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Loss of Lkb1 and Pten Leads to Lung Squamous Cell Carcinoma with Elevated Pdl1 Expression: Epithelial Cells

ABSTRACT: Lung squamous cell carcinoma (SCC) is a deadly disease for which current treatments are inadequate. We demonstrate that bi-allelic inactivation of Lkb1 and Pten in the mouse lung led to SCC that recapitulated the histology, gene expression and microenvironment found in human disease. Lkb1/Pten-null (LP) tumors expressed the squamous markers Krt5, p63 and Sox2, and transcriptionally resembled the basal subtype of human SCC. In contrast to mouse adenocarcinomas, the LP tumors contained immune populations enriched for tumor-associated neutrophils. Sca1+/Ngfr+ fractions were enriched for tumor propagating cells (TPCs) that could serially transplant the disease in orthotopic assays. TPCs in the LP model and Ngfr+ cells in human SCCs highly expressed Pdl1, suggesting a novel mechanism of immune escape for TPCs. We used microarrays to detail the gene expression profles among lung SCC tumor epitheial cell, lung ADC tumor epithelia cell and normal epithelial cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE54351 | GEO | 2014/01/24

SECONDARY ACCESSION(S): PRJNA236308

REPOSITORIES: GEO

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Loss of Lkb1 and Pten Leads to Lung Squamous Cell Carcinoma with Elevated Pdl1 Expression: Stroma Cells

Project description:Lung squamous cell carcinoma (SCC) is a deadly disease for which current treatments are inadequate. We demonstrate that bi-allelic inactivation of Lkb1 and Pten in the mouse lung led to SCC that recapitulated the histology, gene expression and microenvironment found in human disease. Lkb1/Pten-null (LP) tumors expressed the squamous markers Krt5, p63 and Sox2, and transcriptionally resembled the basal subtype of human SCC. In contrast to mouse adenocarcinomas, the LP tumors contained immune populations enriched for tumor-associated neutrophils. Sca1+/Ngfr+ fractions were enriched for tumor propagating cells (TPCs) that could serially transplant the disease in orthotopic assays. TPCs in the LP model and Ngfr+ cells in human SCCs highly expressed Pdl1, suggesting a novel mechanism of immune escape for TPCs. We used microarrays to detail the gene expression profles among lung SCC tumor epitheial cell, lung ADC tumor epithelia cell and normal epithelial cells. Kras tumor stroma cells and LP tumor stroma cells were sorted by FACS, the cells were gated as EpCAM-/CD45+/CD31+

2014-01-24 | E-GEOD-54352 | biostudies-arrayexpress

Loss of Lkb1 and Pten Leads to Lung Squamous Cell Carcinoma with Elevated Pdl1 Expression: Epithelial Cells

Project description:Lung squamous cell carcinoma (SCC) is a deadly disease for which current treatments are inadequate. We demonstrate that bi-allelic inactivation of Lkb1 and Pten in the mouse lung led to SCC that recapitulated the histology, gene expression and microenvironment found in human disease. Lkb1/Pten-null (LP) tumors expressed the squamous markers Krt5, p63 and Sox2, and transcriptionally resembled the basal subtype of human SCC. In contrast to mouse adenocarcinomas, the LP tumors contained immune populations enriched for tumor-associated neutrophils. Sca1+/Ngfr+ fractions were enriched for tumor propagating cells (TPCs) that could serially transplant the disease in orthotopic assays. TPCs in the LP model and Ngfr+ cells in human SCCs highly expressed Pdl1, suggesting a novel mechanism of immune escape for TPCs. We used microarrays to detail the gene expression profles among lung SCC tumor epitheial cell, lung ADC tumor epithelia cell and normal epithelial cells. Normal EpCAM+, Kras tumor EpCAM+ and LP tumor EpCAM+ were sorted by FACS, the cells were gating as EpCAM+/CD45-/CD31-

2014-01-24 | E-GEOD-54351 | biostudies-arrayexpress

Loss of Lkb1 and Pten Leads to Lung Squamous Cell Carcinoma with Elevated Pdl1 Expression: Stroma Cells

2014-01-24 | GSE54352 | GEO

The expression profile of lung sqaumous cell carcinoma (SCC) and adenosquamous carcninoma (ASC) of CCSPiCreLkb1f/fPtenf/f mice

Project description:Lung cancer, majorly divided into non-small cell lung cancer (80-85%) and small cell lung cancer (15-20%), is the leading cause of cancer death in USA. Squamous Cell Carcinoma (SCC) is one of major subtypes of non-small cell lung cancer. Although genomic analysis of tumors from SSC patients have identified frequently mutated genes in these tumors, it’s still largely unknown which genes determine SCC development. Now we found that ablation of Lkb1 and Pten could induce SCC and ASC around 3 months of age. Therefore, transcriptome analysis of lung SCC and ASC of CCSPiCreLkb1f/f mice will help us understand how Lkb1 and Pten regulate the development of lung SCC and ASC.

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Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2

Project description:Adenosquamous lung tumors may result from cellular plasticity. We demonstrate lineage switching of KRAS+ lung adenocarcinomas (ADC) to squamous cell carcinoma (SCC) through deletion of Lkb1 (Stk11) in autochthonous and transplant models. Chromatin analysis reveals loss of H3K27me3 and gain of H3K27ac and H3K4me3 at squamous lineage genes, included Sox2, ΔNp63 and Ngfr. SCC lesions have higher levels of the H3K27 methyltransferase EZH2 than the ADC lesions, but there is a clear lack of the essential Polycomb Repressive Complex 2 (PRC2) subunit EED in the SCC lesions.

2017-02-02 | GSE94365 | GEO

The Role of JNK1/2 in Mouse Lung Squamous Cell Carcinoma (SCC) Development

Project description:Lung cancer is the leading cause of cancer death in USA. Squamous Cell Carcinoma (SCC) is one of the subtypes of lung cancer. It is still largely unknown which genes or pathways regulate lung SCC development. Recently, we found JNK1/2 pathway was inhibited in mouse lung SCC induced by double ablation of Pten and Lkb1 in mouse lung epithelial cells. Now we aim to identify a genome-wide molecular signature of JNK1/2 signaling in mouse squamous cell carcinoma cells and determine pathways that transduce JNK1/2 signaling.

2019-03-01 | GSE111314 | GEO

The Role of Lkb1 in Mouse Lung Squamous Cell Carcinoma (SCC) Development

Project description:Lung cancer, majorly divided into non-small cell lung cancer (80-85%) and small cell lung cancer (15-20%), is the leading cause of cancer death in USA. Squamous Cell Carcinoma (SCC) is one of major subtypes of non-small cell lung cancer. Although genomic analysis of tumors from SSC patients have identified frequently mutated genes in these tumors, it’s still largely unknown which genes determine SCC development. Now we found that ablation of alone Lkb1 could induce SCC around 12 months of age. Therefore, transcriptome analysis of lung SCC of CCSPiCreLkb1f/f mice will help us understand how Lkb1 regulates the development of lung SCC.

2019-03-01 | GSE111313 | GEO

A unique subset of glycolytic tumor propagating cells drives squamous cell carcinoma

Project description:Head and Neck Squamous Cell Carcinoma (HNSCC) remains among the most aggressive human cancers. Tumor progression and aggressiveness in SCC are largely driven by Tumor Propagating Cells (TPCs). Aerobic glycolysis, also known as the Warburg Effect, represents a characteristic of many cancers, yet whether this adaptation is functionally important in SCC, and at which stage, remains poorly understood. Here, we show that the NAD+-dependent histone deacetylase Sirtuin 6 (SIRT6) is a robust tumor suppressor in SCC, acting as a modulator of glycolysis in these tumors. Remarkably, rather than a late adaptation, we find enhanced glycolysis specifically in TPCs. More importantly, using single cell RNA sequencing of TPCs, we identify a subset of TPCs with higher glycolysis and enhanced pentose phosphate pathway and glutathione metabolism, characteristics that are strongly associated with a better antioxidant response. Altogether, our studies uncover enhanced glycolysis as a main driver in SCC, and, more importantly, identify a subset of TPCs as the cell-of-origin for the Warburg effect, defining metabolism as a key feature of intra-tumor heterogeneity.

2021-01-14 | GSE147031 | GEO

A unique subset of glycolytic tumor propagating cells drives squamous cell carcinoma

2021-01-14 | GSE115953 | GEO

miRNA expression profiling in squamous cell carcinoma (SCC)

Project description:Despite its prevalence, the molecular basis of squamous cell carcinoma (SCC) remains poorly understood. We recently identified the developmental transcription factor Grhl3 as a potent tumor suppressor of SCC, and demonstrated that targeting of Grhl3 by a miR-21-dependent proto-oncogenic network underpins SCC in humans. Reduced levels of GRHL3 and its target gene PTEN are evident in human skin, and head and neck SCC, associated with increased expression of miR-21, which targets both tumor suppressors. Our data defines the miR-21-GRHL3-PTEN-axis as a critical tumor suppressor pathway in SCC. Total RNA was isolated from two SCC primary tissue samples and their matched normal skin controls.

2013-01-18 | E-GEOD-32868 | biostudies-arrayexpress

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