Mitochondria! DNA mutations are found in essentially all adult solid tumors yet there remains a great need :or functional and mechanistic studies of these mutations and how they affect the malignant phenotype. Our jroad overarching goal is to understand these mechanisms in order to design more effective therapeutic and diagnostic tools for patient use. Because of our significant patient resources and our substantial previous experience and proven track record in these investigations, we are uniquely positioned to perform rigorous studies of mtDNA mutations in prostate cancer. We present preliminary data that mtDNA mutations enhance cellular reactive oxygen and prostate tumor growth, especially in the bone stromal microenvironment, an observation with obvious relevance to prostate cancer bone metastases. Further, we have begun to identify the (validated) gene expression signature of the interaction between mtDNA mutations in prostate cancer epithelial cells and bone stromal cells, thereby identifying specific signaling pathways (notably FGF-1 and FAK) responsible for this effect. Because these mutations are so common in prostate cancer and appear to be enhancing prostate tumor growth and metastasis, we will test the overall hypothesis that mtDNA mutations in prostate cancer are functionally important in prostate tumorigenesis and metastatic growth and survival in bone. In order to test this hypothesis, three specific aims are proposed. In the first aim we will use new mutations and new prostate cancer nuclear backgrounds to determine the effect of mutations in different respiratory complexes and whether the same signaling pathways already discovered are activated. The effect of mtDNA mutations on reactive oxygen (ROS) production, tumor growth and gene expression will be studied. In the second aim, we will manipulate ROS in both in vivo and in vitro experiments to determine whether this (ROS) is the key signaling pathway for the induction of FGF-1 and focal adhesion kinase (FAK) observed when prostate cancer cells with mtDNA mutation interact with bone stromal cells.
The third aim i s designed to determine whether clinical metastasis involves increased mtDNA mutation and how this affects adaptation in the bone metastatic site and cell signaling.

Public Health Relevance

Mutations in mitochondria! DNA are common in prostate cancer and enhance the cancer's ability to grow, especially in the bone. Because there are so few effective treatments for bone metastases, we will study the ways that these mutations allow this fatal form of prostate cancer to grow. By understanding how this works it is hoped that new treatments may one day be designed targeting this highly malignant form of the disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA098912-10
Application #
8528349
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
10
Fiscal Year
2013
Total Cost
$372,469
Indirect Cost
$39,848
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
Smith, Bethany N; Bhowmick, Neil A (2016) Role of EMT in Metastasis and Therapy Resistance. J Clin Med 5:
Torres, Mylin A; Yang, Xiaofeng; Noreen, Samantha et al. (2016) The Impact of Axillary Lymph Node Surgery on Breast Skin Thickening During and After Radiation Therapy for Breast Cancer. Int J Radiat Oncol Biol Phys 95:590-6
Farach, Andrew; Ding, Yi; Lee, MinJae et al. (2016) Neuronal Trans-Differentiation in Prostate Cancer Cells. Prostate 76:1312-25
Masko, Elizabeth M; Alfaqih, Mahmoud A; Solomon, Keith R et al. (2016) Evidence for Feedback Regulation Following Cholesterol Lowering Therapy in a Prostate Cancer Xenograft Model. Prostate :
Li, Qinlong; Yin, Lijuan; Jones, Lawrence W et al. (2016) Keratin 13 expression reprograms bone and brain metastases of human prostate cancer cells. Oncotarget :
Miyahira, Andrea K; Lang, Joshua M; Den, Robert B et al. (2016) Multidisciplinary intervention of early, lethal metastatic prostate cancer: Report from the 2015 Coffey-Holden Prostate Cancer Academy Meeting. Prostate 76:125-39
Grigore, Alexandru Dan; Jolly, Mohit Kumar; Jia, Dongya et al. (2016) Tumor Budding: The Name is EMT. Partial EMT. J Clin Med 5:
Fong, Eliza L S; Wan, Xinhai; Yang, Jun et al. (2016) A 3D in vitro model of patient-derived prostate cancer xenograft for controlled interrogation of in vivo tumor-stromal interactions. Biomaterials 77:164-72
Liu, Sandy; Cadaneanu, Radu M; Zhang, Baohui et al. (2016) Keratin 13 Is Enriched in Prostate Tubule-Initiating Cells and May Identify Primary Prostate Tumors that Metastasize to the Bone. PLoS One 11:e0163232
You, Sungyong; Knudsen, Beatrice S; Erho, Nicholas et al. (2016) Integrated Classification of Prostate Cancer Reveals a Novel Luminal Subtype with Poor Outcome. Cancer Res 76:4948-58

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