Pharmacological inhibition and reversal of pancreatic acinar ductal metaplasia.
Pharmacological inhibition and reversal of pancreatic acinar ductal metaplasia.
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DOI：
10.1038/s41420-022-01165-4
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发表时间：
2022-09-02
影响因子：
7
通讯作者：
Schmittgen, Thomas D.
中科院分区：
文献类型：
--
作者：
da Silva, Lais;Jiang, Jinmai;Perkins, Corey;Atanasova, Kalina Rosenova;Bray, Julie K.;Bulut, Gamze;Azevedo-Pouly, Ana;Campbell-Thompson, Martha;Yang, Xiaozhi;Hakimjavadi, Hesamedin;Chamala, Srikar;Ratnayake, Ranjala;Gharaibeh, Raad Z.;Li, Chenglong;Luesch, Hendrik;Schmittgen, Thomas D.
胰腺腺泡细胞显示出显著的可塑性，并且可以通过称为腺泡导管化生（ADM）的过程去分化为导管样祖细胞。ADM被认为是胰腺导管腺癌发展的最早前驱病变之一，维持胰腺腺泡细胞表型抑制肿瘤形成。使用来自p48 Cre/+和p48 Cre/+ LSL-KrasG 12 D/+（KC）小鼠的3-D培养物研究新型pStat 3抑制剂（LLL 12 B）和组蛋白脱乙酰酶（HDAC）抑制剂曲马斯他汀A（TSA）的作用。LLL 12 B和TSA抑制KC和p48 Cre/+小鼠胰腺类器官中的ADM。此外，用LLL 12 B或TSA对来自经历了ADM的p48 Cre/+和KC小鼠的去分化腺泡的处理产生了形态学和基因表达变化，这表明ADM逆转。使用LLL 12 B和TSA处理的培养物的qRT-PCR（p48 Cre/+和KC）和RNA测序（KC）的验证实验显示，对于TSA处理，ADM逆转更稳健。途径分析显示TSA在ADM逆转过程中抑制Spink 1和PI 3 K/AKT信号通路。在原代人腺泡培养物中也观察到TSA逆转ADM的能力。我们报告，pStat 3和HDAC抑制可以减弱ADM在体外和逆转ADM的背景下，野生型Kras。我们的研究结果表明，药理学抑制或逆转胰腺ADM是一种潜在的治疗策略，阻断腺泡细胞的异常导管重编程。
Pancreatic acinar cells display a remarkable degree of plasticity and can dedifferentiate into ductal-like progenitor cells by a process known as acinar ductal metaplasia (ADM). ADM is believed to be one of the earliest precursor lesions toward the development of pancreatic ductal adenocarcinoma and maintaining the pancreatic acinar cell phenotype suppresses tumor formation. The effects of a novel pStat3 inhibitor (LLL12B) and the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) were investigated using 3-D cultures from p48Cre/+ and p48Cre/+LSL-KrasG12D/+ (KC) mice. LLL12B and TSA inhibited ADM in both KC and p48Cre/+ mouse pancreatic organoids. Furthermore, treatment with LLL12B or TSA on dedifferentiated acini from p48Cre/+ and KC mice that had undergone ADM produced morphologic and gene expression changes that suggest a reversal of ADM. Validation experiments using qRT-PCR (p48Cre/+ and KC) and RNA sequencing (KC) of the LLL12B and TSA treated cultures showed that the ADM reversal was more robust for the TSA treatments. Pathway analysis showed that TSA inhibited Spink1 and PI3K/AKT signaling during ADM reversal. The ability of TSA to reverse ADM was also observed in primary human acinar cultures. We report that pStat3 and HDAC inhibition can attenuate ADM in vitro and reverse ADM in the context of wild-type Kras. Our findings suggest that pharmacological inhibition or reversal of pancreatic ADM represents a potential therapeutic strategy for blocking aberrant ductal reprogramming of acinar cells.
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影响因子：
2.9
作者：
Kim S;Lahmy R;Riha C;Yang C;Jakubison BL;van Niekerk J;Staub C;Wu Y;Gates K;Dong DS;Konieczny SF;Itkin-Ansari P
通讯作者：
Itkin-Ansari P
影响因子：
4.6
作者：
Chen X;Pan L;Wei J;Zhang R;Yang X;Song J;Bai RY;Fu S;Pierson CR;Finlay JL;Li C;Lin J
通讯作者：
Lin J
影响因子：
29.4
作者：
Houbracken, Isabelle;de Waele, Evelien;Bouwens, Luc
通讯作者：
Bouwens, Luc
影响因子：
15.9
作者：
Collins, Meredith A.;Bednar, Filip;di Magliano, Marina Pasca
通讯作者：
di Magliano, Marina Pasca
影响因子：
1.9
作者：
Da Silva, Lais;Bray, Julie K.;Schmittgen, Thomas D.
通讯作者：
Schmittgen, Thomas D.