Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Transcriptional responses of autophagy proficient and deficient pancreatic tumors and cells treated with TNFα

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE158707 | GEO | 2020/09/30

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Transcriptional profiling of autophagy proficient and compromised cell lines, determined by expression levels of Atg5

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

TNFα-producing Macrophages Determine Subtype Identity and Prognosis via AP1 Enhancer Reprogramming in Pancreatic Cancer [TNFa-treatment RNA-seq]

Project description:In pancreatic cancer, classical and basal-like subtypes are identified as two major PDAC subtypes. Our previous data showed that PDAC tumor cells can switch between the two phenotypes through transcriptional reprogramming particularly in response to inflammatory cues. In this study, we were trying to understand TNFα mediated transcription regulatory network in pancreatic cancer. Hence, we performed RNA-seq in TNFα treated classical cells as well as aqua dest control.

2021-07-02 | GSE152830 | GEO

ERAP2 is a novel target involved in autophagy and activation of pancreatic stellate cells via unfolded protein response signaling pathway

Project description:Pancreatic ductal adenocarcinoma (PDAC) is characterized by excessive desmoplasia and autophagy-dependent tumorigenic growth. Pancreatic stellate cells (PSCs) as a predominant stromal cell type play a critical role in PDAC biology. Autophagy facilitates PSC activation. However, the mechanism remains unknown. To investigate the mechanism of autophagy in PSC activation, gene expression profiles between patient-derived PSCs from pancreatic cancer and chronic pancreatitis were compared using a gene expression microarray. Here, we found that endoplasmic reticulum aminopeptidase 2 (ERAP2), which resides in the endoplasmic reticulum (ER) membrane, was highly expressed in both cancer-associated PSCs and pancreatic cancer cells (PCCs). We found that high stromal ERAP2 expression is associated with a poor prognosis of PDAC patients. Knockdown of ERAP2 inhibited autophagy of PSCs and PCCs. In PSCs, inhibition of autophagy by ERAP2 knockdown led to inactivation of PSCs and attenuated tumor-stromal interactions. This process was mediated by ER stress and consequent IRE1α and PERK unfolded protein response (UPR) signaling pathways. In orthotopic models, ERAP2 knockdown in PSCs inhibited growth and fibrosis of xenografted tumor compared with coimplantation of PSCs without ERAP2 knockdown, and gemcitabine treatment further inhibited tumor growth. Our findings demonstrate a novel mechanism of PSCs activation regulated by autophagy. ERAP2 as a promising therapeutic target may provide a novel strategy for the treatment of PDAC.

2022-04-30 | GSE172168 | GEO

Transcriptional responses of autophagy proficient and deficient pancreatic tumors and cells treated with TNFα

Project description:Transcriptional responses of autophagy proficient and deficient pancreatic tumors and cells treated with TNFα

| PRJNA666326 | ENA

Pancreatic Tumor Microenvironment Maintains Tumor Growth through Nucleosides Secretion

Project description:Cancer-associated fibroblasts (CAFs) are one of the most prominent and active components in the pancreatic tumor microenvironment. Our data show that CAFs are critical for PDAC survival upon glutamine deprivation. Specifically, we uncovered a role for nucleosides, which are secreted by CAFs through autophagy in an NUFIP1-depenent manner, increased glucose utilization and promoted growth of PDAC. Moreover, we demonstrate that CAF-derived nucleosides induced glucose consumption under glutamine-deprived conditions and displayed a dependence on MYC. Using an orthotopic mouse model of PDAC, we found that inhibiting nucleoside secretion by targeting NUFIP1 in the stroma reduced tumor weight. This finding highlights a previously unappreciated metabolic network within pancreatic tumors in which diverse nutrients are used to promote growth in an austere tumor microenvironment.

2021-10-19 | GSE185750 | GEO

ELAPOR1 induces the classical/progenitor subtype and contributes to reduced disease aggressiveness through metabolic reprogramming in pancreatic cancer

Project description:<p>Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous disease with distinct molecular subtypes described as classical/progenitor and basal-like/squamous PDAC. We hypothesized that integrative transcriptome and metabolome approaches can identify candidate genes whose inactivation contributes to the development of the aggressive basal-like/squamous subtype. Using our integrated approach, we identified endosome-lysosome associated apoptosis and autophagy regulator 1 (ELAPOR1/KIAA1324) as a candidate tumor suppressor in both our NCI-UMD-German cohort and additional validation cohorts. Diminished ELAPOR1 expression was linked to high histological grade, advanced disease stage, the basal-like/squamous subtype, and reduced patient survival in PDAC. In vitro experiments demonstrated that ELAPOR1 transgene expression not only inhibited the migration and invasion of PDAC cells but also induced gene expression characteristics associated with the classical/progenitor subtype. Metabolome analysis of patient tumors and PDAC cells revealed a metabolic program associated with both upregulated ELAPOR1 and the classical/progenitor subtype, encompassing upregulated lipogenesis and downregulated amino acid metabolism. 1-methylnicotinamide, a known oncometabolite derived from S-adenosylmethionine, was inversely associated with ELAPOR1 expression and promoted migration and invasion of PDAC cells in vitro. Taken together, our data suggest that enhanced ELAPOR1 expression promotes transcriptome and metabolome characteristics that are indicative of the classical/progenitor subtype, whereas its reduction associates with basal-like/squamous tumors with increased disease aggressiveness in PDAC patients. These findings position ELAPOR1 as a promising candidate for diagnostic and therapeutic targeting in PDAC.</p>

2024-04-02 | MTBLS9418 | MetaboLights

Expression Analysis of Mouse Tumor and Metastatic Pancreatic Ductal Adenocarcinoma Organoids

Project description:This study used Illumina strand-specific, paired-end RNA-sequencing to examine gene expression differences between matched murine tumor- and metastasis-derived mouse pancreatic ductal adenocarcinoma (PDAC) cells grown as three-dimensional, organoid cultures. The study analyzed 16 organoid lines derived from matched primary PDAC tumors and PDAC metastases from 6 KPC (KrasLSL-G12D; Trp53LSL-R172H; Pdx1-Cre) mice.

2020-06-16 | GSE142467 | GEO

NCOA4-mediated ferritinophagy is a pancreatic cancer dependency via maintenance of iron bioavailability for iron-sulfur cluster proteins

Project description:Oncogenic KRAS rewires pancreatic ductal adenocarcinoma (PDAC) metabolism to promote dependence on autophagy and iron metabolism. NCOA4-mediated ferritinophagy links autophagy and iron metabolism as NCOA4 selectively targets ferritin, the cellular iron storage complex, via autophagy to the lysosome for ferritin degradation and release of iron for utilization. Using patient-derived and genetically engineered murine models of PDAC we now demonstrate that ferritinophagy is upregulated in PDAC to sustain iron availability thereby promoting PDAC progression. PDAC global quantitative proteomics reveals that ferritinophagy fuels iron-sulfur cluster synthesis to support mitochondrial homeostasis. Targeting NCOA4 leads to tumor growth delay and prolonged survival but with development of compensatory iron acquisition pathways. Finally, a ferritinophagy gain-of-function PDAC murine model demonstrates worse survival, and an elevated ferritinophagy expression signature predicts for worse overall survival in human PDAC patients. Together, our data define NCOA4-mediated ferritinophagy as a therapeutic target in PDAC and reveal that maintenance of cellular iron homeostasis is a critical cell autonomous function of PDAC autophagy.

2022-08-17 | PXD033356 | Pride

Gasdermin E mediates resistance of pancreatic adenocarcinoma to enzymatic digestion through a YBX1-mucin pathway

Project description:Pancreatic ductal adenocarcinoma (PDAC) originates from normal pancreatic ducts where digestive juice is regularly produced. It remains unclear how PDAC can escape auto-digestion by digestive enzymes. Here we show that human PDAC tumor cells use gasdermin E (GSDME), a pore-forming protein upon caspase 3 cleavage, to mediate the digestive resistance. We find that GSDME facilitates the expression of mucins 1 and 13 in pancreatic tumor cells, which forms a barrier to prevent chymotrypsin-mediated destruction. Inoculation of GSDME-/- PDAC cells results in subcutaneous but not orthotopic tumor formation in mice. Either inhibiting or knocking out MUC1 or MUC13 abrogates orthotopic PDAC growth in NOD-SCID mice. Mechanistically, GSDME interacts with and transports transcription factor YBX1 into the nucleus where YBX1 directly promotes mucin expression. This GSDME-YBX1-mucin axis is also confirmed in PDAC patients. These findings uncover a unique survival mechanism of PDAC cells in pancreatic microenvironments, thus providing a potential target for PDAC treatment.

2022-05-20 | PXD030879 | Pride

Secretome analysis of Pancreatic Cancer Spheroid with myeloid cell infiltration

Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the most hypoxic, lethal, and treatment resistant cancers. Due to its desmoplastic and hypoxic nature along with the abundance of myeloid cell infiltration and scare T cell infiltration, PDAC is considered a cold tumor. Using MiaPaCA-2 as a PDAC spheroid model with hypoxic core grown in serum-free defined media and immune cell infiltration, we assessed the modulation of PDAC secretome and characterized immunomodulatory factors secreted.

2023-12-15 | PXD044177 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data