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In vivo CRISPR screens identify a dual function of MEN1 in regulating tumor-microenvironment interactions [CT26 IMC RNA-seq]

ABSTRACT: In this study, we used a targeted CRISPR/Cas9 screen to identify genes that determine growth of A549 cells in vivo and in vitro.

ORGANISM(S): Mus musculus

PROVIDER: GSE194352 | GEO | 2024/08/01

REPOSITORIES: GEO

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In vivo CRISPR screens identify a dual function of MEN1 in regulating tumor-microenvironment interactions [CRISPR screening]

Project description:In this study, we used a targeted CRISPR/Cas9 screen to identify genes that determine growth of A549 cells in vivo and in vitro respectively.

2024-07-09 | GSE194349 | GEO

In vivo CRISPR screens identify a dual function of MEN1 in regulating tumor-microenvironment interactions [CUT & RUN]

Project description:In this study, we used a targeted CRISPR/Cas9 screen to identify genes that determine growth of A549 cells in vivo and in vitro.

2024-07-09 | GSE194353 | GEO

In vivo CRISPR screens identify a dual function of MEN1 in regulating tumor-microenvironment interactions [ChIP-seq]

Project description:In this study, we used a targeted CRISPR/Cas9 screen to identify genes that determine growth of A549 cells in vivo and in vitro.

2024-07-09 | GSE194354 | GEO

In vivo CRISPR screens identify a dual function of MEN1 in regulating tumor-microenvironment interactions

Project description:Functional genomic screen in 2D cell culture is limited in identifying therapeutic targets that modulates tumor-microenvironment interaction. Through comparison of targeted CRISPR-Cas9 screens in 2D cell culture and cell line derived xenografts of lung cancer A549, we identified MEN1 as the top hit that confers differential essentialities in vitro and in vivo. Knockout of MEN1 in multiple solid cancer types does not impact cell proliferation in vitro, but significantly promotes and inhibits tumor growth in immunodeficient and immunocompetent mice, respectively. Mechanistically, knockout of MEN1 leads to redistribution of its interaction partner MLL1, a histone methyltransferase, to repetitive genomic regions that produce double stranded RNA. This resulted in MARV and cGAS-STING dependent activation of viral mimicry response, which induces tumor promoting neutrophil and tumor suppressing CD8+ T cell infiltrations in immunodeficient and immunocompetent mice, respectively. Consistently, multiple immune cell infiltrations are negatively correlated with MEN1 abundance and positively correlated with that of MLL1 in patient tumors of a broad range of cancer types. Pharmacological inhibition of MEN1-MLL1 interaction reduces tumor growth in CD8+ T cell dependent manner, and synergizes with anti-PD-L1 treatment. These findings reveal tumor microenvironment dependent oncogenic and tumor suppressive function of MEN1 and provide rationale for therapeutic targeting of MEN1 alone or in combination with immunotherapy in multiple solid cancer types.

2024-06-30 | GSE197595 | GEO

In vivo CRISPR screens identify a dual function of MEN1 in regulating tumor-microenvironment interactions [A549 RNA-seq]

Project description:In this study, we used a targeted CRISPR/Cas9 screen to identify genes that determine growth of A549 cells in vivo and in vitro. Functional genomic screens in 2D cell culture are of limited use for identifying therapeutic targets that modulate tumor cell-microenvironment cell interactions. By comparing targeted CRISPR-Cas9 screens in 2D culture of A549 lung cancer cells versus xenografts derived from the same cell line, we identified MEN1 as the top hit that confers differential effects in vitro and in vivo. Knockout of MEN1 in multiple solid cancer types does not impact cell proliferation in vitro, but significantly promotes or inhibits tumor growth in immunodeficient or immunocompetent mice, respectively. Mechanistically, knockout of MEN1 leads to increased chromatin interaction of its interaction partner MLL1 (KMT2A), a histone methyltransferase, to repetitive genomic regions, where it activates expression of double-stranded RNA. This results in MARV and cGAS-STING dependent activation of viral mimicry response, which induces infiltration of neutrophils and CD8+ T cells in immunodeficient and immunocompetent mice respectively. Consistently, multiple immune cell infiltrations are negatively correlated with MEN1 abundance and positively correlated with that of MLL1 in patient tumors of a broad range of cancer types. Pharmacological inhibition of MEN1-MLL interaction reduces tumor growth in CD8+ T cell dependent manner, with enhanced activity in combination with anti-PD-1 treatment. These findings reveal tumor microenvironment dependent oncogenic and tumor suppressive functions of MEN1 and provide rationale for therapeutic targeting of MEN1 alone or in combination with immunotherapy in multiple solid cancer types.

2022-11-03 | GSE194350 | GEO

In vivo CRISPR screens identify a dual function of MEN1 in regulating tumor-microenvironment interactions.

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-11-03 | GSE194355 | GEO

Minimized combinatorial CRISPR screens identify genetic interactions in autophagy.

Project description:Combinatorial CRISPR-Cas screens have advanced the mapping of genetic interactions, but their experimental scale limits the number of targetable gene combinations. Here, we describe 3Cs multiplexing, a rapid and scalable method to generate highly diverse and uniformly distributed combinatorial CRISPR libraries. We demonstrate that the library distribution skew is the critical determinant of its required screening coverage. By circumventing iterative cloning of PCR-amplified oligonucleotides, 3Cs multiplexing facilitates the generation of combinatorial CRISPR libraries with low distribution skews. We show that combinatorial 3Cs libraries can be screened with minimal coverages, reducing associated efforts and costs at least 10-fold. We apply a 3Cs multiplexing library targeting 12,736 autophagy gene combinations with 247,032 paired gRNAs in viability and reporter-based enrichment screens. In the viability screen, we identify, among others, the synthetic lethal WDR45B-PIK3R4 and the proliferation-enhancing ATG7-KEAP1 genetic interactions. In the reporter-based screen, we identify over 1,570 essential genetic interactions for autophagy flux, including interactions among paralogous genes, namely ATG2A-ATG2B, GABARAP-MAP1LC3B and GABARAP-GABARAPL2. However, we only observe few genetic interactions within paralogous gene families of more than two members, indicating functional compensation between them. This work establishes 3Cs multiplexing as a platform for genetic interaction screens at scale.

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GEMINI: a variational Bayesian approach to identify genetic interactions from combinatorial CRISPR screens.

Project description:Systems for CRISPR-based combinatorial perturbation of two or more genes are emerging as powerful tools for uncovering genetic interactions. However, systematic identification of these relationships is complicated by sample, reagent, and biological variability. We develop a variational Bayes approach (GEMINI) that jointly analyzes all samples and reagents to identify genetic interactions in pairwise knockout screens. The improved accuracy and scalability of GEMINI enables the systematic analysis of combinatorial CRISPR knockout screens, regardless of design and dimension. GEMINI is available as an open source R package on GitHub at https://github.com/sellerslab/gemini .

| S-EPMC6624979 | biostudies-literature

Dual genome-wide CRISPR knockout and CRISPR activation screens identify mechanisms that regulate the resistance to multiple ATR inhibitors.

Project description:The ataxia telangiectasia and Rad3-related (ATR) protein kinase is a key regulator of the cellular response to DNA damage. Due to increased amount of replication stress, cancer cells heavily rely on ATR to complete DNA replication and cell cycle progression. Thus, ATR inhibition is an emerging target in cancer therapy, with multiple ATR inhibitors currently undergoing clinical trials. Here, we describe dual genome-wide CRISPR knockout and CRISPR activation screens employed to comprehensively identify genes that regulate the cellular resistance to ATR inhibitors. Specifically, we investigated two different ATR inhibitors, namely VE822 and AZD6738, in both HeLa and MCF10A cells. We identified and validated multiple genes that alter the resistance to ATR inhibitors. Importantly, we show that the mechanisms of resistance employed by these genes are varied, and include restoring DNA replication fork progression, and prevention of ATR inhibitor-induced apoptosis. In particular, we describe a role for MED12-mediated inhibition of the TGFβ signaling pathway in regulating replication fork stability and cellular survival upon ATR inhibition. Our dual genome-wide screen findings pave the way for personalized medicine by identifying potential biomarkers for ATR inhibitor resistance.

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Minimized combinatorial CRISPR screens identify genetic interactions in autophagy

Project description:Development of the 3Cs multiplex technology for combinatorial screening and identification of genetic interactions among human autophagy genes in cell proliferation and autophagy flux.

2021-06-16 | GSE166851 | GEO

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