Spatial EGFR dynamics and metastatic phenotypes modulated by upregulated Ephb2 and Src pathways in advanced prostate cancer

Yen Liang Liu, Aaron M. Horning, Brandon Lieberman, Mirae Kim, Che Kuang Lin, Chia Nung Hung, Chih Wei Chou, Chiou Miin Wang, Chun Lin Lin, Nameer B. Kirma, Michael A. Liss, Rohan Vasisht, Evan P. Perillo, Katherine Blocher, Hannah Horng, Josephine A. Taverna, Jianhua Ruan, Thomas E. Yankeelov, Andrew K. Dunn, Tim H.M. HuangHsin Chih Yeh, Chun Liang Chen

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Advanced prostate cancer is a very heterogeneous disease reflecting in diverse regulations of oncogenic signaling pathways. Aberrant spatial dynamics of epidermal growth factor receptor (EGFR) promote their dimerization and clustering, leading to constitutive activation in oncogenesis. The EphB2 and Src signaling pathways are associated with the reorganization of the cytoskeleton leading to malignancy, but their roles in regulating EGFR dynamics and activation are scarcely reported. Using single-particle tracking techniques, we found that highly phosphorylated EGFR in the advanced prostate cancer cell line, PC3, was associated with higher EGFR diffusivity, as compared with LNCaP and less aggressive DU145. The increased EGFR activation and biophysical dynamics were consistent with high proliferation, migration, and invasion. After performing single cell RNA-seq on prostate cancer cell lines and circulating tumor cells from patients, we identified that upregulated gene expression in the EphB2 and Src pathways are associated with advanced malignancy. After dasatinib treatment or siRNA knockdowns of EphB2 or Src, the PC3 cells exhibited significantly lower EGFR dynamics, cell motility, and invasion. Partial inhibitory effects were also found in DU145 cells. The upregulation of parts of the EphB2 and Src pathways also predicts poor prognosis in the prostate cancer patient cohort of The Cancer Genome Atlas. Our results provide evidence that overexpression of the EphB2 and Src signaling pathways regulate EGFR dynamics and cellular aggressiveness in some advanced prostate cancer cells.

Original languageEnglish (US)
Article number1910
JournalCancers
Volume11
Issue number12
DOIs
StatePublished - Dec 2019

Keywords

  • Actin
  • Compartmentalization
  • Diffusivity
  • EGFR
  • Endocytosis
  • EphB2
  • Epithelial–mesenchymal transition
  • Metastasis
  • Prostate cancer
  • Single-particle tracking
  • Src

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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