Abstract：
Liver kinase B1 (Lkb1), encoded by serine/threonine kinase (Stk11), is a serine/threonine kinase and tumor suppressor that is strongly implicated in Peutz-Jeghers syndrome (PJS). Numerous studies have shown that mesenchymal-specific Lkb1 is sufficient for the development of PJS-like polyps in mice. However, the cellular origin and components of these Lkb1-associated polyps and underlying mechanisms remain elusive. In this study, we generated tamoxifen-inducible Lkb1flox/flox;Myh11-Cre/ERT2 and Lkb1flox/flox;PDGFRα-Cre/ERT2 mice, performed single-cell RNA sequencing (scRNA-seq) and imaging-based lineage tracing, and aimed to investigate the cellular complexity of gastrointestinal polyps associated with PJS. We found that Lkb1flox/+;Myh11-Cre/ERT2 mice developed gastrointestinal polyps starting at 9 months after tamoxifen treatment. scRNA-seq revealed aberrant stem cell-like characteristics of epithelial cells from polyp tissues of Lkb1flox/+;Myh11-Cre/ERT2 mice. The Lkb1-associated polyps were further characterized by a branching smooth muscle core, abundant extracellular matrix deposition, and high immune cell infiltration. In addition, the Spp1-Cd44 or Spp1-Itga8/Itgb1 axes were identified as important interactions among epithelial, mesenchymal, and immune compartments in Lkb1-associated polyps. These characteristics of gastrointestinal polyps were also demonstrated in another mouse model, tamoxifen-inducible Lkb1flox/flox;PDGFRα-Cre/ERT2 mice, which developed obvious gastrointestinal polyps as early as 2-3 months after tamoxifen treatment. Our findings further confirm the critical role of mesenchymal Lkb1/Stk11 in gastrointestinal polyposis and provide novel insight into the cellular complexity of Lkb1-associated polyp biology. © 2024 The Pathological Society of Great Britain and Ireland.
摘要：
肝激酶B1（Lkb1），由丝氨酸/苏氨酸激酶（Stk11）编码，是一种丝氨酸/苏氨酸激酶和肿瘤抑制因子，与Peutz-Jeghers综合征（PJS）密切相关。大量研究表明，间充质特异性Lkb1足以促进小鼠PJS样息肉的发展。然而,这些Lkb1相关息肉的细胞起源和成分以及潜在机制仍然难以捉摸。在这项研究中,我们产生了他莫昔芬诱导型Lkb1flox/flox；Myh11-Cre/ERT2和Lkb1flox/flox；PDGFRα-Cre/ERT2小鼠，进行单细胞RNA测序（scRNA-seq）和基于成像的谱系追踪，并旨在探讨与PJS相关的胃肠息肉的细胞复杂性。我们发现Lkb1flox/;Myh11-Cre/ERT2小鼠在他莫昔芬治疗后9个月开始出现胃肠道息肉。scRNA-seq揭示了来自Lkb1flox/+的息肉组织的上皮细胞的异常干细胞样特征；Myh11-Cre/ERT2小鼠。Lkb1相关的息肉进一步以分支的平滑肌核心为特征，丰富的细胞外基质沉积，和高免疫细胞浸润。此外,Spp1-Cd44或Spp1-Itga8/Itgb1轴被认为是上皮间的重要相互作用，间充质,和Lkb1相关息肉的免疫区室。胃肠道息肉的这些特征在另一个小鼠模型中也得到了证实，他莫昔芬诱导型Lkb1flox/flox;PDGFRα-Cre/ERT2小鼠，早在他莫昔芬治疗后2-3个月就出现了明显的胃肠道息肉。我们的发现进一步证实了间充质Lkb1/Stk11在胃肠道息肉病中的关键作用，并为Lkb1相关息肉生物学的细胞复杂性提供了新的见解。©2024英国和爱尔兰病理学会。
