metastatic progression. We cultured CAFs on 2D polyacrylamide hydrogels with increasing elastic modulus (E) of 1, 10 and 40 kPa, and quantified corresponding cell spreading area and cytoskeletal force. We performed genome-wide transcriptome analyses in these cells to identify differentially expressed genes on 40 KPa compared to those on 1 kPa substrate. The latter represents normal tissue stiffness of colon.

2022-06-15 | GSE205937 | GEO

RNA-seq of primary rat macrophages cultured on substrates of defined stiffness

Project description:Cells interact with their mechanical environment and respond in consequence. Mechanical cues can have a wide range of influences on cell behaviour, ranging from guidance of differentiation and cell fate to immune activation. The impact of substrate stiffness on primary macrophages - a key player in innate immunity and inflammation - had not been previously studied. We prepared bone marrow-derived macrophage cultures from adult rat hematopoietic stem cells exposed to M-CSF, and cultured these on polyacrylamide substrates of controlled stiffness (ranging from 50 to 0.1 kPa shear modulus, covering the range found in physiological tissues) for 3 days. The RNA from these cells was then extracted and sequenced.

2023-04-15 | E-MTAB-7900 | biostudies-arrayexpress

Substrate stiffness-dependent gene expression profile for cortical neurons

Project description:We undertook mRNA microarray and gene ontology analyses to screen out substrate stiffness-dependent genes. Total mRNA were extracted from E17 cortical neurons grown on soft or stiff substrates at 5 or 16 hr time points. We identified 114 differentially-expressed mRNA transcripts in cells grown on 0.1 kPa and 20 kPa gels at the 5 hr time-point. Among them, 66 were upregulated in 0.1 kPa gel cultures and the remainder were downregulated (compared to cells grown on stiffer substrates). The expressions of three endocytic genes (Cltc, Dab2, and Myo6) and four adhesion genes(Vcl, Robo2, Nrcam, and Cad11) were confirmed by QGP and smRNA FISH.

2018-01-08 | GSE102350 | GEO

Next generation seuquencing of 3D breast cancer cell culture in synthetic hydrogels presenting either a collagen mimic or laminin mimic with low and high mechanical properties

Project description:MDA-MB-231 (ER-) and T47D (ER+) breast cancer cells were encapsualted in synthetic hydrogels, formed with a multi-arm bioinert polymer poly(ethylene glycol), cell-degradable peptide crosslinks, and receptor-binding pendant peptides, and cultured for 3 days and up to 40 days to assess initial cell responses to different matrix compositions. The synthetic matrices had a Young's modulus (E) ~ 0.6 kPa (low wt%) and # ~ 5 kPa (high wt%), in the range of bone marrow or healthy mammary tissue and lung tissue, respectively, and Biochemcial cues to mimic binding sites found in collagen (GFOGER peptide) or laminin (IKVAV peptide). After 3 days and 40 days in culture, mRNA was collected and RNA-seq performed to compare cell responses between the collagen and laminin mimetic cultures overtime in both low wt% and high wt% matrices.

2022-03-01 | GSE145696 | GEO

Mesothelioma-associated fibroblasts enhance proliferation and migration of malignant pleural mesothelioma cells via Met/PI3K and WNT signaling but do not protect against cisplatin

Project description:Malignant pleural mesothelioma (MPM) is an aggressive malignancy with poor prognosis. Unlike many other cancers, MPM is mostly characterized by inactivation of tumor suppressor genes. Its highly malignant nature in absence of tumor driving oncogene mutations indicates an extrinsic supply of stimulating signals by cells of the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are an abundant cell type of the TME and have been shown to drive the progression of several cancer types. The aim of the current study was to isolate and characterize patient-derived mesothelioma-associated fibroblasts (Meso-CAFs), and evaluate their impact on MPM cells.

2022-12-31 | E-MTAB-12179 | biostudies-arrayexpress

Evolution of immune and stromal cell states and ecotypes during gastric adenocarcinoma progression

Project description:Understanding how the tumor microenvironment (TME) is orchestrated along the continuum of gastric adenocarcinoma (GAC) may uncover novel therapeutic strategies. Here, we performed comprehensive single-cell profiling of precancerous lesions, localized and metastatic GACs, identifying alterations in TME cell states and phenotypes during tumorigenesis and progression. IgA+ plasma cells appear to be the most active regulators in the premalignant microenvironment, whereas immunosuppressive myeloid and stromal subsets dominated the late-stage GACs. We discover six TME ecotypes, four of which are unique to the premalignant/progression in the continuum, with two ecotypes, identified in primary GACs, showing strong associations with histopathologic, genomic characteristics and prognosis. Extensive stromal remodeling is evident with GAC progression. High SDC2 expression in cancer-associated fibroblasts (CAFs) correlates with aggressive phenotypes and poor survival and SDC2 overexpression in CAFs contributes to tumor growth. This study illustrates a roadmap of the GAC TME and highlights potential targets for further investigation.

2023-06-10 | GSE234129 | GEO

Shifting the optimal stiffness for cell migration

Project description:Cell migration is central to many biological processes including embryonic development, wound healing, and cancer progression. Cell migration is sensitive to environmental stiffness, and many cell types exhibit a stiffness optimum at which migration is maximal. Here we present a cell migration simulator that predicts a stiffness optimum that can be shifted by altering the number of active molecular motors and clutches. This prediction is verified experimentally by comparing cell traction and F-actin retrograde flow for two cell types with differing amounts of active motors and clutches: embryonic chick forebrain neurons (ECFNs; optimum ~1 kPa) and U251 glioma cells (optimum ~100 kPa). In addition, the model predicts, and experiments confirm, that the stiffness optimum of U251 glioma cell migration, morphology, and F-actin retrograde flow rate can be shifted to lower stiffness by simultaneous drug inhibition of myosin II motors and integrin-mediated adhesions.

2017-05-23 | GSE95680 | GEO

Next-generation sequencing facilitates quantitative analysis of rat BMSCs in soft or stiff SA hydrogel

Project description:Purpose: To identify genes and the molecular pathways involved in the MSCs response to extracellular matrix stiffness, we performed RNA-sequencing of MSCs which cultured in soft (2 kPa) and stiff (18 kPa) SA hydrogels. Methods: mRNA profiles of MSCs cultured in soft (2 kPa) and stiff (18 kPa) SA hydrogel for 48 h were generated by deep sequencing, in quadruplicate, using Illumina HiSeq 2000. Results: Using an optimized data analysis workflow, we identified 33950 transcripts in MSCs with BWA workflow. Conclusions: Our results present the detailed analysis of MSCs transcriptomes cultured in soft (2 kPa) and stiff (18 kPa) matrix, and found that matrix stiffness dominated multiple mRNA pathways in MSCs.

2021-08-06 | GSE181512 | GEO

Biomechanical rigidity and quantitative proteomics analyses of segmental regions of the ocular trabecular meshwork at physiologic and elevated pressures

Project description:The extracellular matrix (ECM) of the ocular trabecular meshwork (TM) builds resistance to aqueous humor outflow, thereby regulating intraocular pressure (IOP). Glaucoma, a leading cause of blindness worldwide, is associated with changes in the ECM of the TM. The elastic modulus indicates glaucomatous TM is more rigid than age-matched normal TM; however, the biomechanical properties of segmental low (LF) and high flow (HF) TM regions in response to elevated pressure, are unknown. In this study, we measured the elastic modulus by atomic force microscopy (AFM) and measured protein expression differences in perfused human TM tissues by proteomics analyses. The elastic modulus of LF regions was 2.3-fold stiffer than HF regions at physiological (1x) pressure, and 7.4-fold or 3.5-fold stiffer than HF regions at elevated (2x) pressure after 24 or 72 hours, respectively. Quantitative proteomics using isobaric tandem mass tags (TMT), multi-notch isolation, high resolution, and extended multiplexing were used to compare protein expression levels between normal, LF, and HF regions at the two pressures. A total of 3730 proteins (2 peptides per protein) were identified from the ECM samples, and 2637 proteins were quantified. Statistically significant ECM proteins over expressed in LF compared with HF regions at 2x, and in HF regions at 1x compared with 2x pressure were determined. A sub-set of ECM proteins, including decorin, TGFβ-induced protein, keratocan, lumican, dermatopontin and thrombospondin 4, were common differential candidates in both comparisons. These data suggest a correlation between the biomechanical properties of TM regions and differential levels of specific ECM proteins in response to elevated pressure.

2018-01-22 | PXD006424 | Pride

Tumor-produced and aging-associated oncometabolite, methylmalonic acid, promotes cancer-associated fibroblast activation to drive metastatic progression

Project description:The systemic metabolic shifts that occur during aging and the local metabolic alterations of a tumor, its stroma and their communication cooperate to establish a unique tumor microenvironment (TME) that fosters cancer progression. Here, we show that methylmalonic acid (MMA), an aging-increased oncometabolite that is also produced by aggressive cancer cells, activates fibroblasts in the TME and stimulates the release of extracellular vesicles (EVs) that drive cancer progression, drug resistance and metastasis. The cancer-associated fibroblast (CAF)-released EV cargo is modified as a result of reactive oxygen species (ROS) generation and activation of the canonical and noncanonical TGFβ signaling pathways in CAFs. EV-associated IL-6 functions as a stroma-tumor messenger that activates the JAK/STAT3 and TGFβ signaling pathways in tumor cells and promote an epithelial-to-mesenchymal transition (EMT) and drug resistance in vitro, and metastatic progression in vivo. Our findings reveal the role of MMA in the activation of CAFs to drive metastatic reprogramming, unveiling multiple potential therapeutic avenues to target MMA at the nexus of aging, the tumor microenvironment and metastasis.

2022-10-04 | GSE190929 | GEO

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