Fibroblast growth factor receptor signaling modulates cholesterol storage in a SOAT1-dependent manner to promote mammary tumor cell invasion
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PROVIDER: PRJNA1158773 | ENA |
REPOSITORIES: ENA
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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.
2025-07-07 | GSE276731 | GEO
Project description:The mammalian Endoplasmic Reticulum Membrane protein Complex (mEMC) is an evolutionarily conserved hetero-oligomer whose function and mechanism of action remain elusive. Here we identify a multi-layered contribution of the mEMC to post-translational regulation of cholesterol homeostasis. Mammalian cells employ elaborate sensing and feedback mechanisms to balance free and stored cholesterol through biosynthesis, uptake, efflux and storage. We show that mEMC biogenesis is a prerequisite for optimal maturation of at least two key ER-resident sterol regulatory enzymes: squalene synthase (SQS) and sterol-O-acyltransferase (SOAT1). Without sufficient SQS, mEMC-deficient cells have attenuated cholesterol biosynthetic capability, and loss of SOAT1 significantly reduces the amount of stored cholesteryl esters (CEs). mEMC-deficient cells remain viable, maintaining free cholesterol levels with minimal transcriptional activation of cholesterogenic and uptake pathways by the sterol regulatory element binding protein (SREBP)-2. Consequently, cells lacking the mEMC were susceptible to changes in extracellular cholesterol availability and effectively were transformed into cholesterol auxotrophs. Supplementing mEMC-deficient cells with cholesterol or lanosterol failed to restore SQS or SOAT1. These data are consistent with a direct role for the mEMC in the biogenesis of SQS and SOAT1. The range of phenotypes observed previously with mEMC subunit depletion may result from its impact on fundamental cholesterol homeostatic mechanisms.
2019-01-02 | PXD006603 | Pride
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.
2020-06-16 | GSE141737 | GEO
Project description:Cholesterol performs multiple essential roles in cells. Enhanced cholesterol synthesis and storage in lipid droplets have been linked to cancer aggressiveness, particularly in lipid-rich and hormone-sensitive cancers such as prostate cancer . Cholesterol anabolism and catabolism are finely regulated in tumor cells in response to various nutritional states. Mitochondria have increasingly been recognized as a signal transduction organelle, particularly concerning metabolites derived from mitochondrial activity. The link between mitochondrial regulation and cholesterol synthesis remains inadequately understood. Here, we show that propionyl-CoA promotes cholesterol synthesis, storage, and further progression in prostate cancer cells. We found that propionyl-CoA, mainly produced by isoleucine and valine metabolism in the mitochondria, can translocate through the mitochondrial membrane and serves as a substrate for modifying cleaved SREBP2, stabilizing it and thereby promoting cholesterol synthesis and storage in lipid droplets. This process facilitates cancer metastasis and castration resistant partially through enhancing androgen synthesis in prostate cancer cells. Our results demonstrate that branched-chain amino acid (BCAA) catabolism and propionate metabolism in mitochondria are involved in the regulation of cholesterol synthesis and utilization through metabolite-mediated protein modification. We anticipate that our findings provide a critical link between amino acid metabolism and cholesterol anabolism, highlighting a mechanism that plays a crucial role in the development of castration resistance in prostate cancer patients. This study offers a theoretical rationale for targeting the production of propionyl-CoA, particularly through the metabolism of isoleucine and valine, as an effective strategy to inhibit cholesterol synthesis and its related diseases.
2025-07-11 | GSE272086 | GEO
Project description:SOAT1 knockout enhances the responsiveness of human liver cancers to T cell-based therapies without significantly impacting tumor proliferation. We aimed to elucidate how SOAT1 knockout influences sensitivity to T cell therapy. We performed bulk RNA-seq analysis on SOAT1-KO and vector-transduced Hepa1-6 cells and Huh7 cells.
2025-12-31 | GSE280148 | 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.
2025-12-08 | GSE286092 | 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.
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.
2025-12-08 | GSE309517 | GEO
Project description:Cellular lipid requirements are achieved through a combination of biosynthesis and import programs. Using isotope tracer analysis, we show that type I interferon (IFN) signaling rapidly shifts the balance of these programs by decreasing synthesis and increasing import of cholesterol and long chain fatty acids. Genetically enforcing this metabolic shift in macrophages is sufficient to render mice resistant to viral challenge, demonstrating the importance of reprogramming the balance of these two metabolic pathways in vivo. Unexpectedly, mechanistic studies reveal that limiting flux through the cholesterol biosynthetic pathway spontaneously engages a type I IFN response in a STING-dependent manner. The upregulation of type I IFNs was traced to a decrease in the pool size of synthesized cholesterol, and could be inhibited by replenishing cells with free cholesterol. Taken together, these studies delineate a metabolic-inflammatory circuit that links perturbations in cholesterol biosynthesis with activation of innate immunity. shRNA to SREBF1 (shSREBP1) or SREBF2 (shSREBP2) were stably introduced via 3rd generation lentivirus into human THP1 monocytic cells under puromycin selection. Non-targeting shRNA scramble was used for a control (shControl). shControl, shSREBP1 and shSREBP2 modified cell types were analyzed by RNA-seq in duplicate.
2015-12-10 | E-GEOD-73942 | biostudies-arrayexpress
Project description:Cellular lipid requirements are achieved through a combination of biosynthesis and import programs. Using isotope tracer analysis, we show that type I interferon (IFN) signaling rapidly shifts the balance of these programs by decreasing synthesis and increasing import of cholesterol and long chain fatty acids. Genetically enforcing this metabolic shift in macrophages is sufficient to render mice resistant to viral challenge, demonstrating the importance of reprogramming the balance of these two metabolic pathways in vivo. Unexpectedly, mechanistic studies reveal that limiting flux through the cholesterol biosynthetic pathway spontaneously engages a type I IFN response in a STING-dependent manner. The upregulation of type I IFNs was traced to a decrease in the pool size of synthesized cholesterol, and could be inhibited by replenishing cells with free cholesterol. Taken together, these studies delineate a metabolic-inflammatory circuit that links perturbations in cholesterol biosynthesis with activation of innate immunity.
2015-12-10 | GSE73942 | GEO