ANGPTL4 accelerates KRASG12D-Induced acinar to ductal metaplasia and pancreatic carcinogenesis.

Hong Hua Yan, Kyung Hee Jung, Ji Eun Lee, Mi Kwon Son, Zhenghuan Fang, Jung Hee Park, Soo Jung Kim, Ju Young Kim, Ju Han Lim, Soon-Sun Hong

Cancer letters 2021 Oct 28

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Oncogenic KRASG12D induces neoplastic transformation of pancreatic acinar cells through acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN), and drives pancreatic ductal adenocarcinoma (PDAC). Angiopoietin-like 4 (ANGPTL4) is known to be involved in the regulation of cancer growth and metastasis. However, whether ANGPTL4 affects KRASG12D-mediated ADM and early PDAC intervention remains unknown. In the current study, we investigated the role of ANGPTL4 in KRASG12D-induced ADM, PanIN formation, and PDAC maintenance. We found that ANGPTL4 was highly expressed in human and mouse ADM lesions and contributed to the promotion of KRASG12D-driven ADM in mice. Consistently, ANGPTL4 rapidly induced ADM in three-dimensional culture of acinar cells with KRAS mutation and formed ductal cysts that silenced acinar genes and activated ductal genes, which are characteristic of in vivo ADM/PanIN lesions. We also found that periostin works as a downstream regulator of ANGPTL4-mediated ADM/PDAC. Genetic ablation of periostin diminished the ADM/PanIN phenotype induced by ANGPTL4. A high correlation between ANGPTL4 and periostin was confirmed in human samples. These results demonstrate that ANGPTL4 is critical for ADM/PanIN initiation and PDAC progression through the regulation of periostin. Thus, the ANGPTL4/periostin axis is considered a potential target for ADM-derived PDAC. Copyright © 2021 Elsevier B.V. All rights reserved.

Citation

Hong Hua Yan, Kyung Hee Jung, Ji Eun Lee, Mi Kwon Son, Zhenghuan Fang, Jung Hee Park, Soo Jung Kim, Ju Young Kim, Ju Han Lim, Soon-Sun Hong. ANGPTL4 accelerates KRASG12D-Induced acinar to ductal metaplasia and pancreatic carcinogenesis. Cancer letters. 2021 Oct 28;519:185-198