Abstract 4857: Clonal expansion of Lkb1-deficient stromal cells underlies polyp development in mouse models of Peutz-Jeghers syndrome

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA While the role of LKB1 mutations in the Peutz-Jeghers polyposis syndrome (PJS) is uncontroversial, the originating cell type remains unclear as Lkb1 mutations in both epithelial cells and stromal smooth muscle cells (SMCs) have been proposed as tumor drivers. Since SMCs do not represent a major fraction of stromal cells in polyps, altered signaling from Lkb1-deficient SMCs to epithelium has been suggested as a possible mechanism for polyposis. Here we investigate the cell type origin and tumor development mechanism of PJS type polyps in mice by targeting Lkb1 in either early mesenchymal progenitors (Twist2-Cre) or in stromal fibroblasts (Fsp1-Cre). Remarkably, both Twist2 (Twist2-Cre;Lkb1flox/+) and Fsp1-driven (Fsp1-Cre;Lkb1flox/+ and Fsp1-Cre;Lkb1flox/flox) Lkb1 deletion led to formation of PJS-type gastrointestinal polyps predominantly in the stomach, as noted before for Lkb1+/- mice. Furthermore, lineage-tracing experiments demonstrated that Lkb1 deletion results in early local expansion of Lkb1-deficient myofibroblast-like alpha smooth muscle actin-expressing cells between gastric glands, and subsequent clonal expansion filling the stroma of the forming polyps. The simultaneous expansion of the adjacent epithelium seems to be secondary to the stromal growth, based on lack of noticeable genetic alterations in the epithelial cells. Immunohistochemical and mRNA analyses demonstrate that the polyps arising from the stromal deletion models are indistinguishable from Lkb1+/- mice and PJS patient polyps. These results indicate that polyps in the Twist2-Cre and Fsp1-Cre mice represent stromal tumors, and suggest that the identified tumorigenic mechanism is shared in PJS syndrome. Citation Format: Saara Ollila, Kaisa Laajanen, Iris Wong, Kari Vaahtomeri, Tomi P. Makela. Clonal expansion of Lkb1-deficient stromal cells underlies polyp development in mouse models of Peutz-Jeghers syndrome. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4857. doi:10.1158/1538-7445.AM2014-4857