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Study of LGI4 effects on the mitotic spindle control

Grant number: 16/08860-7
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): July 29, 2016
Effective date (End): July 28, 2017
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Anamaria Aranha Camargo
Grantee:Mariana Lemos Duarte
Supervisor abroad: Karen F. Oegema
Home Institution: Hospital Sírio-Libanês. Sociedade Beneficente de Senhoras (SBSHSL). São Paulo , SP, Brazil
Local de pesquisa : Ludwig Institute for Cancer Research, San Diego, United States  
Associated to the scholarship:13/50101-8 - Interaction analysis between LGI-4 and ADAM23 proteins and their relevance during the metastatic process, BP.PD

Abstract

Aneuploidy, an abnormal balance of chromosomes, is a common feature of solid tumors and is resulting from errors in chromosome segregation. Whether aneuploidy promotes or suppresses tumor initiation and progression is a controversial question, and the identification of new molecular mechanisms that underlie the chromosome segregation is relevant to our full understanding of genetic stability and tumorigenesis. Here we show that Leucine-Rich Glioma Inactivated-4 protein (LGI4), which is a putative secreted protein, was found in the cytoplasm associated with spindles and its knockdown leads to abnormal spindle assembly, reduction in tumor cell proliferation and increased rates of tumor cell death and senescence. In addition, reduced levels of LGI4 gene expression were observed in a variety of tumor tissues compared with their normal counterparts and it was strongly associated with poor prognosis in breast and ovarian cancer. The proposed research combines in vitro and in vivo approaches to elucidate the mechanisms by which LGI4 controls chromosome segregation and aneuploidy. We anticipate our proposal to be a starting point to explore the potential of LGI4 as a new target for anti-mitotic drugs. In order to explore our findings and determine how LGI4 contributes to spindle assembly, we propose a partnership with Dr. Karen Oegema, Head of the Laboratory of Mitotic Mechanisms at Ludwig San Diego and a Professor of Cellular and Molecular Medicine at the University of California. Our unanswered questions about LGI4 functions on tumor cells perfectly fit into Dr. Oegema specific area of interest, knowledge and expertise. In this matter, we believe that this BEPE proposal will be essential to achieve our goals.