Since the majority of cancer deaths and morbidity are due to metastases, major improvements in survival and quality of life will occur when metastasis are prevented or more effectively treated. Determining whether the KISS1 metastasis suppressor can maintain disseminated tumor cells in a non- proliferating, dormant state may provide a novel approach to cancer therapy. BACKGROUND: Re-expression of KISS1 blocks the ability of melanoma cells to colonize multiple ectopic sites while still completing antecedent steps of the metastatic cascade. KISS1 is processed into numerous peptides, termed kisspeptins. Some kisspeptins bind to and stimulate a G-protein coupled receptor, GPR54;however, metastasis suppression does not appear to require tumor cell GPR54 expression. HYPOTHESIS #1: KISS1 re- expression will halt further growth of established (micro)metastases.
Specific Aim 1 : Using Tet-inducible expression vectors in GFP-expressing melanoma cells seeding lung, KISS1 expression will be induced or turned off when lung foci are different sizes. Further growth, regression or induced dormancy will be assessed by fluorescence microscopy. Implications: If KISS1 could halt progression or reverse established metastases, its utility for treatment of human cancer would increase significantly. HYPOTHESIS #2: Selected kisspeptins are responsible for metastasis suppression.
Specific Aim 2 : Preliminary data show that KISS1 ->kisspeptins processing occurs outside the cell, but which kisspeptin(s) suppresses metastasis has not been determined. Using site-directed mutagenesis, disruption of KISS1->kisspeptin processing sites (R-R or R-K) in KISS1 and ectopic expression of the processing mutants will be done followed by assessment of kisspeptin-induced signaling thru GPR54 and metastatic potential. Implications: Identifying which kisspeptin(s) are responsible for metastasis suppression will focus future agonist development. HYPOTHESIS #3: KISS1 suppresses metastasis via paracrine signaling with stromal cells.
Specific Aim 3 : Preliminary data show that tumor cells suppressed by re-expression of KISS1 do not express GPR54, suggesting that KISS1 production by tumor cells acts via intermediary cells (i.e., paracrine). The initial working hypothesis is that stromal fibroblasts are the intermediary cell because they express GPR54 in vitro. Using RTQ and IHC, we will determine which stromal cells express GPR54 in situ. 2D and 3D co-culture of parental and KISS1-expressing cells with fibro- blasts from different tissues will assess whether differential response of tissue stroma to KISS1 returns growth promoting or growth inhibitory signals to tumor cells. Implications: These experiments ultimately test what the actual target of KISS1 is with regard to metastasis suppression. Utilization in the clinic will vary depending upon whether one is targeting tumor cells or normal cells. Data from the proposed experiments will determine the molecular and cellular target(s) of specific kisspeptin(s) and aspects of the timing of exposure required to suppress metastasis. Those data will be crucial if KISS1 is to be developed as an anti-metastatic therapy.

Public Health Relevance

Since the majority of cancer deaths and morbidity are due to metastases, major improvements in survival and quality of life will occur when metastasis are prevented or more effectively treated. We propose a mechanism-based study that will allow us to develop a novel anti-metastasis strategy to treat cancer. The approach is to use the KISS1 metastasis suppressor (or derivative kisspeptins) to maintain disseminated tumor cells in a non-proliferating, dormant state (rendering metastases a chronic, controllable disease rather than an acute situation) while simultaneously determining the molecular and cellular target(s) of specific kisspeptin(s) and aspects of the timing of exposure required to suppress metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA134981-04
Application #
8332140
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Woodhouse, Elizabeth
Project Start
2009-09-01
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$3,278
Indirect Cost
$1,107
Name
University of Kansas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Khotskaya, Yekaterina B; Beck, Benjamin H; Hurst, Douglas R et al. (2014) Expression of metastasis suppressor BRMS1 in breast cancer cells results in a marked delay in cellular adhesion to matrix. Mol Carcinog 53:1011-26
Balgkouranidou, I; Chimonidou, M; Milaki, G et al. (2014) Breast cancer metastasis suppressor-1 promoter methylation in cell-free DNA provides prognostic information in non-small cell lung cancer. Br J Cancer 110:2054-62
Bohl, Christopher R; Harihar, Sitaram; Denning, Warren L et al. (2014) Metastasis suppressors in breast cancers: mechanistic insights and clinical potential. J Mol Med (Berl) 92:13-30
Harihar, Sitaram; Pounds, Keke M; Iwakuma, Tomoo et al. (2014) Furin is the major proprotein convertase required for KISS1-to-Kisspeptin processing. PLoS One 9:e84958
Jones, Jacqueline; Wang, Honghe; Karanam, Balasubramanyam et al. (2014) Nuclear localization of Kaiso promotes the poorly differentiated phenotype and EMT in infiltrating ductal carcinomas. Clin Exp Metastasis 31:497-510
Liu, Wen; Vivian, Carolyn J; Brinker, Amanda E et al. (2014) Microenvironmental Influences on Metastasis Suppressor Expression and Function during a Metastatic Cell's Journey. Cancer Microenviron 7:117-31
Xiao, Lifu; Harihar, Sitaram; Welch, Danny R et al. (2014) Imaging of epidermal growth factor receptor on single breast cancer cells using surface-enhanced Raman spectroscopy. Anal Chim Acta 843:73-82
Liu, Wen; Beck, Benjamin H; Vaidya, Kedar S et al. (2014) Metastasis suppressor KISS1 seems to reverse the Warburg effect by enhancing mitochondrial biogenesis. Cancer Res 74:954-63
Chimonidou, Maria; Kallergi, Galatea; Georgoulias, Vassilis et al. (2013) Breast cancer metastasis suppressor-1 promoter methylation in primary breast tumors and corresponding circulating tumor cells. Mol Cancer Res 11:1248-57
Fetterman, Jessica L; Zelickson, Blake R; Johnson, Larry W et al. (2013) Mitochondrial genetic background modulates bioenergetics and susceptibility to acute cardiac volume overload. Biochem J 455:157-67

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