Metastasis of melanoma occurs from the primary site to draining lymph nodes. Once the malignant cells dislodge from the lymph node(s), they reach the blood circulatory system for dissemination to skin, lungs, and/or brain, where they are arrested in small endothelial vessels. Melanoma cells then invade the endothelial basement membranes and tissue parenchyma for local growth. When the tumor cells invade existing vessels, they begin a new cycle o the metastatic cascade. This proposal describes models that dissect each step of the cascade such as the arrest of melanoma cells in distant blood vessels i the human graft, extravasation, growth in skin, intravasation into new vessels and, finally, metastasis from the first site to a secondary human skin site using in vitro reconstructs of human vessels embedded in artificial human skin and intact human skin grafted to immunodeficient SCID mice. Two adhesion receptors, Mel-CAM and alpha v beta3, are critical for melanoma growth and invasion, because a) their expression correlates with tumor progression; b) overexpression of either receptor in non-invasive and non-tumorigenic melanoma cells of the radial growth phase (RGP) induces an invasive and tumorigenic phenotype; and c) genetic suppressor elements in sense or antisense orientatio that downregulate either the expression or the functions of these receptors suppress the aggressive phenotype in highly tumorigenic and metastatic cells. The applicant will now test the roles in each step of the metastatic cascade, thus linking Mel-CAM, a heterotypic cell-cell adhesion receptor of the immunoglobulin supergene family, and alpha v beta3, the multivalent vitronecti receptor, to tissue degradation, cell motility, and cell growth. The resulting new tools and models will provide a first step in developing adhesion antagonists for melanoma metastasis intervention, and they will help to better understand the signaling pathways triggering melanoma growth and invasion.
| 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 |
Showing the most recent 10 out of 102 publications
