Cancer subtype switching, which involves unclear cancer cell origin, cell fate decision, and transdifferentiation of cells within a confined tumor microenvironment, remains a major problem in pancreatic cancer (PDA). By analyzing PDA subtypes in The Cancer Genome Atlas, we identified that epigenetic silencing of apoptosis-associated tyrosine kinase (AATK) inversely was correlated with mRNA expression and was enriched in the quasi-mesenchymal cancer subtype. By comparing early mouse pancreatic lesions, the non-invasive regions showed AATK co-expression in cells with acinar-to-ductal metaplasia, nuclear VAV1 localization, and cell cycle suppression; but the invasive lesions conversely revealed diminished AATK expression in those with poorly differentiated histology, cytosolic VAV1 localization, and co-expression of p63 and HNF1α. Transiently activated AATK initiates acinar differentiation into a ductal cell fate to establish apical-basal polarization in acinar-to-ductal metaplasia. Silenced AATK and ectopically expressed p63 and HNF1α allow the proliferation of ductal PanINs in mice. Epigenetic silencing of AATK regulates the cellular transdifferentiation, proliferation, and cell cycle progression in converting PDA-subtypes.

中文翻译：

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胰腺癌小鼠模型中腺泡到导管化生中 AATK 的表观遗传沉默。

癌症亚型转换涉及不清楚的癌细胞起源、细胞命运决定和受限肿瘤微环境内的细胞转分化，仍然是胰腺癌 (PDA) 的主要问题。通过分析癌症基因组图谱中的 PDA 亚型，我们发现凋亡相关酪氨酸激酶 (AATK) 的表观遗传沉默与 mRNA 表达呈负相关，并且在准间充质癌亚型中富集。通过比较早期小鼠胰腺病变，非侵袭性区域在腺泡到导管化生、核 VAV1 定位和细胞周期抑制的细胞中显示 AATK 共表达；但侵袭性病变相反显示在组织学分化差、细胞质 VAV1 定位以及 p63 和 HNF1α 共表达的患者中 AATK 表达减少。瞬时激活的 AATK 启动腺泡分化为导管细胞命运，以在腺泡到导管化生中建立根尖-基底极化。沉默的 AATK 和异位表达的 p63 和 HNF1α 允许小鼠中导管 PanIN 的增殖。AATK 的表观遗传沉默在转化 PDA 亚型中调节细胞转分化、增殖和细胞周期进程。