Fibroblast growth factor receptor signaling modulates cholesterol storage in a SOAT1-dependent manner to promote mammary tumor cell invasion
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1158773 | ENA |
REPOSITORIES: ENA
Similar Datasets
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: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: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
Project description:Recent findings have shown that inhibitors targeting BET (bromodomain and extraterminal domain) proteins, such as the small molecule JQ1, are potent growth inhibitors of many cancers and hold promise for cancer therapy. However, some reports also have revealed that JQ1 can activate additional oncogenic pathways and may affect EMT (epithelial mesenchymal transition). Therefore, it is important to address the potential unexpected effect of JQ1 treatment, such as cell invasion and metastasis. Here, we showed that in prostate cancer, JQ1 inhibited cancer cell growth but promoted invasion and metastasis in a BET protein independent manner. Multiple invasion pathways including EMT, BMP (bone morphogenetic protein) signaling, chemokine signaling and focal adhesion pathway were activated by JQ1 to promote invasion. Notably, JQ1 induced upregulation of invasion genes through inhibition of FOXA1, an invasion suppressor in prostate cancer. JQ1 directly interacted with FOXA1, inactivated FOXA1 binding to its interacting repressors, TLE3, HDAC7 and NFIC, thus blocking FOXA1 repressive function and activating the invasion genes. Our finding indicates that JQ1 has an unexpected effect of promoting invasion in prostate cancer. Thus, the ill effect of JQ1 or its derived therapeutic agents could not be ignored during cancer treatment, especially in FOXA1 related cancers.
2022-10-01 | GSE139230 | GEO
Project description:Endocrine therapy resistance remains a critical problem in the treatment of estrogen receptor alpha (ERα) breast cancer. Endocrine therapies target ERα via different modes of action. Drug resistance involves drug specific remodeling of the transcriptional and regulatory landscape. Using epigenomics and transcriptomics, we demonstrate that resistance to aromatase inhibitors (AI) induces phenotypical changes through epigenetic activation of cholesterol biosynthesis (CB) and keratin 80. Epigenetic activation is stable and involves both large topological domains and punctuated activation of single enhancers and super-enhancers. Specialized cancer cells expressing high levels of keratin 80 lead invasion through the extracellular matrix. Strikingly, we demonstrate that anti-cholesterol strategies can effectively arrest breast cancer invasion. Our work identifies a robust strategy to target resistant invasive breast cancer. All cell lines were grown in their respective media until they reached 70% confluency. Specifically, MCF7 were grown in DMEM+10% FBS and 1% Pen-Sprep-Glutamine. MCF7T as MCF7 with the addition of 100nM Tamoxifen. MCF7F as MCF7 with the addition of 100nM Fulvestrant. LTED were grown in DMEM without phenol + 10% DCS-FBS and1% Pen-Sprep-Glutamine. LTEDT as LTED with the addition of 100nM Tamoxifen. LTEDF as LTED with the addition of 100nM of Fulvestrant. All chemicals are purchased from Sigma. ChIP-seq was performed using Illumina methodology.
2015-12-31 | E-GEOD-60517 | biostudies-arrayexpress
Project description:Endocrine therapy resistance remains a critical problem in the treatment of estrogen receptor alpha (ERα) breast cancer. Endocrine therapies target ERα via different modes of action. Drug resistance involves drug specific remodeling of the transcriptional and regulatory landscape. Using epigenomics and transcriptomics, we demonstrate that resistance to aromatase inhibitors (AI) induces phenotypical changes through epigenetic activation of cholesterol biosynthesis (CB) and keratin 80. Epigenetic activation is stable and involves both large topological domains and punctuated activation of single enhancers and super-enhancers. Specialized cancer cells expressing high levels of keratin 80 lead invasion through the extracellular matrix. Strikingly, we demonstrate that anti-cholesterol strategies can effectively arrest breast cancer invasion. Our work identifies a robust strategy to target resistant invasive breast cancer.
2015-12-31 | GSE60517 | GEO
Project description:JQ1 promotes invasion in a BET protein independent manner in prostate cancer
| PRJNA578853 | ENA
Project description:The Wnt pathway, which controls crucial steps of the development and differentiation programs, has been proposed to influence lipid storage and homeostasis. In this paper, using an unbiased strategy based on high content genome-wide RNAi screens that monitored lipid distribution and amounts, we find that Wnt3a regulates cellular cholesterol. We show that Wnt3a stimulates the production of lipid droplets, and that this stimulation strictly depends on endocytosed, LDL-derived cholesterol and on functional early and late endosomes. We also show that Wnt signaling itself controls cholesterol endocytosis and flux along the endosomal pathway, which in turn modulates cellular lipid homeostasis. These results underscore the importance of endosome functions for LD formation and reveal a previously unknown cellular program controlling lipid storage and endosome transport under the control of Wnt signaling.
2015-06-20 | E-MTAB-2872 | biostudies-arrayexpress
Project description:Isoleucine and valine promote prostate cancer progression via propionyl-CoA-mediated cholesterol synthesis and storage
| PRJNA1135101 | ENA