SOAT1 knock-out downregulates the expression of mevalonate pathway genes in PDAC organoids
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA594605 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10620100_1.fastq.gz | Fastqsanger.gz | |||
| SRR10620100_2.fastq.gz | Fastqsanger.gz | |||
| SRR10620101_1.fastq.gz | Fastqsanger.gz | |||
| SRR10620101_2.fastq.gz | Fastqsanger.gz | |||
| SRR10620102_1.fastq.gz | Fastqsanger.gz |
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Project description:One of the emerging cancer vulnerabilities is altered metabolism, and several metabolic pathways have been shown to promote pancreatic ductal adenocarcinoma (PDAC). Here we use genetic targeting to delete SOAT1 from murine PDAC metastasis organoids, and use RNA-seq to identify genes differentially regulated in normal and cholesterol-supplemented media conditions in the presence or absence of SOAT1.
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Project description:Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, and new therapies are needed. Altered metabolism is a cancer vulnerability, and several metabolic pathways have been shown to promote PDAC. However, the changes in cholesterol metabolism and their role during PDAC progression remain largely unknown. Here we used organoid and mouse models to determine the drivers of altered cholesterol metabolism in PDAC and the consequences of its disruption on tumor progression. We identified sterol O-acyltransferase 1 (SOAT1) as a key player in sustaining the mevalonate pathway by converting cholesterol to inert cholesterol esters, thereby preventing the negative feedback elicited by unesterified cholesterol. Genetic targeting of Soat1 impairs cell proliferation in vitro and tumor progression in vivo and reveals a mevalonate pathway dependency in p53 mutant PDAC cells that have undergone p53 loss of heterozygosity (LOH). In contrast, pancreatic organoids lacking p53 mutation and p53 LOH are insensitive to SOAT1 loss, indicating a potential therapeutic window for inhibiting SOAT1 in PDAC.
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Project description:Signaling by fibroblast growth factor receptors (FGFRs) is active in up to 85% of breast cancers and results in enhanced proliferation, migration, and invasion of tumor cells. Here, we show that FGFR signaling regulates cholesterol metabolism in breast cancer. Specifically, we demonstrate that FGFR signaling promotes cellular cholesterol storage by upregulating expression of the enzyme sterol O-acyltransferase 1 (SOAT1). Moreover, we demonstrate that inhibition of SOAT1 attenuates FGFR-driven colony formation and invasion in tumor cells. Finally, we identify a relationship between SOAT1 inhibition and decreased integrin expression and fibronectin binding by tumor cells. Taken together, these findings suggest a previously undiscovered metabolic role for FGFR signaling in breast cancer and present a therapeutic vulnerability that could be targeted in FGFR-driven breast cancer.
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Project description:Simvastatin has been widely used for treatment of hypercholesterolemia due to its ability to inhibit HMG-CoA reductase, the rate limiting enzyme of de novo cholesterol synthesis via mevalonate pathway. Its inhibitory action causes also depletion of pathway intermediates, farnesyl pyrophosphate (FPP) and geranyl-geranyl pyrophosphate (GGPP), which are inevitable for proper targeting of small GTPases (e.g. Ras proteins) to their site of action. We profiled by array the gene expression of MIA PaCa-2 cells treated with simvastatin, FPP, GGPP and their combinations. The inhibitory effect of statins on GFP-K-Ras protein trafficking were partially prevented by addition of the mevalonate pathway intermediates. We conclude that the anticancer effect of simvastatin is to a large extent mediated through isoprenoid intermediates of the mevalonate pathway.
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Project description:SOAT1 (sterol O-acyltransferase 1) serves as a cancer stem cell-specific immune checkpoint that facilitates trans-cellular signaling through the release of 20-Hydroxycholesterol (20-OHC) and subsequent activation of GPR132 on regulatory T cells (Tregs). This pathway plays a crucial role in modulating the tumor immune microenvironment and can significantly influence the balance between immune activation and suppression. In the context of cancer, SOAT1 is instrumental in regulating the cholesterol metabolism of cancer stem cells. When SOAT1 is inhibited, there is an increase in the secretion of 20-OHC by tumor cells. This oxysterol not only functions as a signaling molecule but also acts as a ligand that binds to GPR132, a G protein-coupled receptor primarily expressed on immune cells, including Tregs. This binding triggers a cascade of intracellular signaling pathways that ultimately enhances the immunosuppressive functions of Tregs. Mechanistically, the activation of GPR132 by 20-OHC leads to downstream signaling events that may involve pathways such as JAK-STAT and PKC signaling, promoting the development and survival of Tregs while enabling them to exert their immunosuppressive effects within the tumor microenvironment. This results in the downregulation of effector T cell activities and impairs the maturation and activation of dendritic cells (DCs), which are pivotal for effective anti-tumor immune responses. The presence of Tregs, particularly in elevated frequencies within tumors, can contribute to an immunosuppressive environment that protects cancer cells from immune-mediated destruction. Thus, the SOAT1-20OHC-GPR132 axis represents a critical mechanism through which cancer cells can evade immune surveillance. By controlling cholesterol metabolism through SOAT1, tumors can manipulate the availability of 20-OHC, amplifying the immunosuppressive capacity of Tregs and facilitating an environment conducive to tumor growth and progression. Targeting SOAT1 and the associated 20-OHC signaling pathway may offer a promising therapeutic strategy to neutralize Treg-mediated immunosuppression. Inhibiting SOAT1 not only disrupts the tumor's ability to produce 20-OHC but also potentially reprograms the immune landscape, promoting a more activated and effective anti-tumor immune response. Overall, SOAT1's dual role as a cancer stem cell-specific immune checkpoint and its involvement in the trans-cellular signaling of 20-OHC make it a valuable target for innovative cancer immunotherapies aimed at enhancing immune recognition and attack on cancer cells.
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Project description:SOAT1 (sterol O-acyltransferase 1) serves as a cancer stem cell-specific immune checkpoint that facilitates trans-cellular signaling through the release of 20-Hydroxycholesterol (20-OHC) and subsequent activation of GPR132 on regulatory T cells (Tregs). This pathway plays a crucial role in modulating the tumor immune microenvironment and can significantly influence the balance between immune activation and suppression. In the context of cancer, SOAT1 is instrumental in regulating the cholesterol metabolism of cancer stem cells. When SOAT1 is inhibited, there is an increase in the secretion of 20-OHC by tumor cells. This oxysterol not only functions as a signaling molecule but also acts as a ligand that binds to GPR132, a G protein-coupled receptor primarily expressed on immune cells, including Tregs. This binding triggers a cascade of intracellular signaling pathways that ultimately enhances the immunosuppressive functions of Tregs. Mechanistically, the activation of GPR132 by 20-OHC leads to downstream signaling events that may involve pathways such as JAK-STAT and PKC signaling, promoting the development and survival of Tregs while enabling them to exert their immunosuppressive effects within the tumor microenvironment. This results in the downregulation of effector T cell activities and impairs the maturation and activation of dendritic cells (DCs), which are pivotal for effective anti-tumor immune responses. The presence of Tregs, particularly in elevated frequencies within tumors, can contribute to an immunosuppressive environment that protects cancer cells from immune-mediated destruction. Thus, the SOAT1-20OHC-GPR132 axis represents a critical mechanism through which cancer cells can evade immune surveillance. By controlling cholesterol metabolism through SOAT1, tumors can manipulate the availability of 20-OHC, amplifying the immunosuppressive capacity of Tregs and facilitating an environment conducive to tumor growth and progression. Targeting SOAT1 and the associated 20-OHC signaling pathway may offer a promising therapeutic strategy to neutralize Treg-mediated immunosuppression. Inhibiting SOAT1 not only disrupts the tumor's ability to produce 20-OHC but also potentially reprograms the immune landscape, promoting a more activated and effective anti-tumor immune response. Overall, SOAT1's dual role as a cancer stem cell-specific immune checkpoint and its involvement in the trans-cellular signaling of 20-OHC make it a valuable target for innovative cancer immunotherapies aimed at enhancing immune recognition and attack on cancer cells.
2025-12-08 | GSE286015 | GEO
Project description:SOAT1 (sterol O-acyltransferase 1) serves as a cancer stem cell-specific immune checkpoint that facilitates trans-cellular signaling through the release of 20-Hydroxycholesterol (20-OHC) and subsequent activation of GPR132 on regulatory T cells (Tregs). This pathway plays a crucial role in modulating the tumor immune microenvironment and can significantly influence the balance between immune activation and suppression. In the context of cancer, SOAT1 is instrumental in regulating the cholesterol metabolism of cancer stem cells. When SOAT1 is inhibited, there is an increase in the secretion of 20-OHC by tumor cells. This oxysterol not only functions as a signaling molecule but also acts as a ligand that binds to GPR132, a G protein-coupled receptor primarily expressed on immune cells, including Tregs. This binding triggers a cascade of intracellular signaling pathways that ultimately enhances the immunosuppressive functions of Tregs. Mechanistically, the activation of GPR132 by 20-OHC leads to downstream signaling events that may involve pathways such as JAK-STAT and PKC signaling, promoting the development and survival of Tregs while enabling them to exert their immunosuppressive effects within the tumor microenvironment. This results in the downregulation of effector T cell activities and impairs the maturation and activation of dendritic cells (DCs), which are pivotal for effective anti-tumor immune responses. The presence of Tregs, particularly in elevated frequencies within tumors, can contribute to an immunosuppressive environment that protects cancer cells from immune-mediated destruction. Thus, the SOAT1-20OHC-GPR132 axis represents a critical mechanism through which cancer cells can evade immune surveillance. By controlling cholesterol metabolism through SOAT1, tumors can manipulate the availability of 20-OHC, amplifying the immunosuppressive capacity of Tregs and facilitating an environment conducive to tumor growth and progression. Targeting SOAT1 and the associated 20-OHC signaling pathway may offer a promising therapeutic strategy to neutralize Treg-mediated immunosuppression. Inhibiting SOAT1 not only disrupts the tumor's ability to produce 20-OHC but also potentially reprograms the immune landscape, promoting a more activated and effective anti-tumor immune response. Overall, SOAT1's dual role as a cancer stem cell-specific immune checkpoint and its involvement in the trans-cellular signaling of 20-OHC make it a valuable target for innovative cancer immunotherapies aimed at enhancing immune recognition and attack on cancer cells.
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Project description:Metastasis is an important factor affecting the prognosis and survival of bladder cancer (BLCA) patients. Our previous study found that the mevalonate pathway is associated with the migratory ability of bladder cancer cells, but the exact mechanism is unclear. Here, we found that BLCA patients with mevalonate pathway activation had a poorer prognosis. Inhibition of the mevalonate pathway (simvastatin or zoledronic acid) resulted in a significant decrease in the migratory ability of BLCA cells. Therefore, we used proteomics to detect simvastatin- or zoledronic acid-treated BLCA cells to explore the effect of the mevalonate pathway on key proteins in BLCA cells.
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