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 Huang; Hsin-Chih Yeh; Chun-Liang Chen

doi:10.3390/cancers11121910

Spatial EGFR Dynamics and Metastatic Phenotypes Modulated by Upregulated EphB2 and Src Pathways in Advanced Prostate Cancer

Cancers (Basel). 2019 Dec 1;11(12):1910. doi: 10.3390/cancers11121910.

Authors

Yen-Liang Liu^{1

2}, Aaron M Horning³, Brandon Lieberman⁴, Mirae Kim², Che-Kuang Lin³, Chia-Nung Hung³, Chih-Wei Chou³, Chiou-Miin Wang³, Chun-Lin Lin³, Nameer B Kirma³, Michael A Liss⁵, Rohan Vasisht², Evan P Perillo², Katherine Blocher², Hannah Horng⁶, Josephine A Taverna⁷, Jianhua Ruan⁸, Thomas E Yankeelov^{2

9

10

11

12}, Andrew K Dunn², Tim H-M Huang³, Hsin-Chih Yeh^{2

13}, Chun-Liang Chen³

Affiliations

¹ Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan.
² Department of Biomedical Engineering, University of Texas at Austin, 107 W. Dean Keeton, BME Building, Austin, TX 78712, USA.
³ Department of Molecular Medicine, Mays Cancer Center, University of Texas Health Science Center, 8210 Floyd Curl Drive, Mail code: 8257 , San Antonio, TX 78229, USA.
⁴ Department of Biology, Trinity University, San Antonio, TX 78212, USA.
⁵ Department of Urology, University of Texas Health Science Center, San Antonio, TX 78229, USA.
⁶ Department of Bioengineering, the University of Maryland, College Park, MD 20742, USA.
⁷ Department of Medicine, Mays Cancer Center, University of Texas Health Science Center, San Antonio, TX 78229, USA.
⁸ Department of Computer Science, University of Texas at San Antonio, TX 78249, USA.
⁹ Institute for Computational Engineering and Sciences, University of Texas at Austin, Austin, TX 78712, USA.
¹⁰ Department of Diagnostic Medicine, Dell Medical School, University of Texas at Austin, Austin, TX 78712, USA.
¹¹ Department of Oncology, Dell Medical School, University of Texas at Austin, Austin, TX 78712, USA.
¹² Livestrong Cancer Institutes, University of Texas at Austin, Austin, TX 78712, USA.
¹³ Texas Materials Institute, University of Texas at Austin, Austin, TX 78712, USA.

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.

Keywords: EGFR; EphB2; Src; actin; compartmentalization; diffusivity; endocytosis; epithelial–mesenchymal transition; metastasis; prostate cancer; single-particle tracking.

Abstract

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