The main objective of this proposal is to conduct indepth studies of mechanisms underlying tumor invasion and metastasis in human melanoma. This will be accomplished by gaining a basic understanding of some of the complex processes involved in tumor-cell substratum interactions at the molecular and biological levels. Two major approaches will be employed: First, specific monoclonal and polyclonal antibodies will be used as molecular probes to characterize the structural, functional and biosynthetic properties of two distinct chemically defined antigens expressed on the human melanoma cell surface that are directly involved in the capacity of such cells to adhere to and migrate on the extracellular matrix. The target antigens include the disialogangliosides GD3 and GD2 as well as a 130/105 kDa glycoprotein adhesion receptor complex expressed on the surface of human melanoma cells. Such studies will examine the functional role of these structures in the biological properties of human melanoma cells with regard to attachment and migration on individual adhesive proteins as well as on intact extracellular matrix. Second, an experimental animal model for human melanoma metastasis will be used together with human melanoma cell lines derived from the same patient's primary and metastatic lesions to examine the in vivo significance of these antigenic structures on the surface of human melanoma cells and assess their relevance for metastatic disease. The basic rationale underlying this research proposal is that in order to metastasize a human tumor cell must be able to attach and invade normal host tissues. The extracellular matrix of normal host tissue provides the natural barrier as well as the substrate for the metastatic tumor cell. Therefore, it is imperative to gain an understanding of the molecular and biological events that take place between the tumor cell surface and the extracellular matrix. This will be done by an in depth study of two independent, structurally defined antigenic groups expressed on the surface of metastatic human melanoma cells. One antigenic group includes epitopes associated with the oligosaccharide portion of the disialogangliosides GD2 and GD3. The other antigenic group includes epitopes associated with glycoprotein receptors capable of recognizing individual components within the extracellular matrix by direct recognition of the sequence Arg-Gly-Asp (RGD) known to specify the cell binding domain of the extracellular matrix proteins fibronectin, vitronectin, collagen, von Willebrand factor and fibrinogen. It is anticipated that the approaches delineated here will eventually provide a more basic understanding of tumor invasion and metastasis in human melanoma that may ultimately lead to the development of new approaches for the treatment of metastatic disease.
| Seguin, Laetitia; Camargo, Maria F; Wettersten, Hiromi I et al. (2017) Galectin-3, a Druggable Vulnerability for KRAS-Addicted Cancers. Cancer Discov 7:1464-1479 |
| Cosset, Érika; Ilmjärv, Sten; Dutoit, Valérie et al. (2017) Glut3 Addiction Is a Druggable Vulnerability for a Molecularly Defined Subpopulation of Glioblastoma. Cancer Cell 32:856-868.e5 |
| Seguin, Laetitia; Desgrosellier, Jay S; Weis, Sara M et al. (2015) Integrins and cancer: regulators of cancer stemness, metastasis, and drug resistance. Trends Cell Biol 25:234-40 |
| Franovic, Aleksandra; Elliott, Kathryn C; Seguin, Laetitia et al. (2015) Glioblastomas require integrin ?v?3/PAK4 signaling to escape senescence. Cancer Res 75:4466-73 |
| Desgrosellier, Jay S; Lesperance, Jacqueline; Seguin, Laetitia et al. (2014) Integrin ?v?3 drives slug activation and stemness in the pregnant and neoplastic mammary gland. Dev Cell 30:295-308 |
| Seguin, Laetitia; Kato, Shumei; Franovic, Aleksandra et al. (2014) An integrin ??-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition. Nat Cell Biol 16:457-68 |
| Cheresh, David A; Stupack, Dwayne G (2014) Tumor angiogenesis: putting a value on plastic GEMMs. Circ Res 114:9-11 |
| Seguin, Laetitia; Gozo, Maricel; Weis, Sara M et al. (2014) Targeting the Achilles' heel of drug-resistant cancer stem cells. Cell Cycle 13:2017-8 |
| Lau, Steven K M; Shields, David J; Murphy, Eric A et al. (2012) EGFR-mediated carcinoma cell metastasis mediated by integrin ?v?5 depends on activation of c-Src and cleavage of MUC1. PLoS One 7:e36753 |
| Huang, M; Anand, S; Murphy, E A et al. (2012) EGFR-dependent pancreatic carcinoma cell metastasis through Rap1 activation. Oncogene 31:2783-93 |
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