Epithelial-to-Mesenchymal Transition in Pancreatic Cancer is associated with Restricted Water Diffusion in Diffusion-Weighted Magnetic Resonance Imaging

Abstract

Purpose: This study aimed to evaluate the potential of diffusion-weighted magnetic resonance imaging (DW-MRI) as imaging biomarker for epithelial-to-mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDAC). Methods: In forty-two patients, preoperative apparent diffusion coefficient (ADC) values of therapy-naive PDAC were compared with immunohistochemical expression profiles of the epithelial marker E-cadherin as well as mesenchymal transcription factors Runt-related transcription factor 2 (Runx2) and Zinc finger E-box-binding homeobox 1 (Zeb1), as determined by Allred immunoreactivity score. Results: We observed a significant positive rank correlation between the ADC and the E-cadherin Allred score (ρ = 0.553, p < 0.001) and significant negative rank correlations between the ADC and the Runx2 Allred score (ρ = -0.526, p < 0.001) as well as the Zeb1 Allred score (ρ = -0.710, p < 0.001). Compared to tumors with low ADC values < 1.3 µm²/s, tumors with ADC values ≥ 1.3 µm²/s had significantly higher Allred scores for E-cadherin (median, 4 versus 5; p < 0.001) and significantly lower Allred scores for Runx2 (median, 3 versus 2; p = 0.003) as well as Zeb1 (median, 4 versus 0; p < 0.001). Conclusion: In PDAC, tumor plasticity in terms of EMT is well reflected by ADC values from DW-MRI. In the near future, DW-MRI could be beneficial for identification of PDAC patients that might profit from personalized EMT-targeted therapies.

Keywords: Pancreatic cancer; diffusion-weighted magnetic resonance imaging.; epithelial-to-mesenchymal transition.

Figure 1

Workflow of the study.

Figure 2

Box-and-whisker plots. The box-and-whisker plots show the distribution of ADC values relative to Allred scores of E-cadherin (A), Runx2 (B), and Zeb1 (C).

Figure 3

Images from a patient with high diffusivity. The T2-HASTE (Half-Fourier-Acquired Single-shot Turbo spin Echo) MR image shows the tumor in the pancreatic head (arrows). A VOI in red encompasses the tumor on the DW-MR images. Please note that the tumor is moderately hyperintense in the b₈₀₀ image and moderately hypointense in the ADC map. The ADC value of the tumor was 1.560 µm²/s. In immunohistochemistry (lower row), tumor cells showed a diffuse and strong E-cadherin expression (arrows in the left image) but were widely negative for Runx2 (arrows in the middle image) and Zeb1 (arrows in the right image). Please note the Zeb1-positive stroma cells (arrowheads in the right image).

Figure 4

Images from a patient with low diffusivity. The T2-HASTE MR image shows the tumor in the pancreatic head (arrows). A VOI in red encompasses the tumor on the DW-MR images. Please note that the tumor is markedly hyperintense in the b₈₀₀ image and markedly hypointense in the ADC map. The ADC value of the tumor was 1.048 µm²/s. In immunohistochemistry (lower row), tumor cells showed only focal membranous E-cadherin expression (arrows in the left image) but showed strong nuclear positivity for Runx2 (arrows in the middle image) and Zeb1 (arrows in the right image). Please note the Zeb1-positive stroma cells (arrowheads in the right image).

Figure 5

Schematic representation of the dependency of the MRI diffusivity on EMT. Epithelial type PDAC with high expression of E-cadherin exhibit significantly higher diffusivity (arrows) in DW-MRI than mesenchymal type PDAC with low expression of E-cadherin and higher expression of Runx2 and Zeb1.