A Pancreas Organoids-based Screen Identifies a Specific KRAS Mutation Inhibitor that Attenuating Cholesterol Biosynthesis Pathway in Pancreatic Cancer
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ABSTRACT:
PROVIDER: PRJNA854918 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19920174_1.fastq.gz | Fastqsanger.gz | |||
| SRR19920174_2.fastq.gz | Fastqsanger.gz | |||
| SRR19920175_1.fastq.gz | Fastqsanger.gz | |||
| SRR19920175_2.fastq.gz | Fastqsanger.gz | |||
| SRR26667400_1.fastq.gz | Fastqsanger.gz |
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Project description:we reported a high-content drug screening platform of a series of pancreas organoids which contain common mutations found in human pancreatic cancer, wide type (WT), KC (KRASG12D), KPC (KRASG12D; Tp53R172H), KSC (KRASG12D; SMAD4-/-) and KPSC (KRASG12D; Tp53R172H and SMAD4-/-). Based on this platform, we screened about 6000 compounds and identified Perhexiline, which can inhibit the growth of pancreas organoids with KRAS mutation in vitro and in vivo. Single cell RNA-seq data shows that the cholesterol synthesis pathway is activated specifically caused by KRAS in mutated organoid lines. The key cholesterol synthesis regulator of SREBP2 and its downstream genes are activated in KRAS mutated organoids compared with WT. Interestingly, Perhexiline can reverse the metabolism changes in pancreas organoids with KRAS through downregulating SREBP2 at transcription level. Finally, we further validated targeting SREBP2 can attenuate tumor growth significantly with chemical inhibitor and genetic perturbation. These findings boost further understanding of KRAS in PDAC and provide a valuable resource for targeting KRAS therapeutics development.
2023-11-16 | GSE207352 | GEO
Project description:The goal for this study was to determine the effects of ethanol on pancreas cells and examine how ethanol influences protein expression in non-transformed and mutant KRAS cells. We performed TMT-labeled proteomics of non-transformed (hTERT-HPNE E6/E7) and KRAS mutated (hTERT-HPNE E6/E7/K-RasG12D) human pancreas cell lines following 6 months of 100 mM ethanol treatment.
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Project description:Stromal-derived NRG1 enables oncogenic KRAS bypass in pancreas cancer
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Project description:Intricate regulatory networks govern the net balance of cholesterol biosynthesis, uptake and efflux; however, the mechanisms surrounding cholesterol homeostasis remain incompletely understood. Here, we develop an integrative genomic strategy to detect regulators of LDLR activity and identify 250 genes whose knockdown affects LDL-cholesterol uptake and whose expression is modulated by intracellular cholesterol levels in human hepatic cells. From these hits, we focus on MMAB, an enzyme which catalyzes the conversion of vitamin B12 to adenosylcobalamin, and whose expression has previously been linked to altered levels of circulating cholesterol in humans. We demonstrate that hepatic levels of MMAB are modulated by dietary and cellular cholesterol levels through SREBP2, the master transcriptional regulator of cholesterol homeostasis. Knockdown of MMAB decreases intracellular cholesterol levels and augments SREBP2-mediated gene expression and LDL-cholesterol uptake in human and mouse hepatic cell lines. Reductions in total sterol content were attributed to increased intracellular levels of propionic and methylmalonic acid and subsequent inhibition of HMGCR activity and cholesterol biosynthesis. Moreover, mice treated with antisense inhibitors of MMAB display a significant reduction in hepatic HMGCR activity and hepatic sterol content and increased expression of SREBP2-mediated genes. Collectively, these findings reveal an unexpected role for the adenosylcobalamin pathway in regulating LDLR expression and identify MMAB as an additional control point by which cholesterol biosynthesis is regulated by its end product.
2021-06-01 | GSE169712 | GEO
Project description:Intricate regulatory networks govern the net balance of cholesterol biosynthesis, uptake and efflux; however, the mechanisms surrounding cholesterol homeostasis remain incompletely understood. Here, we develop an integrative genomic strategy to detect regulators of LDLR activity and identify 250 genes whose knockdown affects LDL-cholesterol uptake and whose expression is modulated by intracellular cholesterol levels in human hepatic cells. From these hits, we focus on MMAB, an enzyme which catalyzes the conversion of vitamin B12 to adenosylcobalamin, and whose expression has previously been linked with altered levels of circulating cholesterol in humans. We demonstrate that hepatic levels of MMAB are modulated by dietary and cellular cholesterol levels through SREBP2, the master transcriptional regulator of cholesterol homeostasis. Knockdown of MMAB decreases intracellular cholesterol levels and augments SREBP2-mediated gene expression and LDL-cholesterol uptake in human and mouse hepatic cell lines. Reductions in total sterol content were attributed to increased intracellular levels of propionic and methylmalonic acid and subsequent inhibition of HMGCR activity and cholesterol biosynthesis. Moreover, mice treated with antisense inhibitors of MMAB display a significant reduction in hepatic HMGCR activity, hepatic sterol content and increased expression of SREBP2-mediated genes. Collectively, these findings reveal an unexpected role for the adenosylcobalamin pathway in regulating LDLR expression and identify MMAB as an additional control point by which cholesterol biosynthesis is regulated by its end product.
2021-09-10 | GSE183790 | GEO
Project description:Activating KRAS mutations (KRAS*) in pancreatic ductal adenocarcinoma (PDAC) drive anabolic metabolism and support tumor maintenance. KRAS* inhibitors show initial anti-tumor activity followed by recurrence due to cancer cell intrinsic and immune mediated paracrine mechanisms. Here, we explored the potential role of cancer associated fibroblasts (CAFs) in enabling KRAS* bypass and identified CAF-derived NRG1 activation of cancer cell ERBB2/ERBB3 receptor tyrosine kinases as a mechanism by which KRAS* independent growth is supported. Genetic extinction or pharmacological inhibition of KRAS* resulted in upregulation of ERBB2 and ERBB3 expression in human and murine models, which prompted cancer cell utilization of CAF-derived NRG1 as a survival factor. Genetic depletion or pharmacological inhibition of ERBB2/ERBB3 or NRG1 abolished KRAS* bypass and synergized with KRASG12D inhibitor in combination treatments in mouse and human PDAC models. Thus, we found that CAFs can contribute to KRAS* inhibitor therapy resistance via paracrine mechanisms, providing an actionable therapeutic strategy to improve the effectiveness of KRAS* inhibitors in PDAC patients.
2023-09-22 | GSE240232 | GEO
Project description:Many enveloped viruses bud from cholesterol-rich lipid rafts on the cell membrane. Depleting cellular cholesterol impedes this process and results in viral particles with reduced viability. Viperin (virus inhibitory protein endoplasmic reticulum-associated, interferon-induced) is an ER membrane-associated enzyme that when expressed in response to viral infections exerts broad-ranging antiviral effects, including inhibiting the budding of some enveloped viruses. Here we have investigated the effect of viperin expression on cholesterol biosynthesis. We found that viperin expression reduces cholesterol levels by 20 – 30 % in HEK293T cells. A proteomic screen of the viperin interactome identified several cholesterol biosynthetic enzymes among the top hits. The two most highly enriched proteins were lanosterol synthase and squalene monooxygenase, enzymes that catalyze key steps establishing the sterol carbon skeleton. Co-immunoprecipitation experiments established that viperin, lanosterol synthase and squalene monooxygenase form a complex at the ER membrane. Co-expression of viperin was found to significantly inhibit the specific activity of lanosterol synthase in HEK293T cell lysates. Co-expression of viperin had no effect on the specific activity of squalene monooxygenase, but reduced its expression levels in the cells by approximately 30 %. Despite these inhibitory effects, co-expression of either LS or SM failed to reverse the viperin-induced depletion of cellular cholesterol levels in HEK293T cells. Our results establish a clear link between the down-regulation of cholesterol biosynthesis and viperin, although at this point the effect cannot be unambiguously attributed interactions between viperin and a specific biosynthetic enzyme.
2021-09-10 | PXD023999 | Pride
Project description:A classical epithelial state drives acute resistance to KRAS inhibition in pancreas cancer
| PRJNA1130889 | ENA
Project description:Activation of endogenously expressed KRas[G12D] in the pancreas of mice gives rise primarily to early stage PanIN lesions, however such lesions can occasionally progress to end-stage ductal adenocarcinoma (PDAC). Progression of KRas[G12D]- initiated lesions to PDAC is accelerated by modest expression of MYC from the Rosa26 locus. Deletion of 1 copy of endogenous c-Myc or both copies of endogenous Zbtb17 (aka Miz1), slows progression to PDAC and extends healthful survival of Pdx1-Cre;lsl-KRas[G12D];Rosa26-lsl-MYC[DM] (KMC) mice. Tumours were removed from mice with all 4 genotypes and validated by histological examination prior to RNA-SEQ analysis.
2020-03-16 | E-MTAB-8797 | biostudies-arrayexpress
Project description:Background: Several genetic defects of the nucleotide excision repair (NER) pathway, including deficiency of the Excision Repair Cross-Complementing rodent repair deficiency, complementation group 1 (ERCC1), result in pre-mature aging, impaired growth, microcephaly and delayed development of the cerebellum. Such a phenotype also occurs in ERCC1-knockout mice which survive for up to 4 weeks after birth. Therefore, we analyzed cerebellar and hippocamapal transcriptomes of these animals at 3 weeks of age to identify the candidate mechanisms underlying brain consequences of reduced ERCC1 activity. Results: In the cerebellum, the most prominent change was upregulation of genes that are associated with gliosis. Although Purkinje cell degeneration has been reported in some mouse strains with NER impairment, Purkinje cell transcriptome was mostly unaffected by the ERCC1 knockout. In the hippocampus, the gliosis response was minimal. Instead, there was an extensive downregulation of genes related to lipid metabolism including several enzymes of the cholesterol biosynthesis pathway as well as lipoproteins and plasma membrane proteins. Reduced expression of the cholesterol biosynthesis pathway genes was also present in the neocortex of adult mice whose ERCC1 gene was replaced by a mutant allele with a partial activity. Conclusions: Downregulation of forebrain cholesterol biosynthesis genes is a newly identified consequence of ERCC1 deficiency. Its presence in adult mice suggests that it is not a secondary consequence of brain growth impairment. Instead, reduced cholesterol biosynthesis may contribute to such an impairment as well as affect function of mature synapses. We analyzed the hippocampus and cerebellum from three Ercc1-/- and three WT littermates using the Affymetrix Mouse Genome 430_2.0. Data was analyzed using the dChip DNA-Chip analyzer software .
2011-08-15 | E-GEOD-31199 | biostudies-arrayexpress