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Gene expression profile at single cell level of non-malignant cells in KRAS syngeniec mouse tumor models harboring STK11 and/or KEAP1 co-muation

ABSTRACT: Gene expression profile at single cell level of non-malignant cells in KRAS syngeniec mouse tumor models harboring STK11 and/or KEAP1 co-muation

PROVIDER: PRJNA1111059 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29008419.fastq.gz	Fastqsanger.gz
	SRR29008420.fastq.gz	Fastqsanger.gz
	SRR29008421.fastq.gz	Fastqsanger.gz
	SRR29008422.fastq.gz	Fastqsanger.gz
	SRR29008423.fastq.gz	Fastqsanger.gz

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Gene expression profile at single cell level of non-malignant cells in KRAS syngeniec mouse tumor models harboring STK11 and/or KEAP1 co-muation

Project description:STK11/LKB1 and KEAP1 mutations are associated with immunotherapy resistance. We employed KRAS syngeneic mouse cells (K) and generated KEAP1 loss (KK) or STK11/KEAP1 loss (KLK) by CRISPR/KO. Then we injected these tumor cells and collected the tumor for single-cell RNA-seq. Our aim is to analyze the impact of STK11 and/or KEAP1 deficiency on the immune microenvironment.

2024-05-20 | GSE267321 | GEO

Transcriptional profiling of BL/6 mice with alterations in Kras, Stk11, and/or Keap1/Nrf2.

Project description:Transcriptional profiling of BL/6 mice harboring a mutant Kras allele, with or without knockouts of Stk11 and/or Keap1, or with expression of an Nfe2l2 transgene, Nrf2Tg. In lung adenocarcinoma (LUAD), stabilization of the transcription factor NRF2 through genomic alterations in KEAP1 and NFE2L2 occurs in roughly a quarter of patients, often in the context of STK11 tumor suppressor loss. In this study, we demonstrate that NRF2 activation in the context of concurrent KRAS mutation and STK11 loss promotes aggressive LUAD tumor behavior in both human and mouse preclinical models. This phenotype is associated with metabolic rewiring and rescue by NRF2 of redox stress, high in STK11 null tumors. Applying a novel, pan-lung cancer, diagnostic NRF2 activation gene expression signature that is independent of frequently co-occurring mutations, we dissect the independent contributions of the three most frequent genetic events in human LUAD (NRF2 activation, STK11 loss and KRAS mutations) on patient prognosis and clinical responses in a dataset of second-line LUAD patients treated with immunotherapy or chemotherapy (OAK trial). Our findings underscore that both individual effects and epistatic relationships among oncogenic and tumor suppressor pathways influence tumor biology, immune contexture and patient clinical outcomes. Our work also highlights the value of lung cancer disease sub-classification based on genetic and expression profiling as part of patient clinical management.

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SCD1-dependant activation of GSK3β-NRF2-SLC7A11 pathway regulates lipid metabolism and suppresses ferroptosis in KRAS/STK11/KEAP1 co-mutant lung adenocarcinoma

Project description:InactivatingSTK11/KEAP1 co-mutations are genomic drivers of primary resistance totherapies and worse outcome in KRAS-mutatedlung adenocarcinoma(LUAD), however the underlying mechanisms is still not understood.Here we provide a transcriptomic analysis of over 3800 “real-world” LUAD cases that concomitant loss of STK11 and KEAP1 in a KRAS-mutant tumorleads to significant upregulation of fatty acid metabolism, and redox signaling pathways with significantly high expression of ferroptosis evasion genes, SCD1 and SLC7A11. Global transcriptomics and kinase arrays demonstrate the role SCD1 in regulating AKT/GSK3β/NRF2 signaling mediated modulation of SLC7A11 and GSH metabolism. Furthermore, in a lipidomic assay, SCD1 knockout led to regulation of SFA-MUFA levels that promoted ferroptosis. SCD1 inhibition reverses the resistance to ferroptosis induction promoted by STK11/KEAP1 loss inmouse models. These data provide evidence that SCD1 protects ferroptosis induction and therapeutic targeting of this pathway is a promising translational strategy in KRAS mutant LUADs with concomitant loss ofSTK11 and KEAP1.

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Transcriptional profiling of HCC515 lung cells with dox-inducible KEAP1 knockdown and/or STK11 re-addition, under different metabolic tstress conditions

Project description:HCC515 lung cells with dox-inducible KEAP1 knockdown and/or STK11 re-addition, under two different metabolic stress conditions, baseline vs. suspension, were transcriptionally profiled to investigate whether KEAP1 knockdown can rescue metabolic defects in STK11-null cancer cells and how the regulation of the transcriptome by KEAP1 knockdown is affected by STK11 status and different metabolic stress conditions. In lung adenocarcinoma (LUAD), stabilization of the transcription factor NRF2 through genomic alterations in KEAP1 and NFE2L2 occurs in roughly a quarter of patients, often in the context of STK11 tumor suppressor loss. In this study, we demonstrate that NRF2 activation in the context of concurrent KRAS mutation and STK11 loss promotes aggressive LUAD tumor behavior in both human and mouse preclinical models. This phenotype is associated with metabolic rewiring and rescue by NRF2 of redox stress, high in STK11 null tumors. Applying a novel, pan-lung cancer, diagnostic NRF2 activation gene expression signature that is independent of frequently co-occurring mutations, we dissect the independent contributions of the three most frequent genetic events in human LUAD (NRF2 activation, STK11 loss and KRAS mutations) on patient prognosis and clinical responses in a dataset of second-line LUAD patients treated with immunotherapy or chemotherapy (OAK trial). Our findings underscore that both individual effects and epistatic relationships among oncogenic and tumor suppressor pathways influence tumor biology, immune contexture and patient clinical outcomes. Our work also highlights the value of lung cancer disease sub-classification based on genetic and expression profiling as part of patient clinical management.

2020-01-31 | GSE133715 | GEO

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Project description:While mutations in the KRAS oncogene are amongst the most prevalent in human cancer, there are few successful treatments to target these tumors. It is also likely that heterogeneity in KRAS-mutant tumor biology significantly contributes to the response to therapy. We hypothesized that presence of commonly co-occurring mutations in STK11 and TP53 tumor suppressors may represent a significant source of heterogeneity in KRAS-mutant tumors. To address this, we utilized a large cohort of resected tumors from 442 lung adenocarcinoma patients with data including annotation of prevalent driver mutations (KRAS, EGFR) and tumor suppressor mutations (STK11 and TP53), microarray-based gene expression and clinical covariates including overall survival (OS). Specifically, we determined impact of STK11 and TP53 mutations on a new KRAS mutation-associated gene expression signature as well as previously defined signatures of tumor cell proliferation and immune surveillance responses. Interestingly, STK11, but not TP53 mutations, were associated with highly elevated expression of KRAS mutation-associated genes. Mutations in TP53 and STK11 also impacted tumor biology regardless of KRAS status, with TP53 strongly associated with enhanced proliferation and STK11 with suppression of immune surveillance. These findings illustrate the remarkably distinct ways through which tumor suppressor mutations may contribute to heterogeneity in KRAS-mutant tumor biology. In addition, these studies point to novel associations between gene mutations and immune surveillance that could impact the response to immunotherapy.

2015-10-21 | GSE72094 | GEO

Transcriptional profiling of BL/6 mice with alterations in Kras, Stk11, and/or Keap1/Nrf2.

Project description:Transcriptional profiling of BL/6 mice with alterations in Kras, Stk11, and/or Keap1/Nrf2.

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RNaseq of two human LUAD cell lines with knockout of STK11, KEAP1, both genes or no genes.

Project description:We investigated how selective mutation in STK11 or KEAP1 alters the transcriptional profile of cancer cells, and how the transcriptional profile of co-mutant cells might uniquely affect cancer-related pathways including control of proliferative potential, metabolic homeostasis, and cell death. We performed bulk RNAseq on none, single or double mutation of these genes in single cell knockout clones (n=3 per group) from both H358 and H292 cell lines.

2020-11-12 | E-MTAB-9724 | biostudies-arrayexpress

Gene expression profile at single cell level of non-malignant cells in KRAS syngeneic mouse tumor models

Project description:STK11/LKB1 mutation is a primary driver for immunotherapy resistance. We employed KRAS/LKB1 syngeneic mouse models by injecting tumor cells with Kras mutation, Kras/Stk11 mutation and MCT4 knockout. We used single-cell RNA-seq to analyze the impact of LKB1 deficiency on the immune microenvironment.

2023-05-10 | GSE231742 | GEO

SCD1-dependant activation of GSK3β-NRF2-SLC7A11 pathway regulates lipid metabolism and suppresses ferroptosis in KRAS/STK11/KEAP1 co-mutant lung adenocarcinoma

Project description:SCD1-dependant activation of GSK3β-NRF2-SLC7A11 pathway regulates lipid metabolism and suppresses ferroptosis in KRAS/STK11/KEAP1 co-mutant lung adenocarcinoma

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Divergent clinical and immunologic outcomes based on STK11 co-mutation status in resectable KRAS-mutant lung cancers following neoadjuvant immune checkpoint blockade

Project description:Co-mutations of the KRAS and STK11 genes in advanced non-small cell lung cancer (NSCLC) are associated with immune checkpoint blockade (ICB) resistance. While neoadjuvant chemoimmunotherapy is now a standard of care treatment for early-stage NSCLC, the clinical and immunologic impact of KRAS and STK11 co-mutations in this setting are unknown. We evaluated the clinical outcomes and intratumoral T cell profiles of resected KRAS-mutant tumors treated with neoadjuvant ICB. Relative to KRASmut/STK11wt tumors, KRASmut/STK11mut exhibited significantly higher recurrence risk. Single-cell transcriptomics showed enhanced oxidative phosphorylation with evidence of decreased PGE-2 signaling and increased IL-2 signaling in CD8+ tumor-infiltrating lymphocytes (TIL) from KRASmut/STK11mut tumors, a finding that was mirrored in KRASwt tumors that relapsed. TIL from KRASmut/STK11mut tumors expressed high levels of molecules associated with tumor residence, including CD39 and ZNF683 (HOBIT). These divergent T cell transcriptional fates suggest T cell maintenance and residence may be detrimental to anti-tumor immunity in the context of neoadjuvant ICB for resectable NSCLC, regardless of KRAS mutation status. Our work provides a basis for future investigations into the mechanisms underpinning PGE-2 and IL-2 signaling as they relate to T cell immunity to cancer and to divergent clinical outcomes in KRASmut/STK11mut NSCLC treated with neoadjuvant ICB.

2024-10-24 | GSE280232 | GEO

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