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1.
Cell ; 156(6): 1298-1311, 2014 Mar 13.
Article in English | MEDLINE | ID: mdl-24630729

ABSTRACT

Small cell lung carcinoma (SCLC) is a highly lethal, smoking-associated cancer with few known targetable genetic alterations. Using genome sequencing, we characterized the somatic evolution of a genetically engineered mouse model (GEMM) of SCLC initiated by loss of Trp53 and Rb1. We identified alterations in DNA copy number and complex genomic rearrangements and demonstrated a low somatic point mutation frequency in the absence of tobacco mutagens. Alterations targeting the tumor suppressor Pten occurred in the majority of murine SCLC studied, and engineered Pten deletion accelerated murine SCLC and abrogated loss of Chr19 in Trp53; Rb1; Pten compound mutant tumors. Finally, we found evidence for polyclonal and sequential metastatic spread of murine SCLC by comparative sequencing of families of related primary tumors and metastases. We propose a temporal model of SCLC tumorigenesis with implications for human SCLC therapeutics and the nature of cancer-genome evolution in GEMMs.


Subject(s)
Carcinogenesis , Disease Models, Animal , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Small Cell Lung Carcinoma/genetics , Small Cell Lung Carcinoma/pathology , Animals , Humans , Liver Neoplasms/secondary , Lymphatic Metastasis , Mice , PTEN Phosphohydrolase/genetics , PTEN Phosphohydrolase/metabolism , Small Cell Lung Carcinoma/secondary
2.
Article in English | MEDLINE | ID: mdl-21897809

ABSTRACT

Olfactory sensory neurons (OSNs) are thought to use activity-dependent and independent mechanisms to regulate the expression of axon guidance genes. However, defining the molecular mechanisms that underlie activity-dependent OSN guidance has remained elusive. Only a handful of genes have been identified whose expression is regulated by activity. Interestingly, all of these genes have been shown to play a role in OSN axon guidance, underscoring the importance of identifying other genes regulated by activity. Furthermore, studies suggest that more than one downstream mechanism regulates target gene expression. Thus, both the number of genes regulated by activity and how many total mechanisms control this expression are not well understood. Here we identify delta protocadherin 10 (pcdh10) as a gene regulated by activity. Delta protocadherins are members of the cadherin superfamily, and pcdh10 is known to be important for axon guidance during development. We show pcdh10 is expressed in the nasal epithelium and olfactory bulb in patterns consistent with providing guidance information to OSNs. We use naris occlusion, genetic manipulations, and pharmacological assays to show pcdh10 can be regulated by activity, consistent with activation via the cyclic nucleotide-gated channel. Transgenic analysis confirms a potential role for pcdh10 in OSN axon guidance.

3.
Genes Dev ; 25(14): 1470-5, 2011 Jul 15.
Article in English | MEDLINE | ID: mdl-21764851

ABSTRACT

Small cell lung cancer (SCLC) is an aggressive cancer often diagnosed after it has metastasized. Despite the need to better understand this disease, SCLC remains poorly characterized at the molecular and genomic levels. Using a genetically engineered mouse model of SCLC driven by conditional deletion of Trp53 and Rb1 in the lung, we identified several frequent, high-magnitude focal DNA copy number alterations in SCLC. We uncovered amplification of a novel, oncogenic transcription factor, Nuclear factor I/B (Nfib), in the mouse SCLC model and in human SCLC. Functional studies indicate that NFIB regulates cell viability and proliferation during transformation.


Subject(s)
NFI Transcription Factors/genetics , NFI Transcription Factors/metabolism , Oncogenes/physiology , Small Cell Lung Carcinoma/genetics , Animals , Animals, Genetically Modified , Apoptosis , Cell Line, Tumor , Cell Proliferation , Cell Survival/genetics , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , Disease Models, Animal , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Mice , Oncogenes/genetics
4.
Nature ; 462(7269): 104-7, 2009 Nov 05.
Article in English | MEDLINE | ID: mdl-19847165

ABSTRACT

NF-kappaB transcription factors function as crucial regulators of inflammatory and immune responses as well as of cell survival. They have also been implicated in cellular transformation and tumorigenesis. However, despite extensive biochemical characterization of NF-kappaB signalling during the past twenty years, the requirement for NF-kappaB in tumour development in vivo, particularly in solid tumours, is not completely understood. Here we show that the NF-kappaB pathway is required for the development of tumours in a mouse model of lung adenocarcinoma. Concomitant loss of p53 (also known as Trp53) and expression of oncogenic Kras(G12D) resulted in NF-kappaB activation in primary mouse embryonic fibroblasts. Conversely, in lung tumour cell lines expressing Kras(G12D) and lacking p53, p53 restoration led to NF-kappaB inhibition. Furthermore, the inhibition of NF-kappaB signalling induced apoptosis in p53-null lung cancer cell lines. Inhibition of the pathway in lung tumours in vivo, from the time of tumour initiation or after tumour progression, resulted in significantly reduced tumour development. Together, these results indicate a critical function for NF-kappaB signalling in lung tumour development and, further, that this requirement depends on p53 status. These findings also provide support for the development of NF-kappaB inhibitory drugs as targeted therapies for the treatment of patients with defined mutations in Kras and p53.


Subject(s)
Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Disease Models, Animal , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , NF-kappa B/metabolism , Signal Transduction , Animals , Apoptosis , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line , Cell Line, Tumor , Cell Survival , Cells, Cultured , DNA/metabolism , Fibroblasts , Genes, p53/genetics , Humans , Mice , NF-kappa B/antagonists & inhibitors , Oncogene Protein p21(ras)/genetics , Oncogene Protein p21(ras)/metabolism , Transcription Factor RelA/metabolism , Tumor Suppressor Protein p53/deficiency , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism
5.
Nat Protoc ; 4(7): 1064-72, 2009.
Article in English | MEDLINE | ID: mdl-19561589

ABSTRACT

The development of animal models of lung cancer is critical to our understanding and treatment of the human disease. Conditional mouse models provide new opportunities for testing novel chemopreventatives, therapeutics and screening methods that are not possible with cultured cell lines or xenograft models. This protocol describes how to initiate tumors in two conditional genetic models of human non-small cell lung cancer (NSCLC) using the activation of oncogenic K-ras alone or in combination with the loss of function of p53. We discuss methods for sporadic expression of Cre in the lungs through engineered adenovirus or lentivirus, and provide a detailed protocol for the administration of the virus by intranasal inhalation or intratracheal intubation. The protocol requires 1-5 min per mouse with an additional 30-45 min to set-up and allow for the recovery of mice from anesthesia. Mice may be analyzed for tumor formation and progression starting 2-3 weeks after infection.


Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , Disease Models, Animal , Integrases/genetics , Lung Neoplasms/genetics , Adenoviridae/genetics , Animals , Gene Transfer Techniques , Genetic Vectors , Lentivirus/genetics , Mice
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