Prostate cancer (CaP) metastases, especially to bone, are the cause of significant morbidity and mortality. Since all metastases emanate from disseminated tumor cells (DTC), the study of DTC is critical to our understanding of the metastatic process and the design of novel therapeutic strategies. In the past, the field has generally focused on the detection of these shed cells in the circulation or in bone marrow. We have recently turned our attention to the characterization of DTC which is imperative for further insight. We hypothesize that specific genomic and/or gene expression profiles of the DTC will be prognostic for both biochemical failure post radical prostatectomy and duration of response to androgen ablation. Also, we predict significant differences will be observed between these DTC profiles and those of the primary tumor. We also hypothesize that some of the DTC have cancer stem cell attributes while others isolated from patients who have no evidence of disease (NED) after surgery have attributes of dormant tumor cells.
Our Specific Aims are as follows:
Aim #1 : Detect, isolate and characterize the DTC from patients pre-radical prostatectomy who are at high risk (Gleason sum >6) of recurrence and correlate to outcome and profiles of the primary tumor.
Aim #2 : Detect, isolate and characterize the DTC from patients undergoing androgen ablation with comparison of profiles to that of bone and non-bone metastases.
Aim #3 : Define the biological functionality of DTC with regard to stem cell attributes, tumor cell dormancy and markers associated with bone metastases such as IGF-IR, RUNX2, and TMPRSS2-ERG gene fusions. The successful execution of these three aims will provide considerable insight on the biological character of the DTC in CaP. It may also provide a mechanism whereby the genomic profile of the DTC detected (a) eariy in disease may be predictive of recurrence and (b) late in disease may be predictive of the duration of response to androgen ablation. Finally, one of the most exciting aspects is our quest to determine if in some instances these DTC mimic cancer stem cells while in others they portray tumor cell dormancy.

Public Health Relevance

Since all metastases emanate from disseminated tumor cells (DTC), the study of DTC is critical to our understanding of the metastatic process. The biological and molecular character of these cells is largely unknown due to challenges in isolation and the very few cells obtained for study. We've made significant advances in this area and are prepared to explore potential attributes such as stem-cellness and dormancy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA085859-10
Application #
8518247
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
10
Fiscal Year
2013
Total Cost
$512,493
Indirect Cost
$118,540
Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Faltermeier, Claire M; Drake, Justin M; Clark, Peter M et al. (2016) Functional screen identifies kinases driving prostate cancer visceral and bone metastasis. Proc Natl Acad Sci U S A 113:E172-81
Morrissey, Colm; Vessella, Robert L; Lange, Paul H et al. (2016) The biology and clinical implications of prostate cancer dormancy and metastasis. J Mol Med (Berl) 94:259-65
Kumar, Akash; Coleman, Ilsa; Morrissey, Colm et al. (2016) Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer. Nat Med 22:369-78
Haider, Maahum; Zhang, Xiaotun; Coleman, Ilsa et al. (2016) Epithelial mesenchymal-like transition occurs in a subset of cells in castration resistant prostate cancer bone metastases. Clin Exp Metastasis 33:239-48
Wu, Yu; Schoenborn, Jamie R; Morrissey, Colm et al. (2016) High-Resolution Genomic Profiling of Disseminated Tumor Cells in Prostate Cancer. J Mol Diagn 18:131-43
Henzler, Christine; Li, Yingming; Yang, Rendong et al. (2016) Truncation and constitutive activation of the androgen receptor by diverse genomic rearrangements in prostate cancer. Nat Commun 7:13668
Brocqueville, Guillaume; Chmelar, Renee S; Bauderlique-Le Roy, Hélène et al. (2016) s-SHIP expression identifies a subset of murine basal prostate cells as neonatal stem cells. Oncotarget 7:29228-44
Qu, Xiaoyu; Jeldres, Claudio; Glaskova, Lena et al. (2016) Identification of Combinatorial Genomic Abnormalities Associated with Prostate Cancer Early Recurrence. J Mol Diagn 18:215-24
Yu, Shu-Han; Zheng, Qizhi; Esopi, David et al. (2015) A Paracrine Role for IL6 in Prostate Cancer Patients: Lack of Production by Primary or Metastatic Tumor Cells. Cancer Immunol Res 3:1175-84
Liu, Gang; Sprenger, Cynthia; Wu, Pin-Jou et al. (2015) MED1 mediates androgen receptor splice variant induced gene expression in the absence of ligand. Oncotarget 6:288-304

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