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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.

ORGANISM(S): Mus musculus

PROVIDER: GSE23874 | GEO | 2010/11/24

SECONDARY ACCESSION(S): PRJNA133171

REPOSITORIES: GEO

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

Project description: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. 3 cell lines each treated with Tamoxifen or EtOH vehicle. Tamoxifen treatment results in reactivation of p53 expression

2010-11-24 | E-GEOD-23873 | biostudies-arrayexpress

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

Project description: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

2010-11-24 | E-GEOD-23874 | biostudies-arrayexpress

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

2010-11-24 | GSE23873 | GEO

Alpha-ketoglutarate links p53 to cell fate during tumor suppression

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2019-09-09 | GSE114263 | GEO

Alpha-ketoglutarate links p53 to cell fate during tumor suppression

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2019-05-10 | GSE114342 | GEO

Mesothelioma-associated fibroblasts enhance proliferation and migration of malignant pleural mesothelioma cells via Met/PI3K and WNT signaling but do not protect against cisplatin

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2022-12-31 | E-MTAB-12179 | biostudies-arrayexpress

RABL6A promotes G1-S phase progression and pancreatic neuroendocrine tumor cell proliferation in an Rb1-dependent manner

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2014-07-01 | E-GEOD-53778 | biostudies-arrayexpress

Expression data from proliferating and senescent murine hepatic stellate cells

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2013-04-05 | E-GEOD-39469 | biostudies-arrayexpress

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