Emerging insights into lineage plasticity in pancreatic cancer initiation, progression, and therapy resistance

IF 8.7 1区生物学 Q1 CELL BIOLOGY

Developmental cell Pub Date : 2025-09-22 DOI:10.1016/j.devcel.2025.07.002

Xintong Zhang, Yaru Du, Axel Behrens, Linxiang Lan

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Abstract

Lineage plasticity, the ability of cells to switch from one specialized identity to another, is a fundamental cellular process in embryonic development and tissue regeneration. The process is often hijacked by tumor cells at various stages to facilitate cancer initiation, progression, metastasis, and therapy resistance. It is also recognized as a key contributor to intratumor heterogeneity (ITH). In pancreatic ductal adenocarcinoma (PDAC), lineage plasticity is central to acinar-to-ductal metaplasia (ADM) and its associated acinar-to-ductal reprogramming (ADR), epithelial-mesenchymal transition (EMT), cancer stem cell (CSC) regeneration, and molecular subtype rewiring. These mechanisms generate diverse lineage trajectories that shape PDAC development, progression, and therapeutic outcomes. In this review, we discuss how normal and tumor cells in the pancreatic epithelium acquire lineage plasticity and its implications for PDAC pathogenesis, ITH, metastasis, and therapy resistance. We also highlight recent discoveries suggesting potential therapeutic strategies targeting key regulators of lineage plasticity in PDAC.

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胰腺癌起始、进展和治疗耐药谱系可塑性的新见解

谱系可塑性是细胞从一种特化身份转换到另一种特化身份的能力，是胚胎发育和组织再生的基本细胞过程。这个过程经常被肿瘤细胞在不同阶段劫持，以促进癌症的发生、进展、转移和治疗抵抗。它也被认为是肿瘤内异质性（ITH）的关键因素。在胰腺导管腺癌（PDAC）中，谱系可塑性是腺泡-导管化生（ADM）及其相关的腺泡-导管重编程（ADR）、上皮-间质转化（EMT）、癌症干细胞（CSC）再生和分子亚型重连接的核心。这些机制产生不同的谱系轨迹，影响PDAC的发展、进展和治疗结果。在这篇综述中，我们讨论了胰腺上皮正常细胞和肿瘤细胞如何获得谱系可塑性及其对PDAC发病机制、ITH、转移和治疗耐药性的影响。我们还强调了最近发现的针对PDAC谱系可塑性关键调节因子的潜在治疗策略。

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

Developmental cell 生物-发育生物学

CiteScore

18.90

自引率

1.70%

发文量

203

审稿时长

3-6 weeks

期刊介绍： Developmental Cell, established in 2001, is a comprehensive journal that explores a wide range of topics in cell and developmental biology. Our publication encompasses work across various disciplines within biology, with a particular emphasis on investigating the intersections between cell biology, developmental biology, and other related fields. Our primary objective is to present research conducted through a cell biological perspective, addressing the essential mechanisms governing cell function, cellular interactions, and responses to the environment. Moreover, we focus on understanding the collective behavior of cells, culminating in the formation of tissues, organs, and whole organisms, while also investigating the consequences of any malfunctions in these intricate processes.