In this renewal application we extend previous studies on the metastatic phenotype within the stromal microenvironment by taking into consideration heterogeneity among malignant cells within a tumor, and the resulting biological consequences for long-term tumor maintenance (self-renewal) and metastasis. In preliminary studies we have identified a slowly-cycling sub-population within melanomas that gives rise to a rapidly proliferating progeny and possesses self-renewal capacity. Cells of this sub-population are characterized by expression of the histone 3 K4 demethylase JARID1B, which is a member of the highly conserved jumonji family of chromatin regulators. Knockdown of JARID1B in xenografted melanoma cells leads to a decrease in metastases, suggesting JARID1B-positive cells to be potential 'seeds'for tumor maintenance. Expression of JARID1B is dynamically regulated and does not follow a hierarchical cancer stem cell model as JARID1B-negative cells can become positive, and even single melanoma cells, irrespective of any marker expression, are tumorigenic. Because stable down-regulation of JARID1B expression leads, after several consecutive in vivo passages, to loss of tumorigenicity, we are developing in Specific Aim 1 a dynamic equilibrium model for tumor cells. In this model JARID1B expression is required for tumors to self-renew, but JARID-negative cells can regain JARID1B expression depending on the microenvironmental context. Due to their slowly-cycling phenotype, JARID1B-positive cells are expected to survive exogenous stress, e.g. by an initially hostile microenvironment after implantation or chemotherapy. We address in Specific Aim 2 the 'soil'for malignant cells, which is in part provided by the malignant cells themselves and in part by stromal cells. We are testing the hypothesis that expression of JARID1B at the site of metastasis is dynamically regulated through interactions (i) amongst tumor cells and (ii) tumor cells and matrix. For cell-cell signaling, our focus is on Notch 1, because our preliminary studies suggest that Notch 1 is differentially regulated between the slowly-cycling JARID1B-positive subpopulation and the main population. For cell-matrix interactions, we will focus on the matricellular protein tenascin C, which is highly produced by melanoma cells and is expressed by stromal fibroblasts. We expect from these studies a better understanding of the JARID1B-positive population for metastatic progression.
This application on Biology of Melanoma Metastasis deals with critical questions on tumor latency and progression. In many cancers including melanoma, tumors can recur ten or more years after the initial surgery for removal of the primary lesion. This proposal deals with models to demonstrate that tumors have at least two populations, a small, slowly proliferating population with self-renewal capacity and a rapidly proliferating and invasive major population. We suggest that slow-cycling and self-renewing tumor cells are responsible for progression including metastasis.
|Vultur, A; Villanueva, J; Krepler, C et al. (2014) MEK inhibition affects STAT3 signaling and invasion in human melanoma cell lines. Oncogene 33:1850-61|
|Wang, Tao; Ge, Yingbin; Xiao, Min et al. (2014) SECTM1 produced by tumor cells attracts human monocytes via CD7-mediated activation of the PI3K pathway. J Invest Dermatol 134:1108-18|
|Slipicevic, Ana; Somasundaram, Rajasekharan; Sproesser, Katrin et al. (2014) Isolation of melanoma cell subpopulations using negative selection. Methods Mol Biol 1102:501-12|
|Peng, Hongzhuang; Talebzadeh-Farrooji, Mehdi; Osborne, Michael J et al. (2014) LIMD2 is a small LIM-only protein overexpressed in metastatic lesions that regulates cell motility and tumor progression by directly binding to and activating the integrin-linked kinase. Cancer Res 74:1390-403|
|Swoboda, Rolf K; Herlyn, Meenhard (2013) There is a world beyond protein mutations: the role of non-coding RNAs in melanomagenesis. Exp Dermatol 22:303-6|
|Desai, Brijal M; Villanueva, Jessie; Nguyen, Thierry-Thien K et al. (2013) The anti-melanoma activity of dinaciclib, a cyclin-dependent kinase inhibitor, is dependent on p53 signaling. PLoS One 8:e59588|
|Roesch, Alexander; Vultur, Adina; Bogeski, Ivan et al. (2013) Overcoming intrinsic multidrug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1B(high) cells. Cancer Cell 23:811-25|
|Krepler, Clemens; Chunduru, Srinivas K; Halloran, Molly B et al. (2013) The novel SMAC mimetic birinapant exhibits potent activity against human melanoma cells. Clin Cancer Res 19:1784-94|
|Slipicevic, Ana; Herlyn, Meenhard (2012) Narrowing the knowledge gaps for melanoma. Ups J Med Sci 117:237-43|
|Wang, Tao; Ge, Yingbin; Xiao, Min et al. (2012) Melanoma-derived conditioned media efficiently induce the differentiation of monocytes to macrophages that display a highly invasive gene signature. Pigment Cell Melanoma Res 25:493-505|
Showing the most recent 10 out of 79 publications