Targeting lipid metabolism in pancreatic cancer [RNA-seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE255377 | GEO | 2024/04/10
REPOSITORIES: GEO
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Project description:Pancreatic ductal adenocarcinoma (PDAC) thrives in a nutrient-deprived microenvironment, making it particularly susceptible to treatments that interfere with cancer metabolism. For example, PDAC utilizes and is dependent on high levels of autophagy and other lysosomal processes. Although targeting these pathways has shown potential in pre-clinical studies, progress has been hampered by the challenge of identifying and characterizing favorable targets for drug development. Here, we characterize PIKfyve, a lipid kinase integral to lysosomal functioning as a novel and targetable vulnerability in PDAC. Through comprehensive metabolic analyses we find that PIKfyve inhibition obligates PDAC to upregulate de novo lipid synthesis, a relationship previously undescribed. PIKfyve inhibition triggers a distinct lipogenic gene expression and metabolic program, creating a dependency on de novo lipid metabolism pathways, including genes such as FASN and ACACA. These results suggest that targeting PIKfyve disrupts lysosome-dependent lipid metabolism in PDAC and may be a favorable metabolic target for therapeutic development. Further, this data suggests that one could take advantage of this synthetic dependency by co-targeting PIKfyve and FASN or ACACA as a therapeutic strategy.
2024-04-10 | GSE255375 | GEO
Project description:Despite the remarkable clinical success of immunotherapies in a subset of cancer patients, many fail to respond to treatment and exhibit primary resistance. Here, we found thatgenetic or pharmacologic inhibitionof the lipid kinase PIKfyve, a regulator of autophagic flux and lysosomal biogenesis,upregulated surface expression of major histocompatibility complex class I (MHC-I) in cancer cells via impairing autophagic flux, resulting in enhanced cancer cell killing mediated by CD8+ T cells. Genetic depletion or pharmacologic inhibition of PIKfyve elevated tumor-specific MHC-I surface expression, reduced tumor proliferation, and increased intratumoral functional CD8+T cellsinsyngeneic mouse models. Importantly, enhanced antitumor responses by Pikfyve-depletion was CD8+T cell- and MHC-I-dependent,as CD8+ T cell depletion or B2m knockout rescued tumor growth. Furthermore, PIKfyve inhibition improved response to various immunotherapies, including immune checkpoint blockade (ICB), adoptive cell therapy, and therapeutic vaccines. High expression of PIKFYVE was also predictive of poor response to ICB and prognostic of poor survival in ICB-treated cohorts. Collectively, our findings show that targeting PIKfyve enhances immunotherapies by elevating surface expression of MHC-I in cancer cells, and PIKfyve inhibitors have potential as novel agents to increase immunotherapy response in cancer patients.
2023-11-13 | GSE235945 | GEO
Project description:The de novo synthesis of fatty acids has emerged as a therapeutic target for various diseases including cancer. Since cancer cells are intrinsically buffered to combat metabolic stress, it is important to understand how cells may adapt to loss of de novo fatty acid biosynthesis. Here we use pooled genome-wide CRISPR screens to systematically map genetic interactions (GIs) in human HAP1 cells carrying a loss-of-function mutation in FASN, which catalyzes the formation of long-chain fatty acids. FASN mutant cells show a strong dependence on lipid uptake that is reflected by negative GIs with genes involved in the LDL receptor pathway, vesicle trafficking, and protein glycosylation. Further support for these functional relationships is derived from additional GI screens in query cell lines deficient for other genes involved in lipid metabolism, including LDLR, SREBF1, SREBF2, ACACA. Our GI profiles also identify a potential role for the previously uncharacterized gene LUR1/C12orf49 in exogenous lipid uptake regulation through modulation of SREBF2 signalling in response to lipid starvation. Overall, our data highlight the genetic determinants underlying the cellular adaptation associated with loss of de novo fatty acid synthesis and demonstrate the power of systematic GI mapping for uncovering metabolic buffering mechanisms in human cells.
2020-04-30 | GSE148627 | GEO
Project description:The de novo synthesis of fatty acids has emerged as a therapeutic target for various diseases including cancer. Since cancer cells are intrinsically buffered to combat metabolic stress, it is important to understand how cells may adapt to loss of de novo fatty acid biosynthesis. Here we use pooled genome-wide CRISPR screens to systematically map genetic interactions (GIs) in human HAP1 cells carrying a loss-of-function mutation in FASN, which catalyzes the formation of long-chain fatty acids. FASN mutant cells show a strong dependence on lipid uptake that is reflected by negative GIs with genes involved in the LDL receptor pathway, vesicle trafficking, and protein glycosylation. Further support for these functional relationships is derived from additional GI screens in query cell lines deficient for other genes involved in lipid metabolism, including LDLR, SREBF1, SREBF2, ACACA. Our GI profiles also identify a potential role for the previously uncharacterized gene LUR1/C12orf49 in exogenous lipid uptake regulation through modulation of SREBF2 signalling in response to lipid starvation. Overall, our data highlight the genetic determinants underlying the cellular adaptation associated with loss of de novo fatty acid synthesis and demonstrate the power of systematic GI mapping for uncovering metabolic buffering mechanisms in human cells.
2020-04-30 | GSE147770 | GEO
Project description:Purpose: RNA-seq method was applied to select genes expressed in fat tissue and pinpointed genes potentially associated with fatness traits in pigs. Methods: The RNA-seq analysis was performed on fat tissue collected from 16 Pulawska pigs (8 pigs per two groups - with high and low backfat thickness) maintained at the same environmental and feeding condition. The total RNA was isolated using by TriReagent and 300ng was used to cDNA libraries preparation. The NGS sequencing was performed on HiScan SQ (Illumina) in 90 single-end cycles. The quantifying transcript abundances was made using the RSEM supported by STAR aligner. The raw reads were aligned to the Sus scrofa reference genome. Differentially expressed genes were detected by DESeq2. The RNA-seq results were validated using by qPCR. Results: In the group of pigs characterized by thicker subcutaneous fat, 166 genes with increased expression were identified, including genes involved in biological processes associated with negative regulation of long-chain fatty acid transport (GO: 0010748) (IRS2, THBS1, AKT2), regulation of metabolic lipids ( GO: 0019216) (EEF1A2, IRS2, ACACA, SIK1, ADGRF5, IDH1, FGF2, PDE3B, FASN, AKT2, CYR61, CHD9, ME1, SCD), cellular response to hormonal stimuli (GO: 0032870) (IRS2, ACACA, SIK1 , GHR, NR4A1, PDE3B, PTGER2, AKT2, AACS, ADCY6, KAT2B, RHOQ, FOS). Genes involved in the signaling pathway responsible for the activation of gene expression by SREBF (R-SSC-2426168) (ACACA, FASN, CHD9, SCD ) and the insulin signaling pathway also were identified (RHOQ, SOCS3, IRS2, AKT2, PDE3B, PYGM, FASN, ACACA). Conclusions: The presented results allowed to pinpointed the interesting, candidate genes related with fat content in carcasses in pigs, which can be analyzed in future in the term of using in breeding practice as genetic markers. The study was financed from funds of the project -BIOSTRATEG, the decision number BIOSTRATEG2/297267/14/NCBR/2016.
2018-11-12 | GSE122349 | GEO
Project description:Lower selection intensity resulted in obvious genetically and phenotypically divergences in China indigenous breeds. Nanyang black pig, a China indigenous breed, was famous for its high lipid deposition and high genetic divergence, which made it an ideal model investigating mechanism of lipid position traits in pig. Here, transcriptome and TMT-based proteome analyses were carried out in longissimus dorsi (LD) tissue of high genetic variation individual Nanyang black pigs. After phenotyping in a big population with multi-production traits indexes, six Nanyang black pigs were selected and divided into relatively high and low lipid deposition groups. Combining analyses of transcriptomic and proteomic data identified 15 candidate genes determining lipid deposition genetic divergence in Nanyang black pig. Among them, FASN, CAT, and SLC25A20 were main causal candidate genes. The other genes could be divided as lipid deposition related gene (BDH2, FASN, CAT, DHCR24, ACACA, GK, SQLE, ACSL4, SCD), PPARA-centered fat metabolism regulatory factors (PPARA, UCP3), transcription or translation regulators (SLC25A20, PDK4, CEBPA), and integrin, structural proteins, signal transduction-related genes (EGFR). The multi-omics data set provided a valuable resource for analyses on lipid deposition-traits in pig, especially in Nanyang black pig.
2021-01-28 | GSE165613 | GEO
Project description:The cellular cytotoxicity of APY0201, a PIKfyve inhibitor, against multiple myeloma was initially identified in an unbiased in vitro chemical library screen. Activity was confirmed in all 25 cell lines tested and 40% of 100 ex vivo patient derived primary samples, and positively correlated with samples harboring trisomies and inversely related to t(11;14). The broad anti- multiple myeloma activity of PIKfyve inhibitors was further demonstrated in confirmatory screens and showed the superior potency of APY0201 when compared to the PIKfyve inhibitors YM201636 and apilimod, with a mid-point EC50 at nanomolar concentrations respectively in 65%, 40%, and 5% of the tested cell lines. An up-regulation of genes in the lysosomal pathway and increased cellular vacuolization was observed in vitro in cell lines following APY0201 treatment however this cellular response did not correlate well with responsiveness. We confirm that PIKfyve inhibition is associated with activation of the transcription factor EB, a master regulator of lysosomal biogenesis and autophagy. Furthermore, we established an assay measuring autophagy as a predictive marker of APY0201 sensitivity. Overall, these findings suggest promising activity of PIKfyve inhibitors secondary to disruption of autophagy in multiple myeloma and a strategy to enrich for likely responders.
2019-09-19 | GSE134598 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a disease characterized by aggressive metastasis and resistance to therapy, making clinical management a significant challenge. As cancer progresses, developmental signals are often aberrantly re-activated, driving the self-renewal of cancer cells and malignant features of disease. Given the central role for epigenetic regulation in development, we hypothesized that epigenetic factors may be required to sustain the self-renewal of pancreatic cancer cells. Here, we used a functional screen to identify Smarcd3, a component of the SWI/SNF (BAF) nucleosome remodeling complex, as a novel functional dependency in PDAC. SWI/SNF coordinates context-specific gene regulation in development and is frequently dysregulated in cancer. However, Smarcd3 has not been linked to functions in PDAC and represents a new epigenetic mediator of cancer function. We found that Smarcd3 was uniquely up-regulated in PDAC stem cells and was required for the in vivo propagation of mouse and patient-derived tumors. Furthermore, using integrated RNA-seq, ChIP-seq, and network analysis we showed that Smarcd3 regulates global SWI/SNF binding and histone acetylation, driving the epigenetic regulation of lipid metabolic programs. Specifically, we found that Smarcd3 regulated genes converging on fatty acid metabolism, which has been directly implicated in stem signaling in PDAC. Collectively, these data identify Smarcd3 as a critical novel dependency and epigenetic regulator of lipid metabolism pancreatic cancer.
2022-11-18 | GSE168490 | GEO
Project description:Mechanisms controlling the proliferative activity of neural stem/progenitor cells (NSPCs) play a pivotal role to ensure life-long neurogenesis in the mammalian brain. How metabolic programs are coupled with NSPC activity remains unknown. Here we show that fatty acid synthase (FASN), the key enzyme of de novo lipogenesis, is highly active in adult NSPCs and that conditional deletion of FASN in NSPCs impairs adult neurogenesis. The rate of de novo lipid synthesis and subsequent proliferation of NSPCs is regulated by Spot14, a gene we found to be selectively expressed in low proliferating adult NSPCs. Spot14 reduces the availability of malonyl-CoA, which is an essential substrate for FASN to fuel lipogenesis. Thus, we here identified a functional coupling between the regulation of lipid metabolism and adult NSPC proliferation. 6 samples were analyzed. Spot14+: Spot14 GFP positive mouse neural stem cell, 3 biological rep Spot14-: Spot14 GFP negative mouse neural stem cell, 3 biological rep
2012-11-02 | E-GEOD-27391 | biostudies-arrayexpress
Project description:In order to gain insight into hepatic metabolic pathways and key transcripts affecting traits related to body composition we aimed to compare samples of pigs of two breeds, the âobeseâ German Landrace (DL) and the âleanâ Pietrain (Pi) obtained at prenatal stages (35, 63, and 91 days post conceptionem) and at adult age (180 days). In terms of number of genes regulated the most striking differences between DL and Pi were found at adult age with upregulation of key genes of lipid biosynthesis/metabolism pathways (FASN, ACSS2, ACACA) in obese DL pigs on the one hand and upregulation of genes of cell growth and/or maintenance, protein syntheses as well as cell proliferation pathways (PPARD, POU1F1, IGF2R) in lean Pi pigs on the other hand. Time course analysis of expression profiles of breed differences from foetal to adult stage and functional cluster analysis of the biological processes confirmed the trend of differences between genetically different obese and lean breeds. The highlighted classes of genes showed common breed-typical expression throughout prenatal development and at adult age. The transcriptional differences between obese and lean pigs involving lipid pathways and cell activity are already initiated during early prenatal development. The information about genetic differences between obese and lean pigs reveals a number of functional candidate genes for traits related to obesity and leaness. Porcine liver from three prenatal stages (35, 63, and 91 day post conceptionem, dpc) plus adult age (180 days) of 10 animals of each of the breeds DL and Pi, which differ in body composition, were collected. The hepatic gene expression patterns of DL and Pi breeds were compared at each of the four stages of development. Three or four biological replicate microarray hybridisations were performed for each stage with DL pools labelled with Cy5 and Pi pools labelled with Cy3.
2010-06-30 | E-GEOD-5399 | biostudies-arrayexpress