Identification of genomic and molecular traits that present therapeutic vulnerability to HGF-targeted therapy in glioblastoma

Jason K. Sa, Sung Heon Kim, Jin Ku Lee, Hee Jin Cho, Yong Jae Shin, Hyemi Shin, Harim Koo, Donggeon Kim, Mijeong Lee, Wonyoung Kang, Sung Hee Hong, Jung Yong Kim, Young Whan Park, Seong Won Song, Song Jae Lee, Kyeung Min Joo, Do Hyun Nam

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)


Background Cancer is a complex disease with profound genomic alterations and extensive heterogeneity. Recent studies on large-scale genomics have shed light on the impact of core oncogenic pathways, which are frequently dysregulated in a wide spectrum of cancer types. Aberrant activation of the hepatocyte growth factor (HGF) signaling axis has been associated with promoting various oncogenic programs during tumor initiation, progression, and treatment resistance. As a result, HGF-targeted therapy has emerged as an attractive therapeutic approach. However, recent clinical trials involving HGF-targeted therapies have demonstrated rather disappointing results. Thus, an alternative, in-depth assessment of new patient stratification is necessary to shift the current clinical course. Methods To address such challenges, we have evaluated the therapeutic efficacy of YYB-101, an HGF-neutralizing antibody, in a series of primary glioblastoma stem cells (GSCs) both in vitro and in vivo. Furthermore, we performed genome and transcriptome analysis to determine genetic and molecular traits that exhibit therapeutic susceptibility to HGF-mediated therapy. Results We have identified several differentially expressed genes, including MET, KDR, and SOX3, which are associated with tumor invasiveness, malignancy, and unfavorable prognosis in glioblastoma patients. We also demonstrated the HGF-MET signaling axis as a key molecular determinant in GSC invasion, and we discovered that a significant association in HGF expression existed between mesenchymal phenotype and immune cell recruitment. Conclusions Upregulation of MET and mesenchymal cellular state are essential in generating HGF-mediated therapeutic responses. Our results provide an important framework for evaluating HGF-targeted therapy in future clinical settings.

Original languageEnglish
Pages (from-to)222-233
Number of pages12
Issue number2
Publication statusPublished - 2019 Feb 14
Externally publishedYes


  • HGF
  • MET
  • glioblastoma
  • mesenchymal subtype
  • tumor-associated macrophages

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research


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