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10月17日清华大学生物论坛-Joon Kim
发布时间:2017-10-16关键字:

 Title: YAP mediates BRAF inhibitor resistance and immune evasion in melanoma

Joon Kim, PhD

 

KAIST, Graduate School of Medical Science and Engineering, 291 Daehak-ro, Daejeon 34141, South Korea

 

Biography: Joon Kim is an associate professor at the Korea Advanced Institute of Science and Technology (KAIST). He has a broad background in developmental biology and cell biology. He received his PhD degree from the University of California Irvine. His research topic at the graduate school was cell number control in developing mouse retina (Science 2005, 308:1927). As a postdoc at the University of California San Diego, he studied the pathological mechanism of Joubert syndrome, a genetic disorder characterized by cerebellar vermis hypoplasia (Hum Mol Genet 2008, 17:3796). The unexpected finding that defects in primary cilia are associated with Joubert syndrome prompted him to study the biology of primary cilia (Nature 2010, 464:1048). In 2010, he was appointed as a faculty member at KAIST. His laboratory has two research themes. First, he seeks to understand the regulatory mechanisms governing the assembly of primary cilia (PNAS 2013, 110:5987). He is also interested in the involvement of primary cilia in tumorigenesis. Second, he studies the Hippo-YAP pathway, which plays key roles in tumorigenesis. Originally, he investigated YAP as a novel regulator of primary cilium assembly (Nat Communi 2015, 6:6781). Currently, he focuses on roles of YAP in melanoma (EMBO 2016, 35:462).

 

Abstract: YAP is a transcriptional co-activator that plays key roles in controlling tissue growth, regeneration, and stem cell homeostasis. Multiple functions of YAP in tumor initiation and progression have recently been reported. Moreover, aberrant activation of YAP has been recognized as one of the key resistance mechanisms to BRAF inhibitors (BRAFi) in melanoma. In this study, we show that YAP activation drives evasion of BRAFi-resistant melanoma cells from CD8+ T cell immune responses. We found that the expression of immunecheckpoint ligands is upregulated in BRAFi-resistant melanoma cells and that the upregulation is dependent on YAP activity. YAP binds to enhancer regions of the genes encoding immune checkpoint ligands, and interaction between YAP and the transcription factor TEAD is essential for the YAP-mediated transcriptional upregulation. In addition, we demonstrate that both BRAFi-resistant and constitutively active YAP-expressing melanoma cells can suppress cytotoxic effect and cytokine production of tumor-specific CD8+ T cells. Immunohistochemical staining of tumor specimens from 65 Korean melanoma patients reveals that nuclear YAP localization is associated with increased expression of immune checkpoint ligands in melanoma cells. Our findings suggest that YAP provides a mechanistic link between BRAFi resistance and immune evasion in the course of BRAFi treatment.

 

Time: Oct. 17th, 2017, 16:00

Venue: New Biology Building, Room 143

Host: Prof. Junmin Pan




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