Mus musculus
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ABSTRACT:
PROVIDER: PRJNA326930 | ENA |
REPOSITORIES: ENA
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Project description:Therapeutic vulnerabilities of mesenchymal subpopulations of pancreatic cancer cells undergoing anabolic reprogramming
| PRJNA326925 | ENA
Project description:Therapeutic vulnerabilities of mesenchymal subpopulations of pancreatic cancer cells undergoing anabolic reprogramming [set2]
| PRJNA326929 | ENA
Project description:Malignant neoplasms adapt and evolve in response to changes in oncogenic signaling, tumor microenvironmental stresses,and therapeutic interventions. Cancer cell plasticity in response to these evolutionary pressures is foundational to tumor progression and maintenance and therapeutic resistance. Here, to elucidate the underlying molecular and cellularmechanisms of cancer cell plasticity, integrated system-level, functional and genetic analyses were conducted in a conditional oncogenic Kras model of pancreatic ductal adenocarcinoma (PDAC), amalignancy displaying remarkable phenotypic diversityand morphological heterogeneity. In this model, stochastic extinction of oncogenic Krassignaling and emergence ofKras-independent escaper populationsis associated withde-differentiation and aggressive biological behavior.Transcriptomic and functional analyses ofKras-independent escapers reveal mesenchymal reprogramming driven by aSmarcb1/Mycnetwork and independence from MAPK signaling.A somatic mosaic model of PDAC which can track evolving subpopulations shows that depletion of Smarcb1 activates theMyc network which results in an anabolic switch to increased protein metabolism and the adaptive activation of ERstress-induced survival pathways.Theelevated protein turnover made mesenchymal sub-populationshighly susceptible topharmacological and genetic perturbation of the cellular proteostatic machinery andthe IRE1-α/MKK4 arm of the ER stress response pathway. Specifically, combination regimens impairing the unfolded protein responses (UPR) and the ER stress response can block the emergence of aggressive mesenchymal subpopulations in murine andpatient-derived PDACmodels. These molecular and biological insights inform a potential therapeutic strategy fortargeting aggressive mesenchymal features of PDAC.
2017-02-13 | GSE83753 | GEO
Project description:Malignant neoplasms adapt and evolve in response to changes in oncogenic signaling, tumor microenvironmental stresses,and therapeutic interventions. Cancer cell plasticity in response to these evolutionary pressures is foundational to tumor progression and maintenance and therapeutic resistance. Here, to elucidate the underlying molecular and cellularmechanisms of cancer cell plasticity, integrated system-level, functional and genetic analyses were conducted in a conditional oncogenic Kras model of pancreatic ductal adenocarcinoma (PDAC), amalignancy displaying remarkable phenotypic diversityand morphological heterogeneity. In this model, stochastic extinction of oncogenic Krassignaling and emergence ofKras-independent escaper populationsis associated withde-differentiation and aggressive biological behavior.Transcriptomic and functional analyses ofKras-independent escapers reveal mesenchymal reprogramming driven by aSmarcb1/Mycnetwork and independence from MAPK signaling.A somatic mosaic model of PDAC which can track evolving subpopulations shows that depletion of Smarcb1 activates theMyc network which results in an anabolic switch to increased protein metabolism and the adaptive activation of ERstress-induced survival pathways.Theelevated protein turnover made mesenchymal sub-populationshighly susceptible topharmacological and genetic perturbation of the cellular proteostatic machinery andthe IRE1-α/MKK4 arm of the ER stress response pathway. Specifically, combination regimens impairing the unfolded protein responses (UPR) and the ER stress response can block the emergence of aggressive mesenchymal subpopulations in murine andpatient-derived PDACmodels. These molecular and biological insights inform a potential therapeutic strategy fortargeting aggressive mesenchymal features of PDAC.
2017-02-13 | GSE83752 | GEO
Project description:<p>Metabolic reprogramming is a hallmark of cancer and is crucial for cancer progression, making it an attractive therapeutic target. Understanding the role of metabolic reprogramming in cancer initiation could help identify prevention strategies. To address this, we investigated metabolism during acinar-to-ductal metaplasia (ADM), the first step of pancreatic carcinogenesis. Glycolytic markers were elevated in ADM lesions compared to normal tissue from human samples. Comprehensive metabolic assessment in three mouse models with pancreas-specific activation of KRAS, PI3K or MEK1 using Seahorse measurements, NMR metabolome analysis, mass spectrometry, isotope tracing and RNA-seq analysis revealed a switch from oxidative phosphorylation to glycolysis in ADM. Blocking the metabolic switch attenuated ADM formation. Furthermore, mitochondrial metabolism was required for de novo synthesis of serine and glutathione but not for ATP production. MYC mediated the increase in GSH intermediates in ADM, and inhibition of GSH synthesis suppressed ADM development. This study thus identifies metabolic changes and vulnerabilities in the early stages of pancreatic carcinogenesis.</p>
2024-05-31 | MTBLS9772 | MetaboLights
Project description:<p>The involvement of membrane-bound solute carriers (SLCs) in neoplastic transdifferentiation processes is poorly defined. Here, we examined changes in the SLC landscape during epithelial-mesenchymal transition (EMT) of pancreatic cancer cells. We show that two SLCs from the organic anion/cation transporter family, SLC22A10 and SLC22A15, favor EMT via interferon (IFN) α and γ signaling activation of receptor tyrosine kinase-like orphan receptor 1 (ROR1) expression. In addition, SLC22A10 and SLC22A15 allow tumor cell accumulation of glutathione to support EMT via the IFNα/γ-ROR1 axis. Moreover, a pan-SLC22A inhibitor lesinurad reduces EMT-induced metastasis and gemcitabine chemoresistance to prolong survival in mouse models of pancreatic cancer, thus identifying new vulnerabilities for human PDAC.</p>
2021-10-15 | MTBLS1925 | MetaboLights
Project description:In this study, we applied Drop-seq, a high throughput single cell RNA-seq platform, to characterize the different cell types present in pancreatic cancer organoids. We sequenced the transcriptomes of 7675 single cells from organoids derived from a patient undergoing a Whipple procedure for pancreatic ductal adenocarcinoma (PDAC). We then developed a novel clustering approach based on a class of probabilistic generative models called topic models, leading to the identification of subpopulations of cells.
2020-06-01 | GSE114454 | GEO
Project description:This model is based on:
Computational Modeling of the Crosstalk Between Macrophage Polarization and Tumor Cell Plasticity in the Tumor Microenvironment.
Abstract:
Tumor microenvironments contain multiple cell types interacting among one another via different signaling pathways. Furthermore, both cancer cells and different immune cells can display phenotypic plasticity in response to these communicating signals, thereby leading to complex spatiotemporal patterns that can impact therapeutic response. Here, we investigate the crosstalk between cancer cells and macrophages in a tumor microenvironment through in silico (computational) co-culture models. In particular, we investigate how macrophages of different polarization (M1 vs. M2) can interact with epithelial-mesenchymal plasticity of cancer cells, and conversely, how cancer cells exhibiting different phenotypes (epithelial vs. mesenchymal) can influence the polarization of macrophages. Based on interactions documented in the literature, an interaction network of cancer cells and macrophages is constructed. The steady states of the network are then analyzed. Various interactions were removed or added into the constructed-network to test the functions of those interactions. Also, parameters in the mathematical models were varied to explore their effects on the steady states of the network. In general, the interactions between cancer cells and macrophages can give rise to multiple stable steady-states for a given set of parameters and each steady state is stable against perturbations. Importantly, we show that the system can often reach one type of stable steady states where cancer cells go extinct. Our results may help inform efficient therapeutic strategies.
2019-09-23 | MODEL1909230002 | BioModels
Project description:Non-mesenchymal pancreatic cells are a potential source for cell replacement therapies aiming to restore the endocrine capacity lost during diabetes mellitus. Although a highly complex network of transcription factors underlies the differentiation, growth, and specification of pancreatic precursors, several studies indicated that the transdifferentiation of non-mesenchymal cells can be achieved by epigenetic regulation. The induction of this epithelial-mesenchymal transition through the post-translational modification of histones, exerting control over both dynamic and long-term gene expression, is a promising approach for reprogramming them into mesenchymal cells. The small molecule and histone deacetylase inhibitor valproic acid was linked to the expression of key transcription factors of pancreatic lineage in epithelial cells and insulin transcription. However, the underlying mechanisms are not fully understood. To shed further light on the potential use of valproic acid for cellular reprogramming strategies, we studied its effects on human ductal Panc-1-cells employing next generation RNA sequencing, real-time PCR and protein analysis by ELISA and western blot. Our data indicate a significant regulation of cell cycle, cell adhesion, histone acetyltransferase and metabolism-related genes, and an epithelial–mesenchymal transition through acetylation of histone H3, resulting in the phenotype of a-cells, supporting the prospect of a therapeutic usage of epithelial pancreatic cells for the purpose of reprogramming into hormonesecreting endocrine cells.
2022-02-07 | GSE166640 | GEO
Project description:Carcinoma cells can acquire key malignant traits by reprogramming their differentiation state via an epithelial-to-mesenchymal transition (EMT). Cancer cells that undergo EMT become invasive and resist a wide range of therapies including most chemotherapy drugs and radiation. Such cells are also able to efficiently seed primary and metastatic tumors, making them functionally indistinguishable from tumor-initiating or cancer stem-like cells (TICs or CSCs). Therefore, there is significant interest in finding vulnerabilities of cancer cells that have undergone EMT. A potent EMT-selective small molecule was discovered through a large-scale chemical screen. We used microarray analysis to understand the biological effects of this compound. HMLE_ctrl (human MECs, infected with a pBabe-shGFP retrovirus) and HMLE_Twist (human MECs, infected with a pBabe-Twist retrovirus) cells were treated with solvent control (DMSO), 5 µM or 10 µM of Cmp302 for 6 hours. Microarray analysis was performed to profile global gene expression.
2014-04-09 | E-GEOD-55604 | biostudies-arrayexpress