Targeted Bmi1 inhibition impairs tumor growth in pulmonary adenocarcinomas defined by low CEBPa levels
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE56935 | GEO | 2015/12/31
SECONDARY ACCESSION(S): PRJNA245011
REPOSITORIES: GEO
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Project description:LKB1 is among the most frequently altered tumor suppressors in lung adenocarcinoma. Inactivation of Lkb1 accelerates the growth and progression of oncogenic KRAS-driven lung tumors in mouse models. However, the molecular mechanisms by which LKB1 constrains lung tumorigenesis and whether the aggressive cancer state that stems from Lkb1 deficiency can be reverted remains unknown. To identify the processes governed by LKB1 in vivo, we generated an allele which enables Lkb1 inactivation during tumor development and subsequent Lkb1 restoration in established tumors. Restoration of Lkb1 in oncogenic KRAS-driven lung tumors suppressed proliferation and promoted tumor stasis. Lkb1 restoration activated targets of C/EBP transcription factors and drove the transition of neoplastic cells from a progenitor-like state to a less proliferative alveolar type II cell-like state. We show that C/EBP transcription factors govern a subset of genes that are induced by LKB1 and depend upon NKX2-1. We also demonstrate that a defining factor of the alveolar type II lineage, C/EBPα, constrains oncogenic KRAS-driven lung tumor growth. Thus, we uncover a role for a critical tumor suppressor in the regulation of key lineage-specific transcription factors, thereby constraining lung tumor development through the enforcement of differentiation.
2021-12-23 | PXD026738 | Pride
Project description:Background: LKB1 is among the most frequently altered tumor suppressors in lung adenocarcinoma. Inactivation of Lkb1 accelerates the growth and progression of oncogenic KRAS-driven lung tumors in mouse models. However, the molecular mechanisms by which LKB1 constrains lung tumorigenesis and whether the aggressive cancer state that stems from Lkb1 deficiency can be reverted remains unknown. Purpose: To assess the impact of CRISPR/Cas9-mediated targeting of a subset of LKB1-dependent genes and C/EBP factors on tumor size in the context of a genetically engineered mouse model of oncogenic KRAS-driven lung adenocarcinoma. Approach: Measurements of tumor size across genetic perturbations were obtained by tumor barcode sequencing (Tuba-seq; Rogers et al., 2017 Nature Methods). Briefly, lung tumors were initiated in KrasLSL-G12D/+;R26LSL-tdTomato (KT) and KT;H11LSL-Cas9 mice using a pool of Lenti-sgRNA/Cre vectors that are each modified with two-component barcodes composed of sgRNA-specific and clonal identifiers. This particular pool of Lenti-sgRNA/Cre vectors was composed of vectors targeting a series of LKB1-dependent genes as well a subset of C/EBP transciription factors. Following tumor development, the two-component lentiviral barcodes integrated within transduced populations were amplified from genomic DNA of whole-lung homogenates. The resulting amplicons were then subjected to next-generation sequencing. From the resulting reads, barcode pileups were generated and filtered prior to conversion to absolute numbers of neoplastic cells via normalization to spiked-in samples of known quantities of barcoded neoplastic cells. The resulting tumor size distributions were then analyzed by multiple statistical measures as described previously (Rogers et al., 2017 Nature Methods). Results: Targeting of Lkb1 dramatically increased lung tumor size relative to inert sgRNAs. Little to no impact on tumor size was observed upon targeting LKB1-dependent genes. However, simultaneous targeting of Cebpa/b/d resulted in a significant increase in tumor size. Conclusions: A subset of C/EBP transcription factors constrain oncogenic KRAS-driven lung tumor growth.
2021-12-23 | GSE179497 | GEO
Project description:Background: LKB1 is among the most frequently altered tumor suppressors in lung adenocarcinoma. Inactivation of Lkb1 accelerates the growth and progression of oncogenic KRAS-driven lung tumors in mouse models. However, the molecular mechanisms by which LKB1 constrains lung tumorigenesis and whether the aggressive cancer state that stems from Lkb1 deficiency can be reverted remains unknown. Restoration of Lkb1 in established lung tumors promotes the expression of C/EBP target genes as well as features of alveolar type II cell differentiation, which requires the activity of C/EBP transcription factors in the developmental setting. Purpose: To determine the extent to which the disruption of C/EBP transcription factors recapitulates the transcriptional changes induced by the inactivation of Lkb1.Approach: To assess the changes gene expression induced by CRISPR/Cas9-mediated disruption of either C/EBP transcription factors or Lkb1, we induced lung tumors in KrasLSL-G12D/+;R26LSL-tdTomato;H11LSL-Cas9 mice using Lenti-sgNeo1/sgNT/sgNeo2/Cre (sgInert), Lenti-sgLkb1/Cre (sgLkb1), or Lenti-sgCebpa/sgCebpb/sgCebpd/Cre (sgCebpa/b/d). Neoplastic cells were then isolated from lung tumors by FACS for gene expression profiling by RNA-seq. Results: The disruption of C/EBP transcription factors partially recapitulates the gene expression changes induced by Lkb1 inactivation. Among the genes that are jointly dependent upon C/EBP transcription factors and LKB1 is an enrichment of NKX2-1-dependent target genes. Conclusions: C/EBP transcription factors likely operate downstream of LKB1 in an indirect manner, collaborating with another key developmental regulator, NKX2-1, to enforce alveolar type II cell differentiation to constrain tumor growth.
2021-12-23 | GSE179558 | GEO
Project description:micro RNA expression during adipogenesis of human mesenchynal stem cells. Cells transfected with wildtype human C/EBP-alpha (in expression vector pcDNA3.1) and overexpression of C/EBP-alpha for 48 hours were compared to control cells transfected with the empty vector.
2010-09-02 | E-MEXP-2085 | biostudies-arrayexpress
Project description:Lung cancer is the most common cause of cancer deaths. The expression of the transcription factor C/EBPα (CCAAT/enhancer binding protein α) is frequently lost in non-small cell lung cancer, but the mechanisms by which C/EBPα suppresses tumor formation are not fully understood. In addition, no pharmacological therapy is available to specifically target C/EBPα expression. We discovered a subset of pulmonary adenocarcinoma patients in whom negative/low C/EBPα expression and positive expression of the oncogenic protein BMI1 (B lymphoma Mo-MLV insertion region 1 homolog) have prognostic value. We also generated a lung-specific mouse model of C/EBPα deletion that develops lung adenocarcinomas, which are prevented by Bmi1 haploinsufficiency. BMI1 activity is required for both tumor initiation and maintenance in the C/EBPα-null background, and pharmacological inhibition of BMI1 exhibits antitumor effects in both murine and human adenocarcinoma lines. Overall, we show that C/EBPα is a tumor suppressor in lung cancer and that BMI1 is required for the oncogenic process downstream of C/EBPα loss. Therefore, anti-BMI1 pharmacological inhibition may offer a therapeutic benefit for lung cancer patients with low expression of C/EBPα and high BMI1.
| S-EPMC8214331 | biostudies-literature
Project description:We have examined the microRNA expression in 154 lung adenocarcinoma samples and 20 paired normal lung tissue samples and investigated the microRNA expression to clinical variables, EGFR- and KRAS- mutational status and time to progression. 174 samples are analyzed. 154 from lung adenocarcinoma tumor tissue and 20 from paired normal lung tissue samples. No replicates or control samples included.
2014-03-10 | E-GEOD-48414 | biostudies-arrayexpress
Project description:We have investigated whether the early dissemination of tumor cells into bone marrow is associated with a specific molecular pattern in primary lung cancer Experiment Overall Design: two groups of primary lung adenocarcinomas were compared differentiating in the metastatic potential
2009-03-14 | E-GEOD-10799 | biostudies-arrayexpress
Project description:Background: A gel-free proteomic approach was utilized to perform in-depth tissue protein profiling of lung adenocarcinoma (ADC) and normal lung tissues from early and advanced stages of the disease. The long-term goal of this study is to generate a large-scale, label-free proteomic data set from histologically well-classified lung ADC that can be used to increase further our understanding of disease progression and aid in identifying novel biomarkers. Methods and Results: Cases of early-stage (I-II) and advanced-stage (III-IV) lung ADCs were selected and paired with normal lung tissues from 22 patients. The histologically and clinically stratified human primary lung adenocarcinomas were analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS). From the analysis of ADC and normal specimens, 5,933 protein groups were identified. To examine the protein expression profile of ADC, a peak area-based quantitation method was used. In early- and advanced-stage ADC, 33 and 39 proteins were differentially-expressed respectively between normal and tumor tissue (adjusted p-value < 0.01, fold change ≥ 4). For early- and advanced stage ADC tumors compared to normal patient-matched tissue, 11 and 22 proteins and 23 and 16 proteins were identified as down- and up-regulated, respectively. In silico functional analysis of the up-regulated proteins in both tumor groups revealed that most of the enriched pathways are involved in mRNA metabolism. Furthermore, the most over-represented pathways in the proteins that were unique to ADC are related to mRNA metabolic processes. Conclusions: Further analysis of these data may provide an insight into the molecular pathways involved in disease etiology and may lead to the identification of biomarker candidates and potential targets for therapy. Our study provides potential diagnostic biomarkers for lung ADC and novel stage-specific drug targets for rational intervention.
2021-09-09 | PXD019259 | Pride
Project description:Over-expression of the polycomb group gene BMI-1 is implicated in the pathogenesis of many human cancers. In this study, we investigate the role of BMI-1 as a functional oncogene in the Ewing’s Sarcoma Family of Tumors (ESFT), a highly aggressive group of bone and soft tissue tumors. Our data show that BMI-1 is highly expressed by the majority of primary ESFT and ESFT cell lines. However, in contrast to previous reports in other human cancer cell types, knockdown of BMI-1 in ESFT cell lines has no effect on cell survival. Instead, gain and loss of function studies in vitro and in vivo demonstrate that BMI-1 promotes the anchorage independent growth and tumorigenicity of ESFT. Importantly, we also find that modulation of BMI-1 alters the tumorigenicity of both p16-wild type and p16-null cell lines and that BMI-1-mediated effects on growth promotion are independent of CDKN2a repression. Gene expression profiling of ESFT cells following BMI-1 modulation reveals novel downstream effectors of BMI-1 function including key developmental, cell:cell and cell:matrix adhesion pathways. These data support a central role for BMI-1 in the pathogenesis of ESFT and reveal that p16-independent functions of BMI-1 are largely responsible for its oncogenic function in this tumor family. Keywords: Modification of BMI-1 expression in ESFT cell lines
2008-07-18 | GSE12064 | GEO
Project description:We found that the potent anti-inflammatory enzyme A20 is a potent tumor suppressor and hence often downregulated in human and mouse lung adenocarcinoma. Comparison of gene expression profiles of A20 expressing versus A20 deficient lung tumor tissue samples revealed that loss of A20 enhanced the cellular response to interferons. This hypersensitivity to interferons was responsible to drive immune evasion of A20 deficient lung adenocarcinomas. ,
2021-04-01 | GSE148194 | GEO