CDKN2A-p16 Deletion and Activated KRASG12D Drive Barrett’s-Like Gland Hyperplasia-Metaplasia and Synergize in the Development of Dysplasia Precancer Lesions

IF 7.1 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Cellular and Molecular Gastroenterology and Hepatology Pub Date : 2024-01-01 DOI:10.1016/j.jcmgh.2024.01.014
Jing Sun , Jorge L. Sepulveda , Elena V. Komissarova , Caitlin Hills , Tyler D. Seckar , Narine M. LeFevre , Hayk Simonyan , Colin Young , Gloria Su , Armando Del Portillo , Timothy C. Wang , Antonia R. Sepulveda
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Abstract

Background & Aims

Barrett’s esophagus is the precursor of esophageal dysplasia and esophageal adenocarcinoma. CDKN2A-p16 deletions were reported in 34%–74% of patients with Barrett’s esophagus who progressed to dysplasia and esophageal adenocarcinoma, suggesting that p16 loss may drive neoplastic progression. KRAS activation frequently occurs in esophageal adenocarcinoma and precancer lesions. LGR5+ stem cells in the squamocolumnar-junction (SCJ) of mouse stomach contribute as Barrett’s esophagus progenitors. We aimed to determine the functional effects of p16 loss and KRAS activation in Barrett’s-like metaplasia and dysplasia development.

Methods

We established mouse models with conditional knockout of CDKN2A-p16 (p16KO) and/or activated KRASG12D expression targeting SCJ LGR5+ cells in interleukin 1b transgenic mice and characterized histologic alterations (mucous-gland hyperplasia/metaplasia, inflammation, and dysplasia) in mouse SCJ. Gene expression was determined by microarray, RNA sequencing, and immunohistochemistry of SCJ tissues and cultured 3-dimensional organoids.

Results

p16KO mice exhibited increased mucous-gland hyperplasia/metaplasia versus control mice (P = .0051). Combined p16KO+KRASG12D resulted in more frequent dysplasia and higher dysplasia scores (P = .0036), with 82% of p16KO+KRASG12D mice developing high-grade dysplasia. SCJ transcriptome analysis showed several activated pathways in p16KO versus control mice (apoptosis, tumor necrosis factor-α/nuclear factor-kB, proteasome degradation, p53 signaling, MAPK, KRAS, and G1-to-S transition).

Conclusions

p16 deletion in LGR5+ cell precursors triggers increased SCJ mucous-gland hyperplasia/metaplasia. KRASG12D synergizes with p16 deletion resulting in higher grades of SCJ glandular dysplasia, mimicking Barrett’s high-grade dysplasia. These genetically modified mouse models establish a functional role of p16 and activated KRAS in the progression of Barrett’s-like lesions to dysplasia in mice, representing an in vivo model of esophageal adenocarcinoma precancer. Derived 3-dimensional organoid models further provide in vitro modeling opportunities of esophageal precancer stages.

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CDKN2A-p16 缺失和活化的 KRASG12D 驱动巴雷特氏样腺体增生-肥大,并在发育不良癌前病变的发展过程中协同作用
背景& 目的巴雷特食管(BE)是食管发育不良和腺癌(EAC)的先兆。据报道,34-74%的BE患者会发展为发育不良和EAC,CDKN2A-p16缺失表明p16缺失可能会推动肿瘤的发展。KRAS活化经常发生在EAC和癌前病变中。小鼠胃鳞结膜交界处(SCJ)的LGR5+干细胞可作为BE的祖细胞。方法我们在白细胞介素-1b转基因小鼠中建立了CDKN2A-p16条件性基因敲除(p16KO)和/或KRASG12D表达激活的小鼠模型,靶向SCJ LGR5+细胞,并描述了小鼠SCJ的组织学改变(粘液腺增生/肥大、炎症和发育不良)。通过微阵列、RNAseq和免疫组化测定了SCJ组织和培养的三维器官组织的基因表达。p16KO+KRASG12D组合导致更频繁的发育不良和更高的发育不良评分,82%的p16KO+KRASG12D小鼠出现高级别发育不良(p=0.0036)。SCJ转录组分析表明,p16KO与对照小鼠相比,激活了几种通路(凋亡、TNF-α/NFkB、蛋白酶体降解、p53信号传导、MAPK、KRAS和G1-to-S转换)。KRASG12D与p16缺失协同作用,导致更高级别的SCJ腺体发育不良,模仿巴雷特氏高级别发育不良。这些转基因小鼠模型确立了 p16 和活化的 KRAS 在小鼠巴雷特样病变发展为发育不良过程中的功能性作用,代表了食管癌前病变的体内模型。衍生的三维类器官模型进一步为食管癌前病变阶段的体外建模提供了机会。
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来源期刊
CiteScore
13.00
自引率
2.80%
发文量
246
审稿时长
42 days
期刊介绍: "Cell and Molecular Gastroenterology and Hepatology (CMGH)" is a journal dedicated to advancing the understanding of digestive biology through impactful research that spans the spectrum of normal gastrointestinal, hepatic, and pancreatic functions, as well as their pathologies. The journal's mission is to publish high-quality, hypothesis-driven studies that offer mechanistic novelty and are methodologically robust, covering a wide range of themes in gastroenterology, hepatology, and pancreatology. CMGH reports on the latest scientific advances in cell biology, immunology, physiology, microbiology, genetics, and neurobiology related to gastrointestinal, hepatobiliary, and pancreatic health and disease. The research published in CMGH is designed to address significant questions in the field, utilizing a variety of experimental approaches, including in vitro models, patient-derived tissues or cells, and animal models. This multifaceted approach enables the journal to contribute to both fundamental discoveries and their translation into clinical applications, ultimately aiming to improve patient care and treatment outcomes in digestive health.
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