EZH2 Inhibition as New Epigenetic Treatment Option for Pancreatic Neuroendocrine Neoplasms (PanNENs)

被引:15
作者
April-Monn, Simon Leonhard [1 ,2 ]
Andreasi, Valentina [1 ,3 ,4 ]
Schiavo Lena, Marco [5 ]
Sadowski, Martin Carl [1 ]
Kim-Fuchs, Corina [6 ]
Buri, Michelle Claudine [1 ]
Ketkar, Avanee [1 ]
Maire, Renaud [1 ]
Di Domenico, Annunziata [1 ]
Schrader, Joerg [7 ]
Muffatti, Francesca [3 ]
Doglioni, Claudio [4 ,5 ]
Partelli, Stefano [3 ,4 ]
Falconi, Massimo [3 ,4 ]
Perren, Aurel [1 ,8 ,9 ]
Marinoni, Ilaria [1 ]
机构
[1] Univ Bern, Inst Pathol, CH-3008 Bern, Switzerland
[2] Univ Bern, Grad Sch Cellular & Biomed Sci, CH-3012 Bern, Switzerland
[3] Ist Sci San Raffaele, Pancreas Translat & Clin Res Ctr, Pancreat Surg Unit, I-20132 Milan, Italy
[4] Univ Vita Salute San Raffaele, Fac Med & Surg, I-20132 Milan, Italy
[5] Ist Sci San Raffaele, Unit Pathol, I-20132 Milan, Italy
[6] Univ Bern, Univ Hosp Bern, Dept Visceral Surg & Med, CH-3008 Bern, Switzerland
[7] Univ Med Ctr Hamburg Eppendorf, Dept Med, D-20251 Hamburg, Germany
[8] Univ Bern, Bern Ctr Precis Med, Bern, Switzerland
[9] Univ Hosp Bern, CH-3008 Bern, Switzerland
基金
瑞士国家科学基金会;
关键词
pancreatic neuroendocrine neoplasms; EZH2 (Enhancer of Zest homolog); tumor treatment; epigenetic treatment; histone modification; PROTEIN EZH2; OPEN-LABEL; TAZEMETOSTAT; MULTICENTER; LYMPHOMA; PATHWAY; TUMORS;
D O I
10.3390/cancers13195014
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Pancreatic neuroendocrine neoplasms are epigenetically driven tumors, but therapies against underlying epigenetic drivers are currently not available in the clinical practice. We aimed to investigate EZH2 (Enhancer of Zest homolog) expression in PanNEN and the impact of EZH2 inhibition in three different PanNEN preclinical models. EZH2 expression in PanNEN patient samples (n = 172) was assessed by immunohistochemistry and correlated with clinico-pathological data. Viability of PanNEN cell lines treated with EZH2 inhibitor (GSK126) was determined in vitro. Lentiviral transduction of shRNA targeting EZH2 was performed in QGP1 cells, and cell proliferation was measured. Rip1TAG2 mice underwent GSK126 treatment for three weeks starting from week 10 of age. Primary cells isolated from PanNEN patients (n = 6) were cultivated in 3D as islet-like tumoroids and monitored for 10 consecutive days upon GSK126 treatment. Viability was measured continuously for the whole duration of the treatment. We found that high EZH2 expression correlated with higher tumor grade (p < 0.001), presence of distant metastases (p < 0.001), and shorter disease-free survival (p < 0.001) in PanNEN patients. Inhibition of EZH2 in vitro in PanNEN cell lines and in patient-derived islet-like tumoroids reduced cell viability and impaired cell proliferation, while inhibition of EZH2 in vivo in Rip1TAG2 mice reduced tumor burden. Our results show that EZH2 is highly expressed in high-grade PanNENs, and during disease progression it may contribute to aberrations in the epigenetic cellular landscape. Targeting EZH2 may represent a valuable epigenetic treatment option for patients with PanNEN.
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页数:18
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