Unknown,Transcriptomics,Genomics,Proteomics

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Suppression of Lung Adenocarcinoma Progression by Nkx2-1

ABSTRACT: Despite the high prevalence and poor outcome of patients with metastatic lung cancer, the mechanisms of tumour progression and metastasis remain largely uncharacterized. We modelled human lung adenocarcinoma, which frequently harbours activating point mutations in KRAS1 and inactivation of the p53-pathway2, using conditional alleles in mice3-5. Lentiviral-mediated somatic activation of oncogenic Kras and deletion of p53 in the lung epithelial cells of KrasLSL-G12D/+;p53flox/flox mice initiates lung adenocarcinoma development4. Although tumours are initiated synchronously by defined genetic alterations, only a subset become malignant, suggesting that disease progression requires additional alterations. Identification of the lentiviral integration sites allowed us to distinguish metastatic from non-metastatic tumours and determine the gene expression alterations that distinguish these tumour types. Cross-species analysis identified the NK-2 related homeobox transcription factor Nkx2-1 (Ttf-1/Titf1) as a candidate suppressor of malignant progression. In this mouse model, Nkx2-1-negativity is pathognomonic of high-grade poorly differentiated tumours. Gain- and loss-of-function experiments in cells derived from metastatic and non-metastatic tumours demonstrated that Nkx2-1 controls tumour differentiation and limits metastatic potential in vivo. Interrogation of Nkx2-1 regulated genes, analysis of tumours at defined developmental stages, and functional complementation experiments indicate that Nkx2-1 constrains tumours in part by repressing the embryonically-restricted chromatin regulator Hmga2. While focal amplification of NKX2-1 in a fraction of human lung adenocarcinomas has focused attention on its oncogenic function6-9, our data specifically link Nkx2-1 downregulation to loss of differentiation, enhanced tumour seeding ability, and increased metastatic proclivity. Thus, the oncogenic and suppressive functions of Nkx2-1 in the same tumour type substantiate its role as a dual function lineage factor. 23 cell lines derived from primary tumor or metastasis. 6 samples analyzed to determine the effect of Nkx2-1 knockdown on gene expression

ORGANISM(S): Mus musculus

SUBMITTER: Charles Whittaker

PROVIDER: E-GEOD-26874 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Suppression of lung adenocarcinoma progression by Nkx2-1.

Winslow Monte M MM Dayton Talya L TL Verhaak Roel G W RG Kim-Kiselak Caroline C Snyder Eric L EL Feldser David M DM Hubbard Diana D DD DuPage Michel J MJ Whittaker Charles A CA Hoersch Sebastian S Yoon Stephanie S Crowley Denise D Bronson Roderick T RT Chiang Derek Y DY Meyerson Matthew M Jacks Tyler T

Nature 20110406 7345

Despite the high prevalence and poor outcome of patients with metastatic lung cancer the mechanisms of tumour progression and metastasis remain largely uncharacterized. Here we modelled human lung adenocarcinoma, which frequently harbours activating point mutations in KRAS and inactivation of the p53 pathway, using conditional alleles in mice. Lentiviral-mediated somatic activation of oncogenic Kras and deletion of p53 in the lung epithelial cells of Kras(LSL-G12D/+);p53(flox/flox) mice initiate ...[more]

PMID: 21471965

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Project description:Despite the high prevalence and poor outcome of patients with metastatic lung cancer, the mechanisms of tumour progression and metastasis remain largely uncharacterized. We modelled human lung adenocarcinoma, which frequently harbours activating point mutations in KRAS1 and inactivation of the p53-pathway2, using conditional alleles in mice3-5. Lentiviral-mediated somatic activation of oncogenic Kras and deletion of p53 in the lung epithelial cells of KrasLSL-G12D/+;p53flox/flox mice initiates lung adenocarcinoma development4. Although tumours are initiated synchronously by defined genetic alterations, only a subset become malignant, suggesting that disease progression requires additional alterations. Identification of the lentiviral integration sites allowed us to distinguish metastatic from non-metastatic tumours and determine the gene expression alterations that distinguish these tumour types. Cross-species analysis identified the NK-2 related homeobox transcription factor Nkx2-1 (Ttf-1/Titf1) as a candidate suppressor of malignant progression. In this mouse model, Nkx2-1-negativity is pathognomonic of high-grade poorly differentiated tumours. Gain- and loss-of-function experiments in cells derived from metastatic and non-metastatic tumours demonstrated that Nkx2-1 controls tumour differentiation and limits metastatic potential in vivo. Interrogation of Nkx2-1 regulated genes, analysis of tumours at defined developmental stages, and functional complementation experiments indicate that Nkx2-1 constrains tumours in part by repressing the embryonically-restricted chromatin regulator Hmga2. While focal amplification of NKX2-1 in a fraction of human lung adenocarcinomas has focused attention on its oncogenic function6-9, our data specifically link Nkx2-1 downregulation to loss of differentiation, enhanced tumour seeding ability, and increased metastatic proclivity. Thus, the oncogenic and suppressive functions of Nkx2-1 in the same tumour type substantiate its role as a dual function lineage factor.

Project description:ErbB-2 overexpression and amplification occurs in 15 - 30% of human invasive breast carcinomas associated with poor clinical prognosis. Previously, we have demonstrated that four ErbB-2/Neu tyrosine-autophosphorylation sites within the cytoplasmic tail of the receptor recruit distinct adaptor proteins and are sufficient to mediate transforming signals in vitro. Two of these sites representing the Grb2 (Neu-YB) and Shc (Neu-YD) binding sites can induce mammary tumourigenesis and metastasis. Here we show that Neu-YC and Neu-YE transgenic mice develop metastatic mammary tumours. A detailed comparison of pathological and transcriptional profiles among all Neu mutant mouse models revealed that Neu-YC, -YD and -YE mammary tumours shared similar pathological and transcriptional features correlating with their capacity to signal through a common adaptor like Shc. In contrast, the Neu-YB mouse model displayed a unique pathology with a high metastatic potential that correlates with a distinct transcriptional profile. We identified genes specifically expressed in YB-induced mammary tumours, including CXCL12/SDF-1Î± that promotes malignant tumour progression. Furthermore, Neu-YB tumour epithelial cells showed abundant intracellular CXCL12/SDF-1Î± protein, which may reflect the more aggressive phenotype among all Neu mutant mouse models. These findings indicate that activation of distinct Neu-coupled signalling pathways has a deep impact on the biological behaviour of Neu-induced tumours. Experiment Overall Design: Total RNA was isolated from 10 individual flash frozen mammary tumour samples derived from our MMTV/neundl-NYPD, -YB, -YC, -YD, -YE and the parental MMTV/neu NDL2-5 strains. Two RNA pools, containing equal amount of total RNA from five individual tumours, were generated from each strain and functioned as a biological repeat. Five hundred nanograms of total RNA from each pool was subjected to one round of T7 linear amplification using the Amino Allyl MessageAmpTM aRNA Kit (Ambion, Austin, Texas). Ten micrograms of the resulting aRNA was labelled with Cy3 and Cy5 dyes. Each of the 12 Samples represents a dyeswap pair.

Dataset Information

Suppression of Lung Adenocarcinoma Progression by Nkx2-1

Publications

Suppression of lung adenocarcinoma progression by Nkx2-1.

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