Martens Sandrina, Coolens Katarina, Van Bulck Mathias, Arsenijevic Tatjana, Casamitjana Joan, Fernandez Ruiz Angel, El Kaoutari Abdessamad, Martinez de Villareal Jaime, Madhloum Hediel, Esni Farzad, Heremans Yves, Leuckx Gunter, Heimberg Harry, Bouwens Luc, Jacquemin Patrick, De Paep Diedert Luc, In't Veld Peter, D'Haene Nicky, Bouchart Christelle, Dusetti Nelson, Van Laethem Jean-Luc, Waelput Wim, Lefesvre Pierre, Real Francisco X, Rovira Meritxell, Rooman Ilse
Laboratory of Medical and Molecular Oncology, Vrije Universiteit Brussel, Brussel, Belgium.
Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Bruxelles, Belgium.
Gut. 2021 Jul 30;71(10):2030-42. doi: 10.1136/gutjnl-2020-322874.
The aggressive basal-like molecular subtype of pancreatic ductal adenocarcinoma (PDAC) harbours a ΔNp63 (p40) gene expression signature reminiscent of a basal cell type. Distinct from other epithelia with basal tumours, ΔNp63 basal cells reportedly do not exist in the normal pancreas.
We evaluated ΔNp63 expression in human pancreas, chronic pancreatitis (CP) and PDAC. We further studied in depth the non-cancerous tissue and developed a three-dimensional (3D) imaging protocol (FLIP-IT, Fluorescence Light sheet microscopic Imaging of Paraffin-embedded or Intact Tissue) to study formalin-fixed paraffin-embedded samples at single cell resolution. Pertinent mouse models and HPDE cells were analysed.
In normal human pancreas, rare ΔNp63 cells exist in ducts while their prevalence increases in CP and in a subset of PDAC. In non-cancer tissue, ΔNp63 cells are atypical KRT19 duct cells that overall lack SOX9 expression while they do express canonical basal markers and pertain to a niche of cells expressing gastrointestinal stem cell markers. 3D views show that the basal cells anchor on the basal membrane of normal medium to large ducts while in CP they exist in multilayer dome-like structures. In mice, ΔNp63 is not found in adult pancreas nor in selected models of CP or PDAC, but it is induced in organoids from larger Sox9 ducts. In HPDE, ΔNp63 supports a basal cell phenotype at the expense of a classical duct cell differentiation programme.
In larger human pancreatic ducts, basal cells exist. ΔNp63 suppresses duct cell identity. These cells may play an important role in pancreatic disease, including PDAC ontogeny, but are not present in mouse models.
胰腺导管腺癌（PDAC）的侵袭性基底样分子亚型具有ΔNp63（p40）基因表达特征，使人联想到基底细胞类型。据报道，与其他具有基底肿瘤的上皮不同，正常胰腺中不存在ΔNp63基底细胞。
我们评估了ΔNp63在人胰腺、慢性胰腺炎（CP）和PDAC中的表达。我们进一步深入研究了非癌组织，并开发了一种三维（3D）成像方案（FLIP-IT，石蜡包埋或完整组织的荧光光片显微镜成像），以单细胞分辨率研究福尔马林固定石蜡包埋样本。分析了相关的小鼠模型和人胰腺导管上皮细胞（HPDE）。
在正常人类胰腺中，导管中存在罕见的ΔNp63细胞，而在CP和一部分PDAC中其发生率增加。在非癌组织中，ΔNp63细胞是不典型的KRT19导管细胞，总体上缺乏SOX9表达，同时它们确实表达经典的基底标志物，并属于表达胃肠道干细胞标志物的细胞龛。3D视图显示，基底细胞锚定在正常中到大导管的基底膜上，而在CP中它们存在于多层穹顶状结构中。在小鼠中，成年胰腺、选定的CP或PDAC模型中均未发现ΔNp63，但在较大Sox9导管来源的类器官中可诱导其表达。在HPDE中，ΔNp63支持基底细胞表型，但以经典导管细胞分化程序为代价。
在较大的人类胰腺导管中存在基底细胞。ΔNp63抑制导管细胞特性。这些细胞可能在胰腺疾病（包括PDAC的发生）中起重要作用，但在小鼠模型中不存在。
