研究揭示腺泡细胞克隆扩增在胰腺内环境稳态和癌变中的作用
2021-09-18   阅读:264   来源:自然

美国斯坦福大学医学院Steven E. Artandi课题组近日取得一项新成果。经过不懈努力,他们发现了腺泡细胞克隆扩增在胰腺稳态和癌变中的作用。相关论文于2021年9月15日在线发表在《自然》杂志上。

使用来自内源性端粒酶逆转录酶(Tert)基因座的谱系追踪,研究人员发现了一个罕见的TERT阳性胰腺腺泡细胞亚群,其分布在整个外分泌室中。在机体稳态时,这些TERThigh的腺泡细胞通过开启腺泡细胞扩增克隆来更新胰腺,而随机标记的腺泡细胞不会形成这些克隆。特异性表达Kras突变的TERThigh腺泡细胞加速了腺泡克隆的形成,并通过上调Ras-MAPK信号传导和激活下游激酶ERK(磷酸化ERK)导致导管浸润前胰腺上皮内肿瘤的转分化。

在切除的人胰腺肿瘤中,研究发现磷酸化ERK阳性的腺泡细胞病灶很常见,并经常伴随激活的KRAS突变,这表明这些腺泡区域代表了早期癌症的前体病变。这些数据支持了以下模型,即罕见的TERThigh腺泡细胞可能会维持KRAS突变,诱导腺泡细胞扩增并创造一个导致胰腺肿瘤发生异常的细胞区室。

据悉,胰腺导管腺癌 (PDAC) 是导致癌症死亡的主要类型之一。对人体组织和小鼠模型的研究表明,对于许多癌症而言,干细胞具有促进肿瘤发展的早期突变。然而,对于胰腺,细胞更新和PDAC启动的机制仍然未知。

附:英文原文

Title: Acinar cell clonal expansion in pancreas homeostasis and carcinogenesis

Author: Neuhfer, Patrick, Roake, Caitlin M., Kim, Stewart J., Lu, Ryan J., West, Robert B., Charville, Gregory W., Artandi, Steven E.

Issue&Volume: 2021-09-15

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer deaths worldwide1. Studies in human tissues and in mouse models have suggested that for many cancers, stem cells sustain early mutations driving tumour development2,3. For the pancreas, however, mechanisms underlying cellular renewal and initiation of PDAC remain unresolved. Here, using lineage tracing from the endogenous telomerase reverse transcriptase (Tert) locus, we identify a rare TERT-positive subpopulation of pancreatic acinar cells dispersed throughout the exocrine compartment. During homeostasis, these TERThigh acinar cells renew the pancreas by forming expanding clones of acinar cells, whereas randomly marked acinar cells do not form these clones. Specific expression of mutant Kras in TERThigh acinar cells accelerates acinar clone formation and causes transdifferentiation to ductal pre-invasive pancreatic intraepithelial neoplasms by upregulating Ras–MAPK signalling and activating the downstream kinase ERK (phospho-ERK). In resected human pancreatic neoplasms, we find that foci of phospho-ERK-positive acinar cells are common and frequently contain activating KRAS mutations, suggesting that these acinar regions represent an early cancer precursor lesion. These data support a model in which rare TERThigh acinar cells may sustain KRAS mutations, driving acinar cell expansion and creating a field of aberrant cells initiating pancreatic tumorigenesis.

DOI: 10.1038/s41586-021-03916-2

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