Abstract
BackgroundNon-small cell lung cancer (NSCLC) is the foremost cause of cancer-related death in Western countries, which is due partly to the propensity of NSCLC cells to metastasize. The biologic basis for NSCLC metastasis is not well understood.Methodology/Principal FindingsHere we addressed this deficiency by transcriptionally profiling tumors from a genetic mouse model of human lung adenocarcinoma that develops metastatic disease owing to the expression of K-rasG12D and p53R172H. We identified 2,209 genes that were differentially expressed in distant metastases relative to matched lung tumors. Mining of publicly available data bases revealed this expression signature in a subset of NSCLC patients who had a poorer prognosis than those without the signature.Conclusions/SignificanceThese findings provide evidence that K-rasG12D; p53R172H mice recapitulate features of human NSCLC metastasis and will provide a useful platform on which to study the biologic basis for lung adenocarcinoma metastasis and its prevention by novel agents.
Highlights
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in the United States and other western countries
We postulated that the biologic processes mediating metastasis in KrasLA1/+; p53R172HDG/+ mice would recapitulate those in a subset of NSCLC patients
We identified a metastasis expression signature in KrasLA1/+; p53R172HDG/+ mice that was present in primary tumors from NSCLC patients who had poor prognosis
Summary
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in the United States and other western countries. We understand much more about cancer cell-autonomous genetic and epigenetic changes than about the role of the supportive microenvironment To address this need, we and other investigators have developed mouse models in which lung adenocarcinomas arise spontaneously owing to mutant K-ras alleles expressed inducibly, conditionally, or somatically [1,2,3,4,5]. We and other investigators have developed mouse models in which lung adenocarcinomas arise spontaneously owing to mutant K-ras alleles expressed inducibly, conditionally, or somatically [1,2,3,4,5] An improvement, these models uniformly lack metastatic potential, a serious deficiency given that metastasis is the most common cause of death in NSCLC patients. The biologic basis for NSCLC metastasis is not well understood
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