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A multiplexed in vivo gene knockout approach to identify cancer drivers in small cell lung cancer [LCM Tuba-seq]

ABSTRACT: We generated a model of lentivirus-initiated mouse small cell lung cancer (SCLC) combined with CRISPR/Cas9 knockout and barcoding. We analyzed tumor suppressive functions of 39 gene candidates using these in vivo CRISPR screening approaches and found Tsc1 to be one of the top tumor suppressor genes in SCLC.

ORGANISM(S): Mus musculus

PROVIDER: GSE198635 | GEO | 2023/01/09

REPOSITORIES: GEO

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A multiplexed in vivo gene knockout approach to identify cancer drivers in small cell lung cancer [SCLC Tuba-seq]

Project description:We generated a model of lentivirus-initiated mouse small cell lung cancer (SCLC) combined with CRISPR/Cas9 knockout and barcoding. We analyzed tumor suppressive functions of 39 gene candidates using these in vivo CRISPR screening approaches and found Tsc1 to be one of the top tumor suppressor genes in SCLC.

2023-01-09 | GSE198636 | GEO

A multiplexed in vivo gene knockout approach to identify cancer drivers in small cell lung cancer [RNAseq]

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In vivo multiplexed screen reveals a critical role of Keap1/Nrf2 pathway in small cell lung cancer [RNAseq]

Project description:Approximately 15% of all lung cancer cases are small cell lung cancer (SCLC), which originates from neuroendocrine cells lining the airways (bronchi) of the lung. SCLC is known for its aggressive nature and swift growth, resulting in a five-year survival rate of around 6%. Understanding the genetic pathways that drive tumor development remains an ongoing challenge. In our study, we employed an in vivo multiplexed approach, known as Tuba-seq, to investigate the impact of the functional loss of 18 putative tumor suppressors. Our screening unveiled Pten and Keap1 as top candidates; knocking out either one promoted both tumor initiation and progression. We identified the Keap1/Cul3/Nrf2 pathway as a pivotal regulator for SCLC development, particularly in regulating the susceptibility of SCLC to ferroptosis. Our work not only established an in vivo multiplexed approach for assessing the role of tumor suppressors in SCLC but also uncovers a previously unappreciated role of Keap1 in SCLC.

2024-01-26 | GSE239436 | GEO

In vivo multiplexed screen reveals a critical role of Keap1/Nrf2 pathway in small cell lung cancer [TUBAseq]

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A multiplexed single-cell CRISPR screening platform enables systematic dissection of the unfolded protein response

Project description:Functional genomics efforts face tradeoffs between number of perturbations examined and complexity of phenotypes measured. We bridge this gap with Perturb-seq, which combines droplet-based single-cell RNA-seq with a strategy for barcoding CRISPR-mediated perturbations, allowing many perturbations to be profiled in pooled format. We applied Perturb-seq to dissect the mammalian unfolded protein response (UPR) using single and combinatorial CRISPR perturbations. A genome-scale CRISPR interference (CRISPRi) screen identified genes whose depletion perturbs ER homeostasis. Subjecting ~100 hits to Perturb-seq enabled high-precision functional clustering of genes. Single-cell analyses revealed epistasis among the three UPR branches, bifurcated UPR branch activation between cells subject to the same perturbation, and differential activation of the branches across hits, including a feedback loop between the translocon and the IRE1α branch. These studies provide insight into how the three sensors of ER homeostasis monitor distinct types of stress and highlight the ability of Perturb-seq to dissect complex cellular responses.

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Lineage-specific intolerance to oncogenic drivers restricts histological transformation [ATAC-Seq]

Project description:Lung adenocarcinoma (LUAD) and small cell lung cancer (SCLC) are thought to originate from different epithelial cell types in the lung. Intriguingly, LUAD can histologically transform into SCLC following treatment with targeted therapies. Here we designed models to follow the conversion of LUAD to SCLC and found the barrier to histological transformation converges on tolerance to Myc, which we implicate as a lineage-specific driver of the pulmonary neuroendocrine cell. Histological transformations are frequently accompanied by activation of the Akt pathway. Manipulating this pathway permitted tolerance to Myc as an oncogenic driver, producing rare, stem-like cells, transcriptionally resembling the pulmonary basal lineage. These findings suggest histological transformation may require the plasticity inherent to the basal stem cell, enabling tolerance to previously incompatible oncogenic driver programs.

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Lineage-specific intolerance to oncogenic drivers restricts histological transformation [scRNA-Seq]

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CRISPR-mediated modeling and functional validation of candidate tumor suppressor genes in small cell lung cancer

Project description:Small cell lung cancer (SCLC) is a highly aggressive subtype of lung cancer that remains among the most lethal of solid tumor malignancies. Recent genomic sequencing studies have identified many recurrently mutated genes in human SCLC tumors. However, the functional roles of most of these genes remain to be validated. Here, we adapt the CRISPR-Cas9 system to a well-established murine model of SCLC to rapidly model loss-of-function mutations in candidate genes identified from SCLC sequencing studies. We show that loss of the gene p107 significantly accelerates tumor progression. Notably, compared with loss of the closely related gene p130, p107 loss results in fewer but larger tumors, as well as earlier metastatic spread. In addition, we observe differences in proliferation and apoptosis, as well as altered distribution of initiated tumors in the lung, resulting from loss of p107 or p130. Collectively, these data demonstrate the feasibility of using the CRISPR-Cas9 system to model loss of candidate tumor suppressor genes in SCLC, and we anticipate that this approach will greatly facilitate efforts to investigate mechanisms driving tumor progression in this deadly disease.

2019-12-19 | GSE139444 | GEO

KDM6A Epigenetically Regulates Subtype Plasticity in Small Cell Lung Cancer (scatac)

Project description:Small cell lung cancer (SCLC) exists broadly in four molecular subtypes: ASCL1, NEUROD1,POU2F3, and Inflammatory. Initially SCLC subtypes were thought to be mutually exclusive, butrecent evidence shows intra-tumoral subtype heterogeneity and plasticity between subtypes.Using a CRISPR-based autochthonous SCLC GEMM to study the consequences of KDM6A/UTXinactivation, we found that KDM6A inactivation induced plasticity from ASCL1 to NEUROD1resulting in SCLC tumors with open chromatin at the NEUROD1 promoter that express bothASCL1 and NEUROD1. Mechanistically, KDM6A binds and maintains ASCL1 target genes in anactive chromatin state with its loss increasing H3K27me3 near their promoters leading to a cell state that is primed for ASCL1 to NEUROD1 subtype switching. This work identifies KDM6A as \an epigenetic regulator that controls ASCL1 to NEUROD1 subtype plasticity and provides a novel autochthonous SCLC GEMM to model ASCL1 and NEUROD1 subtype heterogeneity and plasticity, which is found in 35-40% of human SCLCs.

2023-06-08 | GSE215828 | GEO

KDM6A Epigenetically Regulates Subtype Plasticity in Small Cell Lung Cancer (atac batch2)

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