Cellular and molecular characteristics of stromal Lkb1 deficiency-induced gastrointestinal polyposis based on single-cell RNA sequencing.

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.

• Authors: Zhaohua Cai, Yangjing Jiang, Huan Tong, Min Liang, Yijie Huang, Liang Fang, Feng Liang, Yunwen Hu, Xin Shi, Jian Wang, Zi Wang, Qingqi Ji, Huanhuan Huo, Linghong Shen, Ben He
• Journal: The Journal of pathology (J Pathol) Vol. 263 Issue 1 Pg. 47-60 (05 2024) ISSN: 1096-9896 [Electronic] England
• PMID: 38389501 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2024 The Pathological Society of Great Britain and Ireland.

Chemical References

• AMP-Activated Protein Kinases
• Protein Serine-Threonine Kinases
• Receptor, Platelet-Derived Growth Factor alpha
• Serine
• Tamoxifen
• Stk11 protein, mouse

Topics

• Animals
• Mice
• AMP-Activated Protein Kinases
• Peutz-Jeghers Syndrome (genetics, pathology)
• Protein Serine-Threonine Kinases (genetics)
• Receptor, Platelet-Derived Growth Factor alpha (genetics)
• Sequence Analysis, RNA
• Serine
• Tamoxifen (pharmacology)