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 development^2,3. 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 TERT^high 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 TERT^high 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 TERT^high acinar cells may sustain KRAS mutations, driving acinar cell expansion and creating a field of aberrant cells initiating pancreatic tumorigenesis.

胰腺导管腺癌 (PDAC) 是全球癌症死亡的主要原因之一¹。人体组织和小鼠模型的研究表明，对于许多癌症，干细胞维持早期突变，驱动肿瘤发展^2,3。然而，对于胰腺，细胞更新和 PDAC 启动的机制仍未解决。在这里，使用来自内源性端粒酶逆转录酶 ( Tert ) 基因座的谱系追踪，我们确定了一个罕见的 TERT 阳性胰腺腺泡细胞亚群，分散在整个外分泌室中。在稳态期间，这些 TERT^高腺泡细胞通过形成扩大的腺泡细胞克隆来更新胰腺，而随机标记的腺泡细胞不会形成这些克隆。TERT^高腺泡细胞中突变Kras的特异性表达加速了腺泡克隆的形成，并通过上调 Ras-MAPK 信号和激活下游激酶 ERK (phospho-ERK) 导致向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，我们发现磷酸化 ERK 阳性腺泡细胞的病灶很常见，并且经常含有激活的KRAS突变，这表明这些腺泡区域代表了早期癌症前体病变。这些数据支持一个模型，其中罕见的 TERT^高腺泡细胞可以维持KRAS突变，驱动腺泡细胞扩增并产生异常细胞场，引发胰腺肿瘤发生。