The goals of this hamartoma research proposal overall are to elucidate the molecular signaling pathways that regulate cell size and growth responses involving the tumor suppressor genes TSCl, TSC2, LKBI, and PTEN, and to identify molecular markers and therapeutic targets. Thus, the overall goal of this research program is to provide insight into the pathogenesis of the tumors that occur in tuberous sclerosis (TSC), Peutz-Jeghers syndrome (PJS), and the PTEN syndromes. The focus of the studies proposed in Projects 1, 2, and 3 is to improve our understanding the cellular function of the proteins encoded by these genes, through identification and characterization of phosphorylation targets, interacting proteins, and those proteins which are critical downstream or upstream elements in these pathways, and testing these hypothesis in mouse animal models.
The Specific Aims are Aim 1. To provide a pathology expertise and tissue samples for use by investigators of this P01 for the proposed studies of hamartoma tumor suppressor genes.
Aim 2. To perform immunohistochemical studies on human hamartoma and cancer specimens, to extend pathway connections from tissue culture and mouse model studies.
Aim 3. To study renal cell carcinomas related to TSC patients and TSC1/2 genes. TSC patients are known to have increased risk of developing renal cell carcinoma. We will perform whole genome exon squencing of these tumor samples.

Public Health Relevance

The role of this core is to provide critically necessary pathologic materials and pathologic expertise for the review and interpretation of translation of molecular findings discovered by the Projects to human tumor specimens, including hamartoma tumors and human cancers. This is critically important, because findings from cellular and mouse model systems must be validated in human clinical specimens.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-RPRB-O)
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Brigham and Women's Hospital
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Liu, Yang; Kwiatkowski, David J (2015) Combined CDKN1A/TP53 mutation in bladder cancer is a therapeutic target. Mol Cancer Ther 14:174-82
Lall, R; Ganapathy, S; Yang, M et al. (2014) Low-dose radiation exposure induces a HIF-1-mediated adaptive and protective metabolic response. Cell Death Differ 21:836-44
Menon, Suchithra; Dibble, Christian C; Talbott, George et al. (2014) Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell 156:771-85
Tchaicha, Jeremy H; Akbay, Esra A; Altabef, Abigail et al. (2014) Kinase domain activation of FGFR2 yields high-grade lung adenocarcinoma sensitive to a Pan-FGFR inhibitor in a mouse model of NSCLC. Cancer Res 74:4676-84
Bordoli, Mattia R; Yum, Jina; Breitkopf, Susanne B et al. (2014) A secreted tyrosine kinase acts in the extracellular environment. Cell 158:1033-44
Guo, Y; Chirieac, L R; Bueno, R et al. (2014) Tsc1-Tp53 loss induces mesothelioma in mice, and evidence for this mechanism in human mesothelioma. Oncogene 33:3151-60
Tyburczy, Magdalena E; Wang, Ji-An; Li, Shaowei et al. (2014) Sun exposure causes somatic second-hit mutations and angiofibroma development in tuberous sclerosis complex. Hum Mol Genet 23:2023-9
González-Billalabeitia, Enrique; Seitzer, Nina; Song, Su Jung et al. (2014) Vulnerabilities of PTEN-TP53-deficient prostate cancers to compound PARP-PI3K inhibition. Cancer Discov 4:896-904
Kraus, Daniel; Yang, Qin; Kong, Dong et al. (2014) Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity. Nature 508:258-62
Yang, Ping; Cornejo, Kristine M; Sadow, Peter M et al. (2014) Renal cell carcinoma in tuberous sclerosis complex. Am J Surg Pathol 38:895-909

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