Transcriptional responses of autophagy proficient and deficient pancreatic tumors and cells treated with TNFα
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ABSTRACT:
PROVIDER: PRJNA666326 | ENA |
REPOSITORIES: ENA
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Project description:Pancreatic ductal adenocarcinoma (PDAC) cells require substantial metabolic rewiring to overcome nutrient limitations and immune surveillance. However, the metabolic pathways necessary for pancreatic tumor growth in vivo are poorly understood. To address this, we performed metabolism-focused CRISPR screens in PDAC cells grown in culture or engrafted in immunocompetent mice. While most metabolic gene essentialities are unexpectedly similar under these conditions, a small fraction of metabolic genes are differentially required for tumor progression. Our screens identify autophagy as a metabolic requirement for pancreatic tumor immune evasion. Mechanistically, autophagy protects cancer cells from CD8+ T cell killing through TNFα-induced cell death in vitro. This data set contains RNA-seq data of KP pancreas Atg7_KO cells expressing empty vector or Atg7 cDNA. These cells were grown as subcutaenous tumors and also cultured in vitro with and without TNFα.
2020-09-30 | GSE158707 | GEO
Project description:To determine the role of autophagy in the maintenance of genome stability and nucleic acid metabolism, the chromatin-bound proteins in autophagy-deficient ATG7-/- HEK293 cells were compared with autophagy-proficient ATG7+/+ HEK293 cells by Data-independent acquisition mass spectrometry (DIA-MS).
2021-10-27 | PXD028956 | JPOST Repository
Project description:Background: We previously demonstrated that B16F1 melanoma tumors growing in syngeneic germline-deleted TNFR1,2 -/- mice were more sensitive to ionizing radiation (IR) compared to tumors growing in C57BL/6 wild-type mice; however, the mechanisms linked to this difference in radiosensitivity are not fully understood. Methodology/ Principal Findings: We used DNA microarrays to identify alterations in the expression of functional gene clusters associated with the radiosensitization of B16F1 tumors growing in TNFR1,2 -/- mice. At the basal level, disruption of host stromal TNFα signaling resulted in the over-expression of tumor genes involved in extracellular matrix remodeling and angiogenesis. Phenotypically, these tumors exhibited a reduced vascular density, which induced the expression of oxidative stress signaling pathways and increased levels of tissue hypoxia and necrosis. These alterations were paralleled by the suppression of genes involved in chromosomal stability and key effectors of the ATM-dependent/ non-homologous end-joining pathways including phosphorylated-ATM, BRCA1, and RAD51, which resulted in greater DNA double-strand breaks and caspase 3 activation following IR treatment. Conclusions/ Significance: Taken together, these results demonstrate that disruption of TNFα signaling in the host stroma mediates transcriptional and phenotypic changes in tumors which may alter tumor radiosensitivity. These results suggest a critical role for TNFα in the maintenance of tumor-associated vasculature and radioresistance. They also indicate that TNFα signaling blockade in stromal cells may represent a strategy for tumor radiosensitization. To investigate the genes associated with the radiosensitization of B16F1 melanoma tumors in the context of disrupted stromal TNFα signaling, we performed expression profiling of B16F1 tumors grown in syngeneic TNFR 1, 2 -/- and wild-type C57BL/6 mice. Tumors were lysed to collect total RNA, pooled by treatment group according to total RNA level, and analyzed in duplicates with Affymetrix GeneChip® Mouse Genome 430 2.0 Arrays.
2010-07-20 | E-GEOD-23002 | biostudies-arrayexpress
Project description:Background: We previously demonstrated that B16F1 melanoma tumors growing in syngeneic germline-deleted TNFR1,2 -/- mice were more sensitive to ionizing radiation (IR) compared to tumors growing in C57BL/6 wild-type mice; however, the mechanisms linked to this difference in radiosensitivity are not fully understood. Methodology/ Principal Findings: We used DNA microarrays to identify alterations in the expression of functional gene clusters associated with the radiosensitization of B16F1 tumors growing in TNFR1,2 -/- mice. At the basal level, disruption of host stromal TNFα signaling resulted in the over-expression of tumor genes involved in extracellular matrix remodeling and angiogenesis. Phenotypically, these tumors exhibited a reduced vascular density, which induced the expression of oxidative stress signaling pathways and increased levels of tissue hypoxia and necrosis. These alterations were paralleled by the suppression of genes involved in chromosomal stability and key effectors of the ATM-dependent/ non-homologous end-joining pathways including phosphorylated-ATM, BRCA1, and RAD51, which resulted in greater DNA double-strand breaks and caspase 3 activation following IR treatment. Conclusions/ Significance: Taken together, these results demonstrate that disruption of TNFα signaling in the host stroma mediates transcriptional and phenotypic changes in tumors which may alter tumor radiosensitivity. These results suggest a critical role for TNFα in the maintenance of tumor-associated vasculature and radioresistance. They also indicate that TNFα signaling blockade in stromal cells may represent a strategy for tumor radiosensitization.
2010-07-20 | GSE23002 | GEO
Project description:Gene expression profiles of CD3e-proficient and CD3e-deficient were analysed using Affymetrix cDNA arrays (MOAE430)
2009-03-03 | E-MEXP-1590 | biostudies-arrayexpress
Project description:Autophagy is activated in pancreatic ductal adenocarcinoma (PDAC) and is currently being considered a promising therapeutic target in clinical trials. PDAC is a highly lethal disease with incidence rate equalling mortality rate. Main reasons for PDAC lethality are late-stage diagnosis, high agressiveness and metastatic rate, lack of effective treatments as well as specific diagnostic markers. Here we show that varying levels of the Autophagy related gene 5 (Atg5) determine pancreatic tumor formation and malignancy. While homozygous deletion of Atg5 blocks tumor progression in an in vivo model of PDAC, heterozygous deletion increases tumor aggressiveness and metastasis. Further analyses reveal that monoallelic loss of Atg5 affects mitochondrial homeostasis, changes intracellular calcium oscillations, heightens extracellular cathepsin activities , and promotes a pro-tumorigenic inflammatory microenvironment collectively enhancing tumor cell migration, invasion, and metastasis. Future treatments should take into account that variations in the autophagy pathway may have opposing effects on pancreatic tumor load, especially considering the multitude of autophagy inhibitors currently tested in clinical trials.
2018-10-15 | E-MTAB-6275 | biostudies-arrayexpress
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