EZH2 deletion does not affect acinar regeneration but restricts progression to pancreatic cancer in mice
Emilie Jaune-Pons, Xiaoyi Wang, Fatemeh Mousavi, Zachary Klassen, Abdessamad El Kaoutari, Kurt Berger, Charis Johnson, Mickenzie B. Martin, Saloni Aggarwal, Sukhman Brar, Muhammad Khalid, Joanna F. Ryan, Parisa Shooshtari, Angela J. Mathison, Nelson Dusetti, Raul Urrutia, Gwen Lomberk, Christopher L. Pin
Emilie Jaune-Pons, Xiaoyi Wang, Fatemeh Mousavi, Zachary Klassen, Abdessamad El Kaoutari, Kurt Berger, Charis Johnson, Mickenzie B. Martin, Saloni Aggarwal, Sukhman Brar, Muhammad Khalid, Joanna F. Ryan, Parisa Shooshtari, Angela J. Mathison, Nelson Dusetti, Raul Urrutia, Gwen Lomberk, Christopher L. Pin
View: Text | PDF
Research Article Oncology

EZH2 deletion does not affect acinar regeneration but restricts progression to pancreatic cancer in mice

Abstract

Enhancer of zeste homologue 2 (EZH2) is part of the Polycomb Repressor Complex 2, which promotes trimethylation of lysine 27 on histone 3 (H3K27me3) and gene repression. EZH2 is overexpressed in many cancers, and studies in mice attributed both prooncogenic and tumor suppressive functions to EZH2 in pancreatic ductal adenocarcinoma (PDAC). EZH2 deletion enhances de novo KRAS-driven neoplasia following pancreatic injury, while increased EZH2 expression in patients with PDAC is correlated to poor prognosis, suggesting a context-dependant effect for EZH2 in PDAC progression. In this study, we examined EZH2 in pre- and early neoplastic stages of PDAC. Using an inducible model to delete the SET domain of EZH2 in adult acinar cells (EZH2ΔSET), we showed that loss of EZH2 activity did not prevent acinar cell regeneration in the absence of oncogenic KRAS (KRASG12D) nor did it increase PanIN formation following KRASG12D activation in adult mice. Loss of EZH2 did reduce recruitment of inflammatory cells and, when combined with a more aggressive PDAC model, promoted widespread PDAC progression and remodeling of the tumor microenvironment. This study suggests that expression of EZH2 in adult acinar cells restricts PDAC initiation and progression by affecting both the tumor microenvironment and acinar cell differentiation.

Authors

Emilie Jaune-Pons, Xiaoyi Wang, Fatemeh Mousavi, Zachary Klassen, Abdessamad El Kaoutari, Kurt Berger, Charis Johnson, Mickenzie B. Martin, Saloni Aggarwal, Sukhman Brar, Muhammad Khalid, Joanna F. Ryan, Parisa Shooshtari, Angela J. Mathison, Nelson Dusetti, Raul Urrutia, Gwen Lomberk, Christopher L. Pin

×

Figure 8

EZH2ΔSET deletion increases ADM in the absence of the tissue microenvironment.

Options: View larger image (or click on image) Download as PowerPoint
EZH2ΔSET deletion increases ADM in the absence of the tissue microenvir...
(A) Experimental design for acinar cell isolation and embedding into collagen 22 days after KRASG12D induction. (B) Representative images of cell clusters 3 and 7 days after acinar cell isolation. Genotypes are indicated. Scale bar: 100 μm. (C) Quantification of the percentage of cell clusters with visible ADM, 1–9 days after acinar cell isolation. Fifty or more clusters were counted for each condition. Data are shown as mean ± SEM (n = 2 for Mist1creERT/– KRASG12D, n = 3 mice for KRASG12DEzh2ΔSET, n = 4 mice for KRASG12D, n = 5 mice for Ezh2ΔSET, n = 6 mice for control, and n = 7 mice for MKE). (D) Representative images of control acinar after 7 days of treatment with increasing amounts of EZH2 inhibitor EPZ6438. Scale bar: 100 μm. (E) Quantification of 50+ acinar clusters for each condition. Data are shown as mean ± SEM. n = 3. In all cases, significance was measured by a repeated measures 1-way ANOVA followed by Dunnett’s correction. *P ≤ 0.05, **P ≤ 0.01, ***P < 0.001.