Interaction analysis between LGI-4 and ADAM23 proteins and their relevance during the metastatic process

• Grant number: 13/50101-8
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: December 01, 2013
• End date: November 30, 2017
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Anamaria Aranha Camargo
• Grantee: Mariana Lemos Duarte
• Host Institution: Hospital Sírio-Libanês. Sociedade Beneficente de Senhoras (SBSHSL). São Paulo , SP, Brazil
• Associated scholarship(s): 16/08860-7 - Study of LGI4 effects on the mitotic spindle control, BE.EP.PD

Abstract

Metastasis, the spreading and the growth of tumor cells in discontinuous anatomic sites from the primary tumor, is the major cause of death for cancer patients. Ironically, on the perspective of tumor biology, mechanisms of action remain among the most obscure events of carcinogenesis. In this project, we intent to continue one line of research that initially appeared in our group, when we correlated the hypermethylation of Adam23 gene promoter with reduced levels of expression and characterized it, clinically, as an independent marker of worse prognosis for metastatic disease-free survival and overall survival. Our subsequent functional studies demonstrated that Adam23 acts as a pleiotropic molecule capable of both: positively modulate cell proliferation and tumorigenesis and negatively modulate migratory and invasive cell behavior. More recently, we found that the expression levels of Adam23 in human primary tumors may be heterogeneous, favoring the growth and progression of tumor metastasis through the cooperation between Adam23-positive and Adam23-negative cells coexisting within a single tumor. In this cooperative environment, Adam23-neaative cells induce a proliferative response in adjacent Adam23-positive cells through production of LGI-4 - a known Adam23-ligand. In this project we propose to understand the mechanisms triggered by interaction LGI-4/ADAM23, characterize their phenotypic effects in breast and melanoma human tumor cell lines, as well to develop small molecules that specifically interfere with this signaling and thereby negatively modulates cell proliferation. (AU)