| First Author | Cai Z | Year | 2024 |
| Journal | J Pathol | Volume | 263 |
| Issue | 1 | Pages | 47-60 |
| PubMed ID | 38389501 | Mgi Jnum | J:374856 |
| Mgi Id | MGI:8163871 | Doi | 10.1002/path.6259 |
| Citation | Cai Z, et al. (2024) Cellular and molecular characteristics of stromal Lkb1 deficiency-induced gastrointestinal polyposis based on single-cell RNA sequencing. J Pathol 263(1):47-60 |
| abstractText | 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 Lkb1(flox/flox);Myh11-Cre/ERT2 and Lkb1(flox/flox);PDGFRalpha-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 Lkb1(flox/+);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 Lkb1(flox/+);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 Lkb1(flox/flox);PDGFRalpha-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. (c) 2024 The Pathological Society of Great Britain and Ireland. |
