Lfng-expressing centroacinar cell is a unique cell-of-origin for p53 deficient pancreatic cancer.

IF 6.9 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Oncogene Pub Date : 2024-11-15 DOI:10.1038/s41388-024-03226-7

Wen-Cheng Chung, Shubing Zhang, Azeddine Atfi, Keli Xu

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with limited understanding of etiology. Studies in mice showed that both acinar and ductal cells of the pancreas can be targeted by combination of oncogenic Kras and p53 mutations to form PDAC. How the transforming capacities of pancreatic cells are constrained, and whether a subset of cells could serve as a prime target for oncogenic transformation, remain obscure. Here we report that expression of a Notch modulator, Lunatic Fringe (Lfng), is restricted to a limited number of cells with centroacinar location and morphology in the adult pancreas. Lfng-expressing cells are preferentially targeted by oncogenic Kras along with p53 deletion to form PDAC, and deletion of Lfng blocks tumor initiation from these cells. Notch3 is a functional Notch receptor for PDAC initiation and progression in this context. Lfng is upregulated in acinar- and ductal-derived PDAC and its deletion suppresses these tumors. Finally, high LFNG expression is associated with high grade and poor survival in human patients. Taken together, Lfng marks a centroacinar subpopulation that is uniquely susceptible to oncogenic transformation when p53 is lost, and Lfng functions as an oncogene in all three lineages of the exocrine pancreas.

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表达 Lfng 的中心acinar 细胞是缺乏 p53 的胰腺癌的独特起源细胞。

胰腺导管腺癌（PDAC）是致死率最高的恶性肿瘤之一，但对其病因的了解却十分有限。对小鼠的研究表明，致癌基因 Kras 和 p53 基因突变可导致胰腺的针叶细胞和导管细胞成为 PDAC 的靶细胞。胰腺细胞的转化能力如何受到限制，以及是否有细胞亚群可作为致癌转化的主要靶点，这些问题仍不清楚。在这里，我们报告了 Notch 调制剂 Lunatic Fringe（Lfng）的表达仅限于成人胰腺中具有中心acinar位置和形态的少数细胞。表达 Lfng 的细胞是致癌 Kras 和 p53 基因缺失形成 PDAC 的首选靶细胞，缺失 Lfng 会阻止这些细胞引发肿瘤。在这种情况下，Notch3是PDAC发生和发展的功能性Notch受体。Lfng在来源于尖头和导管的PDAC中上调，删除Lfng可抑制这些肿瘤。最后，LFNG的高表达与人类患者的高分级和低生存率有关。综上所述，Lfng标志着一个中心胰腺亚群，当p53缺失时，该亚群特别容易发生致癌转化，Lfng在胰腺外分泌的所有三个系中都起着癌基因的作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Oncogene 医学-生化与分子生物学

CiteScore

15.30

自引率

1.20%

发文量

404

审稿时长

1 months

期刊介绍： Oncogene is dedicated to advancing our understanding of cancer processes through the publication of exceptional research. The journal seeks to disseminate work that challenges conventional theories and contributes to establishing new paradigms in the etio-pathogenesis, diagnosis, treatment, or prevention of cancers. Emphasis is placed on research shedding light on processes driving metastatic spread and providing crucial insights into cancer biology beyond existing knowledge. Areas covered include the cellular and molecular biology of cancer, resistance to cancer therapies, and the development of improved approaches to enhance survival. Oncogene spans the spectrum of cancer biology, from fundamental and theoretical work to translational, applied, and clinical research, including early and late Phase clinical trials, particularly those with biologic and translational endpoints.