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 #
5R01CA134981-05
Application #
8545686
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
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$275,619
Indirect Cost
$93,090
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
Kurahara, Hiroshi; Bohl, Christopher; Natsugoe, Shoji et al. (2016) Suppression of pancreatic cancer growth and metastasis by HMP19 identified through genome-wide shRNA screen. Int J Cancer 139:628-38
Welch, Danny R (2016) Tumor Cell Invasion-Not All Barriers Are Created Equal. Cancer Res 76:1675-6
Kesterson, Robert A; Johnson, Larry W; Lambert, Laura J et al. (2016) Generation of Mitochondrial-nuclear eXchange Mice via Pronuclear Transfer. Bio Protoc 6:
Welch, Danny R (2016) Tumor Heterogeneity--A 'Contemporary Concept' Founded on Historical Insights and Predictions. Cancer Res 76:4-6
Bi, Qian; Ranjan, Atul; Fan, Rui et al. (2015) MTBP inhibits migration and metastasis of hepatocellular carcinoma. Clin Exp Metastasis 32:301-11
Feeley, Kyle P; Bray, Alexander W; Westbrook, David G et al. (2015) Mitochondrial Genetics Regulate Breast Cancer Tumorigenicity and Metastatic Potential. Cancer Res 75:4429-36
Welch, Danny R; Antalis, Toni M; Burnstein, Kerry et al. (2015) Essential Components of Cancer Education. Cancer Res 75:5202-5
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

Showing the most recent 10 out of 34 publications