Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition

ABSTRACT: Loss of the tumor suppressors RB1 and TP53 and MYC amplification are frequent oncogenic events in small cell lung cancer (SCLC). We show that Myc expression cooperates with Rb1 and Trp53 loss in the mouse lung to promote aggressive, highly metastatic tumors, that are initially sensitive to chemotherapy followed by relapse, similar to human SCLC. Importantly, MYC drives a neuroendocrine-low “variant” subset of SCLC with high NEUROD1 expression corresponding to transcriptional profiles of human SCLC. Targeted drug screening reveals that SCLC with high MYC expression is vulnerable to Aurora kinase inhibition, which combined with chemotherapy strongly suppresses tumor progression and increases survival. These data identify molecular features for patient stratification and uncover a novel targeted treatment approach for MYC-driven SCLC.

PROVIDER: EGAS00001002115 | EGA |

REPOSITORIES: EGA

ACCESS DATA

Json Xml

Similar Datasets

Comparison of gene expression patterns of two SCLC genetically-engineered mouse models; Rb1 floxed, Trp53 floxed, LSL-Myc T58A-IRES-Luc vs. Rb1 floxed, Trp53 floxed, Rbl2 (p130) floxed

Project description:Myc expression cooperates with Rb1 and Trp53 loss in mouse lungs to generate rapid, aggressive, highly metastatic and neuroendocrine-low tumors that are similar to human variant subset of SCLC with high NEUROD1 expression. Targeted drug screening reveals that mouse and human MYC-driven SCLC are vulnerable to Aurora kinase inhibition in combination with chemotherapy in vivo.

2017-01-12 | GSE89660 | GEO

ASCL1 represses a SOX9+ neural-crest-stem-like state in small cell lung cancer

Project description:ASCL1 is a neuroendocrine-lineage-specific oncogenic driver of small cell lung cancer (SCLC), highly expressed in a significant fraction of tumors. However, ~25% of human SCLC are ASCL1-low and associated with low-neuroendocrine fate and high MYC expression. Using genetically-engineered mouse models (GEMMs), we show that alterations in Rb1/Trp53/Myc in the mouse lung induce an ASCL1+ state of SCLC in multiple cells of origin. Genetic depletion of ASCL1 in MYC-driven SCLC dramatically inhibits tumor initiation and progression to the NEUROD1+ subtype of SCLC. Surprisingly, ASCL1 loss promotes a SOX9+ mesenchymal/neural-crest-stem-like state and the emergence of bone and more rarely, cartilaginous tumors. ASCL1 is critical for expression of key lineage-related transcription factors NKX2-1, FOXA2, and INSM1, and represses regulators of Hippo, Wnt and Notch developmental pathways in vivo. ASCL1 also represses SOX9 expression in human SCLC cells, suggesting a conserved function for ASCL1. Here, we utilize single-cell RNA sequencing to capture transcriptomic signatures of RPM (Rb1/Trp53/Myc), RPR2 (Rb1/Trp53/Rbl2), and RPMA (Rb1/Trp53/Myc/Ascl1) GEMM tumors to support our conclusion that in MYC-driven SCLC, ASCL1 promotes neuroendocrine fate and represses the emergence of SOX9+ non-endodermal stem-like or mesenchymal fates. These data were integrated with 4 additional invasive RPM tumors from NCBI GEO: GSE149180.

2021-05-22 | GSE169529 | GEO

RB1 expression and targeting by CDK4/6 inhibitors in small cell lung cancer

Project description:The canonical model of small cell lung cancer (SCLC) depicts tumors arising from dual inactivation of TP53 and RB1. However, many genomic studies have persistently identified tumors with no RB1 mutations. Here, we examined RB1 protein expression and function in SCLC. RB1 expression was examined by immunohistochemical analysis of 62 human SCLC tumors. These studies showed that ~14% of SCLC tumors expressed abundant RB1 protein, which is associated with neuroendocrine (NE) gene expression and is enriched in YAP1 expression, but no other lineage proteins that stratify SCLC. SCLC cells and xenograft tumors with RB1 protein expression were sensitive to growth inhibition by the CDK4/6 inhibitor palbociclib, and this inhibition was shown to be dependent on RB1 expression by CRISPR knockout. Furthermore, a patient with biopsy-validated wt RB1 SCLC who received the CDK4/6 inhibitor abemaciclib demonstrated a dramatic decrease in mutant TP53 ctDNA allelic fraction from 62.1% to 0.4% and decreased tumor mass on CT scans. Importantly, immunohistochemistry of the diagnostic biopsy specimen showed RB1 positivity. Finally, we identified a transcriptomics-based RB1 loss-of-function signature that discriminates between SCLC cells with or without RB1 protein expression and validated it in the patient who was responsive to abemaciclib, suggesting its potential use to predict CDK4/6 inhibitor response in SCLC patients. Our study demonstrates that RB1 protein is an actionable target in a subgroup of SCLC, a cancer that exhibits no currently targetable mutations.

2022-11-14 | GSE217646 | GEO

In-depth proteomic analyses reveal unique subtype-specific signatures in small cell lung cancer (part I: cell pellets)

Project description:Small-cell lung cancer (SCLC) represents about 13–15% of all lung cancers and with a five-year survival rate of less than 7%, it remains one of the most lethal forms of malignant diseases. It has a very aggressive course and is characterized by extensive chromosomal rearrangements, high mutation burden, and almost universal inactivation of the tumor suppressor genes TP53 and RB1. Therefore, the vast majority of SCLC patients are diagnosed with extensive-stage disease when surgery is not feasible and the treatment options are mostly limited to cytotoxic chemotherapy (CHT) and radiation. Importantly, targeted therapies for these patients have so far failed, and the success of immunotherapy in non-SCLC (NSCLC) has not been reflected in SCLC. Although SCLC has been formerly considered as a homogeneous disease with a single morphological type, recent advances in SCLC research have led to the development of subtype-specific classifications primarily based on neuroendocrine (NE) features and unique molecular profiles. Here, we investigate the general cell line characteristics on protein level, the relationship between the RNA-based classification and the protein expression profile, and the distinct biological processes specific for each subtype.

2022-10-14 | PXD029805 | Pride

In-depth proteomic analyses reveal unique subtype-specific signatures in small cell lung cancer (part II: cell media)

2022-10-14 | PXD029821 | Pride

ASCL1 represses a latent osteogenic program in small cell lung cancer in multiple cells of origin [RNA-Seq]

Project description:ASCL1 is a neuroendocrine-lineage-specific oncogenic driver of small cell lung cancer (SCLC), highly expressed in a significant fraction of tumors. However, ~25% of human SCLC are ASCL1-low and associated with low-neuroendocrine fate and high MYC expression. Using genetically-engineered mouse models (GEMMs), we show that alterations in Rb1/Trp53/Myc in the mouse lung induce an ASCL1+ state of SCLC in multiple cell types. Genetic depletion of ASCL1 in MYC-driven SCLC dramatically inhibits tumor initiation, but surprisingly converts tumors to a SOX9+mesenchymal/neural-crest-stem-like state that has the capacity to differentiate into RUNX2+bone tumors. ASCL1 represses SOX9 expression, as well as WNT and NOTCH developmental pathways, consistent with human gene expression data. SCLC demonstrates remarkable cell fate plasticity with ASCL1 repressing the emergence of non-endodermal stem-like fates that have the capacity for bone differentiation. Here we perform bulk RNA sequencing on RPMA tumor samples to compare gene expression patterrns with RPM tumors with intact ASCL1.

2021-05-22 | GSE155691 | GEO

3prime RNA-seq of murine SCLC cell line modified with CRISPR-activation of Myc, Mycl or Mycn

Project description:In cells derived from a genetically engineered Rb1 and Trp53 loss mouse model of SCLC (RP) expression of one of the three MYC family members induced from the endogenous locus using CRISPR activation. Cells were first stably transfected with the lenti-MS2-p65-HSF1 activator plasmid. Respective sgRNAs targeting either Myc, Mycl or MYCN were then cloned into the lentiSAMv2 system and transfected separately into the MS2-p65-HSF1 cells using lentiviral delivery.

2019-07-09 | E-MTAB-7411 | biostudies-arrayexpress

ASCL1 represses a latent osteogenic program in small cell lung cancer in multiple cells of origin [ChIP-Seq]

Project description:ASCL1 is a neuroendocrine-lineage-specific oncogenic driver of small cell lung cancer (SCLC), highly expressed in a significant fraction of tumors. However, ~25% of human SCLC are ASCL1-low and associated with low-neuroendocrine fate and high MYC expression. Using genetically-engineered mouse models (GEMMs), we show that alterations in Rb1/Trp53/Myc in the mouse lung induce an ASCL1+ state of SCLC in multiple cell types. Genetic depletion of ASCL1 in MYC-driven SCLC dramatically inhibits tumor initiation, but surprisingly converts tumors to a SOX9+ mesenchymal/neural-crest-stem-like state that has the capacity to differentiate into RUNX2+bone tumors. ASCL1 represses SOX9 expression, as well as WNT and NOTCH developmental pathways, consistent with human gene expression data. SCLC demonstrates remarkable cell fate plasticity with ASCL1 repressing the emergence of non-endodermal stem-like fates that have the capacity for bone differentiation. Here, we perform ChIP on RPM tumors against ASCL1, NEUROD1, and H3k27Ac to view binding profiles and identify target genes of ASCL1 and NEUROD1.

2021-05-22 | GSE155690 | GEO

Small cell lung cancer responds to inhibition of Jumonji enzyme in vitro and in vivo

Project description:Small-cell lung cancer (SCLC) arises from neuroendocrine cells within the lung. Along with deletion or loss of function Rb and TP53 mutations, which occur in almost all cases, subsets of SCLC are driven by specific transcription factors including ASCL1, NEUROD1, POU2F3, or YAP1. Various MYC family members provide further inter-tumor heterogeneity. Despite this heterogeneity in SCLC, current treatment for SCLC is subtype agnostic. Although most patients are initially responsive to first line etoposide and platin chemotherapy they soon develop resistance with no effective second line therapy. A recent large NCI screen showed that over 60 SCLC cell line models responded to 500+ investigational drugs in a manner highly correlated with etoposide responses, suggesting none of these drugs would provide benefit for SCLC therapy beyond current chemotherapy. By analyzing publicly available data of shRNA and CRISPR screens in addition to our own RNA-seq expression data we identified KDM4A as a potential candidate to target in SCLC. To underscore the potential of KDM4A as an anti-SCLC target, we tested chemotherapy drug and three JmjC KDM inhibitors across a panel of SCLC cell lines representing all the SCLC transcription factor subtypes and found that SCLC responses to JmjC KDM inhibitors do not correlate to their responses to chemotherapy. Furthermore, we found upon treatment with pan-JmjC KDM inhibitor, JIB-04, many genes in the ER stress signaling pathways are upregulated in SCLC lines, suggesting this is the mechanistic path leading to SCLC slower growth or death. Additionally, analysis found that JIB-04 resistant cells activate pro-survival pathways such as mTOR to perhaps overcome the effects of JIB-04 treatment. Furthermore, the loss of KDM4A in SCLC cell line led to slower proliferation and activity in the ER stress signaling pathway.

2024-10-10 | GSE208446 | GEO

Array CGH-based Characterization of Genetic Alterations in Pulmonary Neuroendocrine Tumors

Project description:The goal of this study was to characterize and classify pulmonary neuroendocrine tumors based on Array Comparative Genomic Hybridization (aCGH). Using aCGH, we performed karyotype analysis of 33 small cell lung cancer (SCLC) tumors, 13 SCLC cell lines, 19 bronchial carcinoids, and 9 gastrointestinal (GI) carcinoids. In contrast to the relatively stable karyotypes of carcinoid tumors, the karyotypes of SCLC tumors and cell lines were highly aberrant. High copy number (CN) gains were detected in SCLC tumors and cell lines in cytogenetic bands encoding JAK2, FGFR1, and MYC family members. In some of those samples, the CN of these genes exceeded 100, suggesting that they could represent driver alterations and potential drug targets in subgroups of SCLC patients. Recurrent CN alterations of a total of 203 genes, including the RB1 gene, and 59 microRNAs, most of which locate in the DLK1-DIO3 domain, were observed in SCLC tumors, bronchial carcinoids and carcinoids of GI origin; in contrast, CN alterations of the TP53 gene and the MYC family members were observed more frequently in SCLC. These findings suggest the existence of partially shared tumor-specific CN alterations in these tumors. Furthermore, we demonstrated that the aCGH profile of SCLC cell lines highly resemble that of clinical SCLC specimens. Finally, by analyzing potential drug targets, we provide a genomics based rationale for targeting the AKT-mTOR and apoptosis pathways in SCLC. Carcinoids, including 19 bronchial carcinoids and 9 carcinoid of gastrointestinal origin, and small cell lung cancer, including 33 patients' tumor samples and 13 cell line samples, were compared.

2010-04-22 | E-GEOD-21468 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data