Glycosphingolipid synthesis mediates immune evasion in Kras-driven cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE270660 | GEO | 2024/06/30
REPOSITORIES: GEO
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Project description:Cancer cells frequently alter their lipids to grow and adapt to their environment1–3. Despite the critical functions of lipid metabolism in membrane physiology, signaling, and energy production, how specific lipids contribute to tumorigenesis is incompletely understood. Here, using functional genomics and lipidomic approaches, we identified de novo sphingolipid synthesis as an essential pathway for cancer immune evasion. Synthesis of sphingolipids is surprisingly dispensable for cancer cell proliferation in culture or in immunodeficient mice but required for tumor growth in multiple syngeneic models. Blocking sphingolipid production in cancer cells enhances the anti-proliferative effects of natural killer (NK) and CD8+ T cells partly via interferon gamma (IFNg) signaling. Mechanistically, depletion of glycosphingolipids increases surface levels of IFNg receptor subunit 1 (Ifngr1), mediating IFNg-induced growth arrest and proinflammatory signaling. Finally, pharmacological inhibition of glycosphingolipid synthesis synergizes with checkpoint blockade therapy to enhance anti-tumor immune response. Altogether, our work identifies glycosphingolipids as necessary and limiting metabolites for cancer immune evasion.
2024-06-26 | PXD052718 | Pride
Project description:Glycosphingolipid metabolism is reprogrammed during neural development with a switch from globo to ganglio-series glycosphingolipids production. We discovered that globo-series glycosphingolipids repress the epigenetic regulator of neuronal genes expression AUTS2. AUTS2 in turn, binds and activates the promoter of the first and rate limiting ganglioside producing enzyme GM3 synthase, thus fostering the synthesis of gangliosides. By this mechanism the globo-AUTS2 axis controls glycosphingolipid reprogramming and neural genes expression during neural differentiation, which involves this circuit in neurodevelopment and its defects in neuropathology. We report Gb3 globoside suppresses the expression of the epigenetic modulator AUTS2. The silencing of Gb3 synthase in HeLa cells induces the thepletion of Gb3 globoside, consequentially promoting AUTS2 expression. AUTS2 in turn, binds and activates the promoter of the target genes promoting local histone hyperacetylation and gene expression. Thus, the globo-series glycosphingolipids, by counteracting the expression of AUTS2, decrease histone acetylation at neuronal gene promoters repressing their transcription in HeLa cells.
2017-12-22 | GSE107044 | GEO
Project description:The cleavage of sphingoid base phosphates by sphingosine-1-phosphate (S1P) lyase to produce phosphoethanolamine and a fatty aldehyde is the final degradative step in the sphingolipid metabolic pathway. We have studied mice with an inactive S1P lyase gene and have found that, in addition to the expected increase of sphingoid base phosphates, other sphingolipids (including sphingosine, ceramide, and sphingomyelin) were substantially elevated in the serum and /or liver of these mice. This latter increase is consistent with a reutilization of the sphingosine backbone for sphingolipid synthesis due to its inability to exit the sphingolipid metabolic pathway. Furthermore, the S1P lyase deficiency resulted in changes in the levels of serum and liver lipids not directly within the sphingolipid pathway, including phospholipids, triacyglycerol, diacylglycerol, and cholesterol. Even though lipids in serum and lipid storage were elevated in liver, adiposity was reduced in the S1P lyase-deficient mice. Microarray analysis of lipid metabolism genes in liver showed that the S1P lyase deficiency caused widespread changes in their expression pattern. These results demonstrate that S1P lyase is a key regulator of the levels of multiple sphingolipid substrates and reveal functional links between the sphingolipid metabolic pathway and other lipid metabolic pathways that may be mediated by shared lipid substrates and changes in gene expression programs. The disturbance of lipid homeostasis by altered sphingolipid levels may be relevant to metabolic diseases. Experiment Overall Design: RNA samples from liver for three sphingosine-1-phosphate lyase knock-out and three WT mice.
2010-02-05 | E-GEOD-18745 | biostudies-arrayexpress
Project description:The cleavage of sphingoid base phosphates by sphingosine-1-phosphate (S1P) lyase to produce phosphoethanolamine and a fatty aldehyde is the final degradative step in the sphingolipid metabolic pathway. We have studied mice with an inactive S1P lyase gene and have found that, in addition to the expected increase of sphingoid base phosphates, other sphingolipids (including sphingosine, ceramide, and sphingomyelin) were substantially elevated in the serum and /or liver of these mice. This latter increase is consistent with a reutilization of the sphingosine backbone for sphingolipid synthesis due to its inability to exit the sphingolipid metabolic pathway. Furthermore, the S1P lyase deficiency resulted in changes in the levels of serum and liver lipids not directly within the sphingolipid pathway, including phospholipids, triacyglycerol, diacylglycerol, and cholesterol. Even though lipids in serum and lipid storage were elevated in liver, adiposity was reduced in the S1P lyase-deficient mice. Microarray analysis of lipid metabolism genes in liver showed that the S1P lyase deficiency caused widespread changes in their expression pattern. These results demonstrate that S1P lyase is a key regulator of the levels of multiple sphingolipid substrates and reveal functional links between the sphingolipid metabolic pathway and other lipid metabolic pathways that may be mediated by shared lipid substrates and changes in gene expression programs. The disturbance of lipid homeostasis by altered sphingolipid levels may be relevant to metabolic diseases.
2010-01-28 | GSE18745 | GEO
Project description:DUX4 activates the first wave of zygotic gene expression in the early embryo. Mis-expression of DUX4 in skeletal muscle causes facioscapulohumeral dystrophy (FSHD), whereas expression in cancers suppresses IFNg-induction of MHC Class I and contributes to immune evasion. We show that the DUX4 protein broadly suppresses immune signaling pathways—including IFNg, IFNb, DDX58, IFIH1 and cGAS mediated pathways. A conserved region containing (L)LxxL(L) motifs in the DUX4 carboxyterminal domain (CTD) was necessary to suppress interferon stimulated genes (ISGs). Co-immunoprecipitation identified DUX4-CTD interaction with multiple immune signaling factors, including STAT1. The DUX4-CTD (L)LxxL(L) region interacts with phosphorylated STAT1, sequesters it in the nucleus, modestly reduces its DNA binding, and prevents STAT1 from inducing ISG transcription. Mouse Dux similarly interacted with STAT1 and suppressed IFNg induction of ISGs. These findings identify an evolved role of the DUXC family in modulating immune signaling pathways with implications for development, cancers, and FSHD.
2023-05-10 | PXD029215 | Pride
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Project description:Sphingolipids are essential components of eukaryotic cells with important functions in membrane biology and cellular signaling. Their levels are tightly controlled and coordinated with the abundance of other membrane lipids. How sphingolipid homeostasis is achieved is not yet well understood. Studies performed primarily in yeast showed that the phosphorylation states of several enzymes and regulators of sphingolipid synthesis are important, although a global understanding for such regulation is lacking. Here, we used high-resolution mass-spectrometry-based proteomics and phosphoproteomics, in combination with data from a chemical genetic screen, to analyze the cellular response to sphingolipid synthesis inhibition. Our dataset reveals that changes in protein phosphorylation, rather than protein abundance, dominate the response to blocking sphingolipid synthesis. We identified Ypk1 signaling as a major pathway that is activated under these conditions, and we confirmed and identified Ypk1 targets. We also revealed key aspects of the cellular response to sphingolipid deprivation, including nodes that intersect with sterol metabolism and modification of lipid transport. Our data provide a rich resource for on-going mechanistic studies of key elements of the cellular response to the depletion of sphingolipid levels and the maintenance of sphingolipid homeostasis.
2016-12-23 | PXD003854 | Pride
Project description:The genetic circuits that allow cancer cells to evade destruction by the host immune system remain poorly understood. To identify a phenotypically robust core set of genes and pathways that facilitate cancer cell-intrinsic evasion to cytotoxic T lymphocyte (CTL)-mediated killing, we performed genome-wide CRISPR screens across a panel of genetically diverse cancer models cultured in the presence of CTLs. We uncovered a core set of 182 genes whose individual perturbation leads to either cancer cell sensitivity or resistance to CTL toxicity. Systematic exploration of our dataset using genetic co-similarity reveals the hierarchical and coordinated nature by which genes and pathways act to orchestrate intrinsic CTL evasion, with discrete functional modules controlling the interferon response and tumor necrosis factor alpha (TNFa)-induced cytotoxicity emerging as dominant sub-phenotypes. Our data establish a central role for previously identified negative regulators of the Type II interferon response (e.g. Ptpn2, Socs1, Adar1) in mediating intrinsic CTL evasion and demonstrate a requirement for the lipid droplet related gene Fitm2 for maintaining cell fitness upon exposure to interferon gamma (IFNg). Additionally, we identify the autophagy pathway as a conserved mediator of cancer intrinsic CTL evasion, required to resist cytokine-mediated cytotoxicity caused by IFNg and TNFa. By mapping cytokine- and CTL-based genetic interactions, as well as in vivo CRISPR screens, we illuminate the pleiotropic nature by which autophagy acts to orchestrate intrinsic CTL evasion and highlight the importance of our observed effects within the tumor microenvironment. Collectively, our data expands our appreciation of the genetic circuits that contribute to cancer intrinsic immune evasion, highlighting the importance of leveraging systematic functional genomics approaches for furthering our understanding of this biology.
2020-07-31 | GSE153397 | GEO
Project description:The genetic circuits that allow cancer cells to evade destruction by the host immune system remain poorly understood. To identify a phenotypically robust core set of genes and pathways that facilitate cancer cell-intrinsic evasion to cytotoxic T lymphocyte (CTL)-mediated killing, we performed genome-wide CRISPR screens across a panel of genetically diverse cancer models cultured in the presence of CTLs. We uncovered a core set of 182 genes whose individual perturbation leads to either cancer cell sensitivity or resistance to CTL toxicity. Systematic exploration of our dataset using genetic co-similarity reveals the hierarchical and coordinated nature by which genes and pathways act to orchestrate intrinsic CTL evasion, with discrete functional modules controlling the interferon response and tumor necrosis factor alpha (TNFa)-induced cytotoxicity emerging as dominant sub-phenotypes. Our data establish a central role for previously identified negative regulators of the Type II interferon response (e.g. Ptpn2, Socs1, Adar1) in mediating intrinsic CTL evasion and demonstrate a requirement for the lipid droplet related gene Fitm2 for maintaining cell fitness upon exposure to interferon gamma (IFNg). Additionally, we identify the autophagy pathway as a conserved mediator of cancer intrinsic CTL evasion, required to resist cytokine-mediated cytotoxicity caused by IFNg and TNFa. By mapping cytokine- and CTL-based genetic interactions, as well as in vivo CRISPR screens, we illuminate the pleiotropic nature by which autophagy acts to orchestrate intrinsic CTL evasion and highlight the importance of our observed effects within the tumor microenvironment. Collectively, our data expands our appreciation of the genetic circuits that contribute to cancer intrinsic immune evasion, highlighting the importance of leveraging systematic functional genomics approaches for furthering our understanding of this biology.
2020-07-31 | GSE149935 | GEO
Project description:The genetic circuits that allow cancer cells to evade destruction by the host immune system remain poorly understood. To identify a phenotypically robust core set of genes and pathways that facilitate cancer cell-intrinsic evasion to cytotoxic T lymphocyte (CTL)-mediated killing, we performed genome-wide CRISPR screens across a panel of genetically diverse cancer models cultured in the presence of CTLs. We uncovered a core set of 182 genes whose individual perturbation leads to either cancer cell sensitivity or resistance to CTL toxicity. Systematic exploration of our dataset using genetic co-similarity reveals the hierarchical and coordinated nature by which genes and pathways act to orchestrate intrinsic CTL evasion, with discrete functional modules controlling the interferon response and tumor necrosis factor alpha (TNFa)-induced cytotoxicity emerging as dominant sub-phenotypes. Our data establish a central role for previously identified negative regulators of the Type II interferon response (e.g. Ptpn2, Socs1, Adar1) in mediating intrinsic CTL evasion and demonstrate a requirement for the lipid droplet related gene Fitm2 for maintaining cell fitness upon exposure to interferon gamma (IFNg). Additionally, we identify the autophagy pathway as a conserved mediator of cancer intrinsic CTL evasion, required to resist cytokine-mediated cytotoxicity caused by IFNg and TNFa. By mapping cytokine- and CTL-based genetic interactions, as well as in vivo CRISPR screens, we illuminate the pleiotropic nature by which autophagy acts to orchestrate intrinsic CTL evasion and highlight the importance of our observed effects within the tumor microenvironment. Collectively, our data expands our appreciation of the genetic circuits that contribute to cancer intrinsic immune evasion, highlighting the importance of leveraging systematic functional genomics approaches for furthering our understanding of this biology.
2020-07-31 | GSE149933 | GEO