Targeting the lipid metabolism proteins FASN and GPAM in alveolar type II cells decreases lung metastasis
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE318532 | GEO | 2026/02/10
REPOSITORIES: GEO
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Project description:Targeting the lipid metabolism proteins FASN and GPAM in alveolar type II cells decreases lung metastasis
| PRJNA1419183 | ENA
Project description:When tumor cells colonize distant organs during metastasis, they interact extensively with surrounding cells. These interactions often change the behavior of surrounding cell populations which collectively induce a pro-tumor microenvironment that permits tumor cell outgrowth into overt, clinically detectable metastatic disease. The lung is one of the most common sites of breast cancer (BC) metastasis. A chronic wound repair-related phenotype developed within the lung microenvironment during metastatic outgrowth in immunocompetent preclinical mouse models of BC. This phenotype was characterized by an increased number and activation of lung type II alveolar epithelial (AT2) cells surrounding growing metastases. Metastatic outgrowth significantly changed AT2 gene expression, resulting in a modified secretome. AT2-derived secreted factors also promote triple-negative breast cancer (TNBC) growth. AT2 secreted factors are regulated by the cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB). Targeting CREB signaling with the phosphodiesterase 4 (PDE4) inhibitor roflumilast reduced AT2-BC reciprocal interactions in vitro and metastatic outgrowth in vivo. Finally, AT2 cells adjacent to metastases in lungs from patients with metastatic BC express higher PDE4B compared to AT2 cells in normal lungs. Alveolar epithelial cells are the most common cell type in the lung. Our studies demonstrate the potential for targeting metastasis-associated wound repair and lung epithelial cell activation during metastatic outgrowth with FDA-approved PDE4 inhibitors. This strategy may be an effective way to treat and manage progression of established metastatic BC within the lung.
2026-03-04 | GSE319843 | GEO
Project description:When tumor cells colonize distant organs during metastasis, they interact extensively with surrounding cells. These interactions often change the behavior of surrounding cell populations which collectively induce a pro-tumor microenvironment that permits tumor cell outgrowth into overt, clinically detectable metastatic disease. The lung is one of the most common sites of breast cancer (BC) metastasis, and alveolar epithelial cells are the most common cell type in the lung. A gap in our ability to treat patients with established lung metastases lies in our lack of knowledge regarding how the lung microenvironment is remodeled during metastatic outgrowth and how this contributes to disease progression. Immunocompetent preclinical mouse models of BC metastasis were used to study late-stage lung metastatic outgrowth, the stage at which most patients are diagnosed with metastatic disease. A custom imaging panel was developed to quantify lung wound repair and inflammation, and single-cell RNA-sequencing (scRNAseq) was performed on mouse lungs with high or low metastatic burden to identify cell-type specific genes altered during metastatic outgrowth. No-contact co-culture experiments were used to examine reciprocal paracrine interactions between lung type II alveolar epithelial (AT2) cells and BC cells. A chronic wound repair-related phenotype developed within the lung microenvironment during metastatic outgrowth, which was characterized by an increased number and activation of AT2 cells surrounding growing metastases. scRNAseq of lungs with a high versus low metastatic burden showed that metastatic outgrowth significantly changed AT2 gene expression, resulting in a modified secretome. No-contact co-culture experiments indicated that BC-derived secreted factors alter AT2 gene expression, while AT2-derived secreted factors promoted TNBC growth. We investigated the possible mechanism(s) responsible for these effects and found that AT2 secreted factor genes, regulated by the cAMP response element-binding protein (CREB), contribute to BC proliferation. Targeting CREB signaling with the phosphodiesterase 4 (PDE4) inhibitor roflumilast reduced AT2-BC reciprocal interactions in vitro and metastatic outgrowth in vivo. Our studies demonstrate the potential for targeting metastasis-associated wound repair and lung epithelial cell activation with PDE4 inhibitors. This strategy may be an effective way to treat and manage metastatic BC progression in established, clinically detectable disease.
2026-03-06 | GSE294453 | GEO
Project description:Dysregulated lipid metabolism is an oncogenic mechanism that leads to increased de novo fatty acid biosynthesis via elevated expression of fatty acid synthase (FASN) in cancer. FASN catalyzes biosynthesis of (C16) palmitic acid by using Acetyl CoA, malonyl CoA and NADPH as substrates. Palmitic acid and its derivatives participate as signaling lipids andinvolved in the regulation of receptor functions associated with many biological processes. and furtherThis includes contribute formation of cell structures, and all these processes which are essential for both normal and malignant cell growth and proliferation. In this study, we investigated the biological impact of FASN inhibition in B cell Non Hodgkin Lymphoma (bNHL) cells using FASN inhibitors Cerulenin and other novel agents (TVB3166, TVB3567). Inhibition of FASN resulted in a dose dependent increase in cell death and apoptosis in the bNHL and primary tumor cells. Transcriptomic and comprehensive systems biology analysis of cerulenin, TVB3166 or TVB3567 treated bNHL cells revealed conserved activation of (TNF) immune and PI3K signaling, and inhibition of cell cycle pathways as prominent responses to FASN inhibition. Cell fractionation and western blot analysis of cCerulenin treated cells showed translocation of TNF receptor adaptor proteins (TRAF2 and RIP), docking of AKT and PI3K/p110 subunits to cell membrane and activation of PI3K/AKT pathways by phosphorylation in SUDHL2 and SUDHL4 bNHL cells, while these mechanisms were constitutively active in cerulenin treated SUDHL10 bNHL cells. Disruption of lipid raft formation by methyl β cyclodextrin inhibited PI3K signaling and downregulated FASN expression in SUDHL10 cells. Subsequently, we observed that combination of FASN (cerulenin) and PI3K (Buparlisib) inhibitors resulted in synergistic cell death in bNHL cell lines and increased apoptosis accompanied with down-regulation of FASN expression in bNHL cell lines and primary cells, implicating the importance of PI3K in the regulation of lipid metabolism. Further mass spectrometric evaluation of cerulenin and Buparlisib treated DLBCL cells fed with C14C glucose, synergistically decreased the biosynthesis of palmitic acid and its derivatives compared to single agent treatments. Our conclusions from these investigations suggest that simultaneous blocking of PI3K and FASN is likely to exert stronger inhibition of lipid metabolism and enhance cell death in lymphoma.
2018-02-01 | GSE102764 | GEO
Project description:Dysregulated lipid metabolism is an oncogenic mechanism that leads to increased de novo fatty acid biosynthesis via elevated expression of fatty acid synthase (FASN) in cancer. FASN catalyzes biosynthesis of (C16) palmitic acid by using Acetyl CoA, malonyl CoA and NADPH as substrates. Palmitic acid and its derivatives participate as signaling lipids andinvolved in the regulation of receptor functions associated with many biological processes. and furtherThis includes contribute formation of cell structures, and all these processes which are essential for both normal and malignant cell growth and proliferation. In this study, we investigated the biological impact of FASN inhibition in B cell Non Hodgkin Lymphoma (bNHL) cells using FASN inhibitors Cerulenin and other novel agents (TVB3166, TVB3567). Inhibition of FASN resulted in a dose dependent increase in cell death and apoptosis in the bNHL and primary tumor cells. Transcriptomic and comprehensive systems biology analysis of cerulenin, TVB3166 or TVB3567 treated bNHL cells revealed conserved activation of (TNF) immune and PI3K signaling, and inhibition of cell cycle pathways as prominent responses to FASN inhibition. Cell fractionation and western blot analysis of cCerulenin treated cells showed translocation of TNF receptor adaptor proteins (TRAF2 and RIP), docking of AKT and PI3K/p110 subunits to cell membrane and activation of PI3K/AKT pathways by phosphorylation in SUDHL2 and SUDHL4 bNHL cells, while these mechanisms were constitutively active in cerulenin treated SUDHL10 bNHL cells. Disruption of lipid raft formation by methyl β cyclodextrin inhibited PI3K signaling and downregulated FASN expression in SUDHL10 cells. Subsequently, we observed that combination of FASN (cerulenin) and PI3K (Buparlisib) inhibitors resulted in synergistic cell death in bNHL cell lines and increased apoptosis accompanied with down-regulation of FASN expression in bNHL cell lines and primary cells, implicating the importance of PI3K in the regulation of lipid metabolism. Further mass spectrometric evaluation of cerulenin and Buparlisib treated DLBCL cells fed with C14C glucose, synergistically decreased the biosynthesis of palmitic acid and its derivatives compared to single agent treatments. Our conclusions from these investigations suggest that simultaneous blocking of PI3K and FASN is likely to exert stronger inhibition of lipid metabolism and enhance cell death in lymphoma.
2018-02-01 | GSE102760 | GEO
Project description:Dysregulated lipid metabolism is an oncogenic mechanism that leads to increased de novo fatty acid biosynthesis via elevated expression of fatty acid synthase (FASN) in cancer. FASN catalyzes biosynthesis of (C16) palmitic acid by using Acetyl CoA, malonyl CoA and NADPH as substrates. Palmitic acid and its derivatives participate as signaling lipids andinvolved in the regulation of receptor functions associated with many biological processes. and furtherThis includes contribute formation of cell structures, and all these processes which are essential for both normal and malignant cell growth and proliferation. In this study, we investigated the biological impact of FASN inhibition in B cell Non Hodgkin Lymphoma (bNHL) cells using FASN inhibitors Cerulenin and other novel agents (TVB3166, TVB3567). Inhibition of FASN resulted in a dose dependent increase in cell death and apoptosis in the bNHL and primary tumor cells. Transcriptomic and comprehensive systems biology analysis of cerulenin, TVB3166 or TVB3567 treated bNHL cells revealed conserved activation of (TNF) immune and PI3K signaling, and inhibition of cell cycle pathways as prominent responses to FASN inhibition. Cell fractionation and western blot analysis of cCerulenin treated cells showed translocation of TNF receptor adaptor proteins (TRAF2 and RIP), docking of AKT and PI3K/p110 subunits to cell membrane and activation of PI3K/AKT pathways by phosphorylation in SUDHL2 and SUDHL4 bNHL cells, while these mechanisms were constitutively active in cerulenin treated SUDHL10 bNHL cells. Disruption of lipid raft formation by methyl β cyclodextrin inhibited PI3K signaling and downregulated FASN expression in SUDHL10 cells. Subsequently, we observed that combination of FASN (cerulenin) and PI3K (Buparlisib) inhibitors resulted in synergistic cell death in bNHL cell lines and increased apoptosis accompanied with down-regulation of FASN expression in bNHL cell lines and primary cells, implicating the importance of PI3K in the regulation of lipid metabolism. Further mass spectrometric evaluation of cerulenin and Buparlisib treated DLBCL cells fed with C14C glucose, synergistically decreased the biosynthesis of palmitic acid and its derivatives compared to single agent treatments. Our conclusions from these investigations suggest that simultaneous blocking of PI3K and FASN is likely to exert stronger inhibition of lipid metabolism and enhance cell death in lymphoma.
2018-02-01 | GSE102791 | GEO
Project description:Lipid uptake occurs through caveolae, plasma membrane invaginations formed by caveolins (CAV) and caveolae-associated protein 1 (CAVIN1). Genetic alterations of CAV1N1 and CAV1 modify lipid metabolism and underpin lipodystrophy syndromes. Lipids contribute to tumorigenesis by providing fuel to cancer metabolism and supporting growth and signaling. Tumor stroma supports tumor proliferation, invasion and metastasis but how stromal lipids influence these processes remain to be defined. Here we show that stromal CAVIN1 regulates lipid abundance in the prostate cancer microenvironment and suppresses metastasis. We show that depletion of CAVIN1 in prostate stromal cells markedly reduces their lipid droplet accumulation and increases inflammation.
2022-01-19 | GSE146229 | GEO
Project description:The molecular mechanisms underlying the development of bone metastases in breast cancer remain unclear. Disseminated tumour cells (DTCs) in the bone marrow of breast cancer patients are commonly identified, even in early stage disease, but their potential to initiate metastases is not known. The mechanism whereby DTCs become overt metastatic tumour cells (MTCs) is therefore, an area of considerable interest. This study explored the analysable yield of genetic material from human biopsy samples in order to describe differences in gene expression between DTCs and bone MTCs. Thirteen breast cancer patients with bone metastases underwent a CT-guided bone metastasis biopsy and a bone marrow biopsy. Tumour cells were enriched and gene expression profiling was conducted to identify differentially expressed genes. The analysable yield of sufficient RNA for microarray analysis was 60% from bone metastasis biopsies and 80% from bone marrow biopsies. A signature of 133 candidate genes differentially expressed between DTCs and MTCs was identified. Several genes relevant to breast cancer metastasis to bone (osteopontin, CTGF, parathyroid hormone receptor, EGFR) were significantly overexpressed in MTCs as compared to DTCs. Biopsies of bone metastases and bone marrow rarely yield enough tissue for robust molecular biology studies using clinical samples. The findings obtained however are interesting and seem to overlap with the bone metastasis gene expression signature described in murine xenograft models. Larger biopsy specimens or improved RNA extraction techniques may improve analysable yield and feasibility of these techniques. Gene expression profiling was utilized to compare DTCs obtained from bone marrow aspirates (A) to MTCs isolated from Computed Tomography (C) guided biopsies of bone metastases.
2012-07-05 | E-GEOD-14776 | biostudies-arrayexpress
Project description:Failure of neural stem/progenitor cell (NSPC) activity and subsequently neurogenesis during brain development has been linked to cognitive impairment and intellectual disability. However, it remains unclear if changes in metabolism, recently discovered as a key regulator of somatic stem cell activity, contribute to altered neurogenesis and cognitive deficits in humans. To investigate a link between NSPC-associated lipid metabolism and brain development, we generated mice and human embryonic stem cells (hESCs) mimicking a variant in fatty acid synthase (FASN; R1819W), a metabolic regulator of rodent NSPC activity recently identified in humans with intellectual disability. Mice homozygous for the FASN R1812W variant have impaired hippocampal NSPC activity associated with cognitive impairment due to presumed toxic accumulation of lipids in NSPCs and subsequent lipogenic ER stress. Human NSPCs homozygous for the FASN R1819W variant show reduced rates of proliferation in embryonic 2D cultures and 3D forebrain regionalized organoids, revealing that the functional significance of lipid metabolism for neurogenic proliferation of progenitors is conserved between rodents and humans. By taking a disease modeling approach, using mouse and human tissue genome engineering, our data provide genetic evidence for a link between altered lipid metabolism, NSPC activity and brain function.
2020-03-18 | GSE115851 | GEO
Project description:E3 ubiquitin-ligases are important for the cellular protein homeostasis and their deregulation is implicated in cancer. The E3 ubiquitin-ligase Hakai is involved in tumour progression and metastasis, through the regulation of the tumour suppressor E-cadherin. Hakai is overexpressed in colon cancer, however, the implication in colitis-associated cancer is unknown. Here, we investigated the potential role of Hakai in intestinal inflammation and cancer bowel disease.Several mouse models of colitis and associated cancer were used including AOM-DSS, acute colitis, and genetically modified mice deficient for the IL-10 gene, to analyse Hakai expression by immunohistochemistry. Interactome analysis of Hakai was performed and effect on selected protein was determined by plasmid and siRNA transfection, western-blotting, immunoprecipitation, immunofluorescence and ubiquitination assays. Lipid accumulation was assayed by oil red staining. Immunohistochemistry was also performed in inflamed colon biopsies from ulcerative colitis, Crohn's disease and colorectal cancer patients. Our results show that Hakai was downregulated in inflammatory tissues in different mouse models. Fatty Acid Synthase (FASN) protein was identified as a novel Hakai-interacting protein. Hakai induces FASN ubiquitination and degradation via lysosome, thus regulating FASN-mediated lipid accumulation. An inverse expression of FASN with Hakai expression was detected in inflammatory AOM/DSS mouse model. In conclusion, Hakai regulates FASN ubiquitination and degradation, resulting in the regulation of FASN-mediated lipid accumulation, which is associated to the development of inflammatory bowel disease. The interaction between Hakai and FASN may be an important mechanism for the homeostasis of intestinal barrier function and in the pathogenesis of this disease.
2022-10-25 | PXD029136 | Pride