Unknown,Transcriptomics,Genomics,Proteomics

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Stage-specific sensitivity to p53 restoration in lung cancer: tumor data

ABSTRACT: Tumorigenesis is a multistep process that results from the sequential accumulation of mutations in key oncogene and tumor-suppressor pathways. The quest to personalize cancer medicine based on targeting these underlying genetic abnormalities presupposes that sustained inactivation of tumor suppressors and activation of oncogenes are required for tumor maintenance. Mutations in the p53 tumor-suppressor pathway are a hallmark of cancer and significant efforts toward pharmaceutical reactivation of mutant p53 pathways are underway1-3. Here we show that restoration of p53 in established murine lung tumors leads to significant but incomplete tumor cell loss specifically in malignant adenocarcinomas but not in adenomas. Also, we define amplification of MAPK signaling as a critical determinant of malignant progression. The differential response to p53 restoration depends on activation of the Arf tumor suppressor downstream of hyperactive MAPK signaling. We propose that p53 naturally limits malignant progression by responding to increased oncogenic signaling, but is unresponsive to low levels of oncogene activity that are sufficient for early stages of lung tumor development. These data suggest that restoration of pathways important in tumor progression, as opposed to initiation, may lead to incomplete tumor regression due to the stage-heterogeneity of tumor cell populations. 18 tumors of different grade and treatment status. 6 treated grade 3, 4 treated grade2, 4 untreated grade3, 4 untreated grade2

ORGANISM(S): Mus musculus

SUBMITTER: Charles Whittaker

PROVIDER: E-GEOD-23874 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Stage-specific sensitivity to p53 restoration during lung cancer progression.

Feldser David M DM Kostova Kamena K KK Winslow Monte M MM Taylor Sarah E SE Cashman Chris C Whittaker Charles A CA Sanchez-Rivera Francisco J FJ Resnick Rebecca R Bronson Roderick R Hemann Michael T MT Jacks Tyler T

Nature 20101101 7323

Tumorigenesis is a multistep process that results from the sequential accumulation of mutations in key oncogene and tumour suppressor pathways. Personalized cancer therapy that is based on targeting these underlying genetic abnormalities presupposes that sustained inactivation of tumour suppressors and activation of oncogenes is essential in advanced cancers. Mutations in the p53 tumour-suppressor pathway are common in human cancer and significant efforts towards pharmaceutical reactivation of d ...[more]

PMID: 21107428

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Project description:Glioblastoma (GBM) is a highly lethal brain tumor presenting as one of two subtypes with distinct clinical histories and molecular profiles. The primary GBM subtype presents acutely as high-grade disease that typically harbors EGFR, PTEN and Ink4a/Arf mutations, and the secondary GBM subtype evolves from the slow progression of low-grade disease that classically possesses PDGF and p53 events1. Here, we show that concomitant CNS-specific deletion of p53 and Pten in the mouse CNS generates a penetrant acute-onset high-grade malignant glioma phenotype with striking clinical, pathological and molecular resemblance to primary GBM in humans. This genetic observation prompted p53 and PTEN mutational analysis in human primary GBM, demonstrating unexpectedly frequent inactivating mutations of p53 as well the expected PTEN mutations. Integrated transcriptomic profling, in silico promoter analysis and functional studies of murine neural stem cells (NSCs) established that dual, but not singular, inactivation of p53 and Pten promotes an undifferentiated state with high renewal potential and drives elevated c-Myc levels and its associated signature. Functional studies validated increased c-Myc activity as a potent contributor to the impaired differentiation and enhanced renewal of p53-Pten null NSCs as well as tumor neurospheres (TNSs) derived from this model. c-Myc also serves to maintain robust tumorigenic potential of p53-Pten null TNSs. These murine modeling studies, together with confirmatory transcriptomic/promoter studies in human primary GBM, validate a pathogenetic role of a common tumor suppressor mutation profile in human primary GBM and establish c-Myc as a key target for cooperative actions of p53 and Pten in the regulation of normal and malignant stem/progenitor cell differentiation, self-renewal and tumorigenic potential. We used microarrays to detail the gene expression difference of the p53-null and p53/Pten-doubly null neural stem cell after differentiation . Experiment Overall Design: transcriptome comparisons of 2 independent p53-null with 3 p53/Pten double-null murine NSCs at 1 day post exposure to the differentiation inducer.

Dataset Information

Stage-specific sensitivity to p53 restoration in lung cancer: tumor data

Publications

Stage-specific sensitivity to p53 restoration during lung cancer progression.

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