Therapeutic vulnerabilities of mesenchymal subpopulations of pancreatic cancer cells undergoing anabolic reprogramming
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PROVIDER: PRJNA326925 | ENA |
REPOSITORIES: ENA
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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:This SuperSeries is composed of the SubSeries listed below.
2017-02-13 | GSE83754 | GEO
Project description:Therapeutic vulnerabilities of mesenchymal subpopulations of pancreatic cancer cells undergoing anabolic reprogramming [set2]
| PRJNA326929 | ENA
Project description:Therapeutic vulnerabilities of mesenchymal subpopulations of pancreatic cancer cells undergoing anabolic reprogramming [set 1]
| PRJNA326930 | ENA
Project description:Malignant neoplasms evolve in response to changes in oncogenic signalling. Cancer cell plasticity in response to evolutionary pressures is fundamental to tumour progression and the development of therapeutic resistance. Here we determine the molecular and cellular mechanisms of cancer cell plasticity in a conditional oncogenic Kras mouse model of pancreatic ductal adenocarcinoma (PDAC), a malignancy that displays considerable phenotypic diversity and morphological heterogeneity. In this model, stochastic extinction of oncogenic Kras signalling and emergence of Kras-independent escaper populations (cells that acquire oncogenic properties) are associated with de-differentiation and aggressive biological behaviour. Transcriptomic and functional analyses of Kras-independent escapers reveal the presence of Smarcb1-Myc-network-driven mesenchymal reprogramming and independence from MAPK signalling. A somatic mosaic model of PDAC, which allows time-restricted perturbation of cell fate, shows that depletion of Smarcb1 activates the Myc network, driving an anabolic switch that increases protein metabolism and adaptive activation of endoplasmic-reticulum-stress-induced survival pathways. Increased protein turnover renders mesenchymal sub-populations highly susceptible to pharmacological and genetic perturbation of the cellular proteostatic machinery and the IRE1-α-MKK4 arm of the endoplasmic-reticulum-stress-response pathway. Specifically, combination regimens that impair the unfolded protein responses block the emergence of aggressive mesenchymal subpopulations in mouse and patient-derived PDAC models. These molecular and biological insights inform a potential therapeutic strategy for targeting aggressive mesenchymal features of PDAC.
| S-EPMC7609022 | biostudies-literature
Project description:ATM Loss and Therapeutic Vulnerabilities in Bladder Cancer
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Project description:No approved therapy exists for cancer-associated cachexia. The colon-26 mouse model of cancer cachexia mimics recent late stage clinical failures of anabolic anti-cachexia therapy, and was unresponsive to anabolic doses of diverse androgens, including the selective androgen receptor modulator (SARM) GTx-024. The histone deacetylase inhibitor (HDACi) AR-42 exhibited anti-cachectic activity in this model. We explored combined SARM/AR-42 therapy as an improved anti-cachectic treatment paradigm. A reduced dose of AR-42 provided limited anti-cachectic benefits, but, in combination with GTx-024, significantly improved body weight, hind limb muscle mass, and grip strength versus controls. AR-42 suppressed the IL-6/GP130/STAT3 signaling axis in muscle without impacting circulating cytokines. GTx-024-mediated β-catenin target gene regulation was apparent in cachectic mice only when combined with AR-42. Our data suggest cachectic signaling in this model involves catabolic signaling insensitive to anabolic GTx-024 therapy and a blockade of GTx-024-mediated anabolic signaling. AR-42 mitigates catabolic gene activation and restores anabolic responsiveness to GTx-024. Combining GTx-024, a clinically established anabolic therapy, with AR-42, a clinically evaluated HDACi, represents a promising approach to improve anabolic response in cachectic patients.
2019-11-20 | GSE138464 | GEO
Project description:All living cells require a minimal iron threshold to sustain anabolic metabolism. However, the mechanisms by which cells sense iron to regulate anabolic processes are unclear. Here, we report a universal eukaryotic pathway for iron sensing in which molecular iron is required to sustain active histone demethylation and maintain the expression of critical components of the pro-anabolic mTORC1 pathway. Specifically, we identify the iron-binding histone-demethylase KDM3B as an intrinsic iron sensor that regulates mTORC1 activity by demethylating H3K9me2 at enhancers of a high-affinity leucine transporter and RAPTOR. By directly suppressing leucine availability and RAPTOR levels, iron deficiency (ID) supersedes other nutrient inputs into mTORC1. This process occurs in vivo, and is not an indirect effect by canonical iron-utilizing pathways. These data demonstrate a novel mechanism of eukaryotic iron sensing through dynamic chromatin remodeling and repression of mTORC1 mediated anabolism. Due to ancestral eukaryotes sharing homologues of KDMs and mTORC1 core components, this pathway likely predated the emergence of the other kingdom-specific nutrient sensors for mTORC1.
2023-07-20 | PXD043952 | Pride