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.
| Jenkins, Russell W; Aref, Amir R; Lizotte, Patrick H et al. (2018) Ex Vivo Profiling of PD-1 Blockade Using Organotypic Tumor Spheroids. Cancer Discov 8:196-215 |
| Chen, Gang; Huang, Alexander C; Zhang, Wei et al. (2018) Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature 560:382-386 |
| Perego, M; Maurer, M; Wang, J X et al. (2018) A slow-cycling subpopulation of melanoma cells with highly invasive properties. Oncogene 37:302-312 |
| Cañadas, Israel; Thummalapalli, Rohit; Kim, Jong Wook et al. (2018) Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses. Nat Med 24:1143-1150 |
| Vitiello, Marianna; Tuccoli, Andrea; D'Aurizio, Romina et al. (2017) Context-dependent miR-204 and miR-211 affect the biological properties of amelanotic and melanotic melanoma cells. Oncotarget 8:25395-25417 |
| Krepler, Clemens; Sproesser, Katrin; Brafford, Patricia et al. (2017) A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma. Cell Rep 21:1953-1967 |
| Somasundaram, Rajasekharan; Zhang, Gao; Fukunaga-Kalabis, Mizuho et al. (2017) Tumor-associated B-cells induce tumor heterogeneity and therapy resistance. Nat Commun 8:607 |
| Leu, Julia I-Ju; Barnoud, Thibaut; Zhang, Gao et al. (2017) Inhibition of stress-inducible HSP70 impairs mitochondrial proteostasis and function. Oncotarget 8:45656-45669 |
| Shaffer, Sydney M; Dunagin, Margaret C; Torborg, Stefan R et al. (2017) Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance. Nature 546:431-435 |
| Shannan, Batool; Watters, Andrea; Chen, Quan et al. (2016) PIM kinases as therapeutic targets against advanced melanoma. Oncotarget 7:54897-54912 |
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