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Downregulation of KEAP1 in melanoma promotes resistance to immune checkpoint blockade [scRNA-seq]

ABSTRACT: Immune checkpoint blockade (ICB) has demonstrated efficacy in patients with melanoma, but many exhibit poor responses. Using single cell RNA sequencing of melanoma patient-derived circulating tumor cells (CTCs) and functional characterization using mouse melanoma models, we show that the KEAP1/NRF2 pathway modulates sensitivity to ICB, independently of tumorigenesis. The NRF2 negative regulator, KEAP1, shows intrinsic variation in expression, leading to tumor heterogeneity and subclonal resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE218429 | GEO | 2023/02/24

REPOSITORIES: GEO

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Downregulation of KEAP1 in melanoma promotes resistance to immune checkpoint blockade [scBisulfite-seq]

Project description:Immune checkpoint blockade (ICB) has demonstrated efficacy in patients with melanoma, but many exhibit poor responses. Using single cell RNA sequencing of melanoma patient-derived circulating tumor cells (CTCs) and functional characterization using mouse melanoma models, we show that the KEAP1/NRF2 pathway modulates sensitivity to ICB, independently of tumorigenesis. The NRF2 negative regulator, KEAP1, shows intrinsic variation in expression, leading to tumor heterogeneity and subclonal resistance.

2023-02-24 | GSE218423 | GEO

Expression data from Keap1 overexpression and Nrf2 knockdown lung cancer cell

Project description:Keap1 overexpressed and Nrf2 depleted CL1-5 cells were used to identify genes regulated by Keap1/Nrf2 axis-dependent gene regulations We used microarrays to detail the global programme of gene expression underlying metastasis and identified distinct classes of Keap1/Nrf2-regulated genes during this process. CL1-5 cells stably expressed Keap1 expressing construct and Nrf2-specific shRNA were analyzed compared to control cells

2015-03-04 | E-GEOD-66473 | biostudies-arrayexpress

Nrf2 sequesters Keap1 preventing podosome disassembly

Project description:Nrf2 is a transcription factor playing an essential role in stress response. A knowledge of the significance of Nrf2 in cell function has not, as yet, reached out beyond transactivation of gene expression. This paper shows that GDF-15 and SDF-1-induced angiogenesis strongly depends on Nrf2 presence, but is not related to its transcriptional activity. We propose, that Nrf2 serves as a protein restraining Keap1, its known transcriptional repressor. Deficiency of Nrf2 protein available for Keap1 leads to overabundance of RhoGAP1, the protein regulating Cdc42 activity, and impairs podosome assembly, thereby indisposing actin rearrangements, preventing migration and angiogenesis. These activities can be rescued by concomitant deletion of RhoGAP1 or Keap1. We suggest that a new Nrf2 function of a Keap1 scavenger implies revising the established murine model of Nrf2 deficiency as a transcriptional knock out (tKO) mouse. The N-terminal fragment of Nrf2, containing Neh2 domain binding Keap1, is present in these animals. Thus, regarding the function of Nrf2 as a protein sequestering Keap1, both published and unpublished data on Nrf2-Keap1 duet may gain new interpretation.

2018-11-28 | PXD009161 | Pride

Patient-derived KEAP1 superbinder mutants stabilize KEAP1 structure and sequester NRF2 in p62-dependent clusters

Project description:Cancer-derived loss-of-function mutations in the KEAP1 tumor suppressor gene stabilize the NRF2 transcription factor, resulting in a pro-survival gene expression program that alters cellular metabolism and neutralizes oxidative stress. In a previous study of KEAP1 mutations observed in lung cancer, we classified 40% of the mutations as ‘superbinders’ (superbinders). These mutants bind and ubiquitylate NRF2 but do not promote NRF2 degradation. Here, we further investigated the molecular mechanism(s) driving the superbinder phenotype. BioID-based quantitative proteomic analysis of the R320Q and R470C superbinder mutations revealed increased co-complexed NRF2 without significant alteration to other KEAP1-associated proteins, including CUL3, VCP, and several ubiquitin receptors within the proteasome lid. Dynamic simulation modeling and limited proteolysis analyses suggest that superbinder mutations stabilize residues in KEAP1 that contact NRF2. In cells, KEAP1 R320Q and R470C mutants co-localize with NRF2, p62/SQSTM1 and polyubiquitin in spherical clusters that rapidly fuse and dissolve; KEAP1-NRF2 localization to these clusters requires p62. Expression of R320Q and R470C in lung cancer cells provided resistance to the reactive oxygen species-inducing drug bleomycin. We present a model wherein superbinder mutations alter the conformational dynamics of the KEAP1-NRF2 complex to alter the cycling of KEAP1 between open and closed conformations, thus inhibiting NRF2 degradation.

2018-11-07 | PXD008411 | Pride

Keap1-dependent gene expression determined in the liver using conditional Keap1 knockout mice vs. genetic control mice

2008-05-01 | GSE11287 | GEO

Transcription profiling of mouse liver from conditional Keap1 knockout mice vs. genetic control mice

Project description:To compare hepatic gene expression in conditional Keap1 knockout (Alb-Cre:Keap1(flox/-)) and genetic control mice. Disruption of Keap1-mediated repression of Nrf2 signaling was expected to result in increased expression of Nrf2-regulated genes. Experiment Overall Design: Hepatic gene expression was compared in conditional Keap1 knockout and genetic control mice (Alb-Cre:Keap1(flox/+)) mice. Male 9 week old mice were used, n=3/group.

2008-06-11 | E-GEOD-11287 | biostudies-arrayexpress

Expression data from Keap1 overexpression and Nrf2 knockdown lung cancer cell

2015-03-04 | GSE66473 | GEO

Characterization of RA839, a non-covalent small-molecule binder to Keap1 and selective activator of Nrf2 signalling

Project description:The activation of the transcription factor NF-E2-related factor 2 (Nrf2) maintains cellular homeostasis in response to oxidative stress by the regulation of multiple cytoprotective genes. Without stressors the activity of Nrf2 is inhibited by its interaction with the kelch-like ECH-associated protein 1 (Keap1). Here, we describe RA839, a small molecule that binds non-covalently to the Nrf2-interacting kelch domain of Keap1 with a Kd of approximately 6 µM, as demonstrated by X-ray co-crystallization and isothermal titration calorimetry. Whole-genome DNA arrays showed that at 10 µM RA839 significantly regulated 105 genes in bone marrow-derived macrophages. Canonical pathway mapping of these genes revealed an activation of pathways linked with Nrf2 signalling. These pathways were also activated after the activation of Nrf2 by the silencing of Keap1 expression. RA839 regulated only two genes in Nrf2 knockout macrophages. Similar to the activation of Nrf2 by either silencing of Keap1 expression or by the reactive compound CDDO-Me, RA839 prevented the induction of both inducible nitric oxide synthase expression and nitric oxide release in response to lipopolysaccharides in macrophages. In mice RA839 acutely induced Nrf2-target gene expression in liver. RA839 is a selective inhibitor of the Keap1/Nrf2 interaction and a useful tool compound to study the biology of Nrf2. Gene expression profile of bone marrow derived murine macrophages (BMDM) from Nrf2+/+ or Nrf2-/- mice treated with RA838, siKeap1-1 or siKeap1-2 were compared to untreated DMSO control or siControl. Four biological replicates were used for each sample group.

2015-10-31 | E-GEOD-71695 | biostudies-arrayexpress

Transcription profiling of mouse Keap1-null (CKO) to investigate genetic and pharmacologic activation of Nrf2 signaling

Project description:Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct hepatic gene expression profiles between Keap1 knockout and triterpenoid treated mice; Loss of Nrf2 signaling increases susceptibility to acute toxicity, inflammation, and carcinogenesis in mice due to the inability to mount adaptive responses. By contrast, disruption of Keap1 (a cytoplasmic modifier of Nrf2 turnover) protects against these stresses in mice; although dominant negative mutations in Keap1 have been identified recently in some human cancers. Global characterization of Nrf2 activation is important to exploit this pathway for chemoprevention in healthy, yet at-risk individuals and also to elucidate the consequences of hijacking the pathway in Keap1-mutant human cancers. This analysis also enables a global characterization of the pharmacodynamic action of CDDO-Im at a low dose that is relevant to chemoprevention. Experiment Overall Design: Liver-targeted conditional Keap1-null (CKO) mice provide a model of genetic activation of Nrf2 signaling. By coupling global gene expression analysis of CKO mice with analysis of pharmacologic activation using the synthetic oleanane triterpenoid CDDO-Im, we are able to gain insight into pathways affected by Nrf2 activation. CDDO-Im is an extremely potent activator of Nrf2 signaling. CKO mice were used to identify genes modulated by genetic activation of Nrf2 signaling. The CKO response was compared to hepatic global gene expression changes in wild-type mice treated with CDDO-Im at a maximal Nrf2 activating dose. n=3/group, male 9 week old mice were used. Mice were treated with a single dose of vehicle (10% Cremophor-EL, 10% DMSO, and PBS) or 30 umol CDDO-Im/kg body weight by gavage and sacrificed 6 h later.

2009-05-11 | E-GEOD-15633 | biostudies-arrayexpress

Whole esophagi of WT, Nrf2-/- and Keap1-/- mice on C57BL background at E11.5, E15.5, P0 and P7, and esophageal epithelium of adult (8 weeks old) mice

Project description:Transcriptional profiling of mouse esophageal development. Goal was to globally profile critical genes and signaling pathways during the development of mouse esophagus and determine how Nrf2/Keap1 pathway regulates the morphogenesis of the esophageal epithelium. Mutiple-comparison. WT-E11.5 vs. WT-E15.5 vs. WT-P0 vs. WT-P7; WT-P7 vs. WT-adult; WT-adult vs. Nrf2-/--adult; WT-P7 vs. Nrf2-/--P7 vs. Keap1-/--P7 vs. Nrf2-/-Keap1-/--P7. Biological replicates: 3 replicates for each group.

2011-12-09 | E-GEOD-34278 | biostudies-arrayexpress

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