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

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.

Post-Translational Modifications That Drive Prostate Cancer Progression

“…As seen on Figure 1 , functional studies have revealed many kinases to be involved in prostate cancer biology. Growth factor and cytokine signaling conveyed by different receptor kinases (e.g., ErbB2 [ 47 ], FGFRs [ 48 , 49 , 50 , 51 , 52 , 53 ], IGF1R [ 54 , 55 , 56 , 57 , 58 ], CXCRs [ 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 ]) as well as plasma membrane and cytoplasm located kinases are shown to critically influence prostate cancer. As an example, MAPKs are serine/threonine kinases that link extracellular signals to downstream machinery that influences cell behaviors.…”

Investigating epithelial‐mesenchymal heterogeneity of tumors and circulating tumor cells with transcriptomic analysis and biophysical modeling

“…more mesenchymal) that the CTCs; moreover, it can have variable cell fractions too (Figure 5C, right). Moreover, three other CTC datasets from prostate, myeloma, and breast cancer [44][45][46] are mapped onto distinct model contour lines (Figure S7A). Interestingly, measuring both tumor and CTC MLR score allows to identify a single (k, c) parameter combination.…”

A comprehensive mechanistic basis of prostate cancer advancement & its personalized implementation-bridging the gap: present state and future prospect

“…Although, EGF functions as the predominant ligand for EGFR in early phases of localized prostate cancer formation but during late phase of metastatic CRPC development, TGFA plays a characteristic leading role in EGFR activation [98]. EGFR is primarily responsible for constitutive activation of oncogenesis through subsequent stimulation of diverse essential signaling mediators in order to trigger self-sufficiency in growth signaling through enhancement of prostate cancer cell growth and proliferation programs [99]. EGFR plays the most critical modulatory role during the development of androgen independence through post translational modification of androgen receptor (AR) in order to reactivate its downstream signaling in castration resistant condition [100].…”

“…Several pre-clinical studies on mouse model and clinical trials have indicated limited efficacies of EGFR targeting therapeutic inhibitors like Gefitinib, Erlotinib and BIBW-2992 due to overproduction of EGFR ligands by prostate tumor and its stromal microenvironments [101]. Currently, a number of EGFR targeting combination therapy and immunotherapy based approaches are evaluating their efficiencies for treatment of hormone refractory prostate cancer [97][98][99][100][101].…”