Impact of ECM Stiffness on Breast Cancer Dormancy in BC-M1 Cells
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PROVIDER: PRJEB89749 | ENA |
REPOSITORIES: ENA
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Project description:ECM Stiffness and Breast Cancer Dormancy
| PRJEB89750 | ENA
Project description:The Rho family GTPases, Rac and Rho, play critical roles in transmitting mechanical information contained within the extracellular matrix (ECM) to the cell. Rac and Rho have well described roles in regulating stiffness-dependent actin remodeling, proliferation and motility. However, much less is known about the relative roles of these GTPases in stiffness-dependent transcription, particularly at the genome-wide level. Here, we selectively inhibited Rac and Rho in mouse embryonic fibroblasts cultured on deformable substrata and used RNA sequencing to elucidate and compare the contribution of these GTPases to the early transcriptional response to ECM stiffness. Surprisingly, we found that the stiffness-dependent activation of Rac is dominant over Rho in the initial transcriptional response to ECM stiffness. We also identified Activating Transcription Factor 3 (ATF3) as a major target of stiffness/Rac-mediated signaling and show that ATF3 repression by ECM stiffness helps to explain how the stiffness-dependent activation of Rac results in the induction of cyclin D1.
2023-10-04 | GSE236266 | GEO
Project description:We report the expression profiles of MCF10A cells encapsulated in hydrogels of varying stiffness and composition. Cells were encapsulated for 7 days in either 1.) soft alginate and reconstituted basement membrane (rBM), 2.) stiff alginate and rBM, 3,) soft col-1 and rBM, or 4.) stiff col-1. We find global gene expression changes in response to enhanced ECM stiffness, independent of expression changes in response to col-1 exposure. These results provide a comprehensive study of the gene expression changes associated with increased ECM stiffness in addition to the gene expression changes associated with increased col-1 concentration in combination with, and independent of, ECM stiffness.
2019-03-25 | GSE102506 | GEO
Project description:Cell dormancy is a major factor leading to drug resistance as well as the high rate of late recurrence and mortality in estrogen receptor-positive (ER+) breast cancer. Although some studies have highlighted the significant impact of the microenvironment on dormant cells, they have largely overlooked the mechanical forces stemming from the stiffness of the surrounding extracellular matrix. Previously, we demonstrated that soft matrix promotes tumor cell proliferation and migration, while stiff matrix induces tumor cell dormancy and drug resistance. In this study, we present a comprehensive analysis of the proteome and phosphoproteome in response to gradient changes in matrix stiffness, elucidating the mechanisms behind cell dormancy induced drug resistance. Overall, we found that membrane transport and anti-apoptotic processes may be mainly involved in mechanical force induced dormancy resistance of ER+ breast cancer cells.
2024-09-11 | PXD046799 |
Project description:The interplay between the extracellular matrix (ECM) and prostate cancer (PCa) tumor has been shown to increase ECM stiffness, correlating with more aggressive disease forms. However, the impact of ECM stiffness on the androgen receptor (AR), a primary PCa treatment target, remains elusive. Here, we aimed to explore whether matrix stiffness influences PCa progression, transcriptional regulation, chromatin state, and AR function in AR-positive PCa cells under varying ECM stiffness conditions. We utilized ATAC-seq and RNAseq in different ECM conditions and the SUC2 metastatic prostate adenocarcinoma patient dataset to understand the role of ECM stiffness on chromatin state, androgen response genes and to evaluate the effect of matrix stiffness on prostate cancer progression. Results showed that increased ECM stiffness elevated the expression of genes related to proliferation and differentiation. In contrast, androgen response genes were most induced in soft ECM conditions. Combining chromatin accessibility with transcriptomic results revealed that androgen response genes were more transcriptionally available in soft ECM conditions. Additionally, increased ECM stiffness upregulated genes associated with low overall survival in the SUC2 dataset. Taken together, our results indicate that high expression of hard matrix stiffness genes potentially promotes prostate cancer progression leading to more aggressive forms of the disease with poor survival rate.
2025-03-06 | GSE272028 | GEO
Project description:The interplay between the extracellular matrix (ECM) and prostate cancer (PCa) tumor has been shown to increase ECM stiffness, correlating with more aggressive disease forms. However, the impact of ECM stiffness on the androgen receptor (AR), a primary PCa treatment target, remains elusive. Here, we aimed to explore whether matrix stiffness influences PCa progression, transcriptional regulation, chromatin state, and AR function in AR-positive PCa cells under varying ECM stiffness conditions. We utilized ATAC-seq and RNAseq in different ECM conditions and the SUC2 metastatic prostate adenocarcinoma patient dataset to understand the role of ECM stiffness on chromatin state, androgen response genes and to evaluate the effect of matrix stiffness on prostate cancer progression. Results showed that increased ECM stiffness elevated the expression of genes related to proliferation and differentiation. In contrast, androgen response genes were most induced in soft ECM conditions. Combining chromatin accessibility with transcriptomic results revealed that androgen response genes were more transcriptionally available in soft ECM conditions. Additionally, increased ECM stiffness upregulated genes associated with low overall survival in the SUC2 dataset. Taken together, our results indicate that high expression of hard matrix stiffness genes potentially promotes prostate cancer progression leading to more aggressive forms of the disease with poor survival rate.
2025-03-06 | GSE272027 | GEO
Project description:Vascular extracellular matrix (ECM) stiffening is a risk factor for aortic and coronary artery disease. How matrix stiffening regulates the transcriptome profile of human aortic (Ao) and coronary (Co) vascular smooth muscle cells (VSMCs) is not well understood. Furthermore, the role of long non-coding RNAs (lncRNAs) in the cellular response to stiffening has never been explored. This study characterizes the stiffness-sensitive transcriptome of human Ao and Co VSMCs and identify potentially key lncRNA regulators of stiffness-dependent VSMC functions. Ao and Co VSMCs were cultured on hydrogel substrates mimicking physiologic and pathologic ECM stiffness. Total RNA-seq was performed to compare the stiffness-sensitive transcriptome profiles of Ao and Co VSMCs.
2017-12-01 | GSE100081 | GEO
Project description:Treating recurrent GBM is a clinical challenge due to its highly resistant and aggressive nature. In order to develop new therapeutic targets for recurrent GBM a better understanding of its molecular landscape is necessary. Here we used a cellular model, developed in our lab which generates paired primary and recurrent samples from GBM cell lines and primary patient samples hence allowing us to compare the molecular differences between the two populations. Total RNA seq analysis of parent and recurrent population of two cell lines and one patient sample revealed a significant upregulation of Extracellular matrix interaction in recurrent population. Since matrix stiffness plays a pivotal role in cell-ECM interaction and downstream signaling, we developed a system that mimicked the brain like substrate stiffness by using collagen coated polyacrylamide-based substrate whose stiffness can be modified from normal brain (0.5kPa) to tumorigenic (10kPa). Using these substrates, we were able to capture the morphological and physiological differences between parent and recurrent GBM which were not evident on plastic surfaces (~1 GPa). On 0.5kPa, unlike circular parent cells, recurrent GBM cells showed two morphologies (circular and elongated). The recurrent cells growing on 0.5kPa also showed higher proliferation, invasion, migration and in-vivo tumorigenicity in orthotropic GBM mouse model, compared to parent cells. Furthermore, recurrent cells exhibited elevated velocity irrespective of substrate stiffness, which indicated that recurrent cells may possess inherent differential mechanosignalling ability which was reflected by higher expression of ECM proteins like Collagen IVA, MMP2 and MMP9. Moreover, mice brain injected with recurrent cells grown on 0.5kPa substrate showed higher Young’s modulus values suggesting that recurrent cells conditioned on 0.5kPa make the surrounding ECM stiffer. Importantly, inhibition of EGFR signaling, that is amplified with tissue stiffening in GBM resulted in decreased invasion, migration and proliferation in 0.5kPa recurrent cells, but interestingly survival remained unaffected, highlighting the importance of mimicking the physiological stiffness of the brain mimicking clinical scenario. Total RNA seq analysis of parent and recurrent cells grown on plastic and 0.5kPa substrate identified PLEKHA7 as significantly upregulated gene specifically in 0.5kPa recurrent sample. Higher protein expression of PLEKHA7 in recurrent GBM as compared to primary GBM was validated in patient biopsies. Accordingly, PLEKHA7 knockdown reduced invasion and survival of recurrent GBM cells. Together, these data provides a model system that captures the differential mechanosensing signals of primary and recurrent GBM cells and identifies a novel potential target specific for recurrent GBM.
2023-06-29 | E-MTAB-11293 | biostudies-arrayexpress
Project description:Key role for Rac in the early transcriptional response to ECM stiffness and the stiffness-dependent repression of ATF3
| PRJNA989598 | ENA
Project description:The goal of this project is to characterize the ECM composition of actively proliferative and dormant head and neck squamous cell carcinoma xenografts and identify components of the ECM niche instructing tumor cell dormancy.
2021-08-26 | PXD018883 | Pride