Investigating Mechanisms Of Gastrointestinal Polyposis And Osteoblastic Tumor Formation Induced By Mesenchymal Lkb1 Deficiency

Lkb1 has emerged as an important tumor suppressor gene in both sporadic and hereditary cancer. Inactivating germline mutations in the LKB1 gene underlie familial Peutz-Jeghers Syndrome (PJS), a cancer-prone disorder characterized by predisposition to gastrointestinal polyposis. Targeted disruption of Lkb1 in mesenchymal smooth muscle cells was sufficient to recapitulate PJS-type polyposis in mice (Katajisto et al , 2008) and Lkb1 heterozygous mice develop osteoblastic tumors (Robinson et al , 2008). To investigate the mechanism(s) by which Lkb1 loss in mesenchymal tissues drives tumorigenesis, we deleted Lkb1 using two mesenchymal deletors (Fsp1-Cre and Twist2-Cre) expressed in mesenchymal progenitors. Heterozygous deletion of Lkb1 with either Fsp1-Cre (Lkb1flox/+;Fsp1-Cre) or Twist2-Cre (Lkb1flox/+;Twist2-Cre) results in both polyposis and osteoblastic tumor. Homozygous Lkb1 deletion using Fsp1-Cre (Lkb1flox/flox;Fsp1-Cre) leads to rapid polyposis and osteoblastic tumors with complete penetrance, indicating that complete loss of Lkb1 is advantageous for tumorigenesis. AMPK, a key substrate of Lkb1 connected to several other tumor suppressors, has been proposed to mediate Lkb1 tumor suppressive function. However, homozygous deletion of both AMPKα1 and AMPKα2 using Fsp1-Cre does not lead to tumorigenesis. These results implicate other Lkb1 substrate kinases in tumor suppression and suggest Lkb1 loss in a common progenitor underlies mesenchymal tumorigenesis. Katajisto P, et al. , (2008) LKB1 signaling in mesenchymal cells required for suppression of gastrointestinal polyposis. Nat Genet , 40 (4): p. 455-9 Robinson J, et al. , (2008) Osteogenic tumours in Lkb1-deficient mice. Exp Mol Pathol , 85 (3): p. 223-6 Citation Format: Kaisa Laajanen, Saara Ollila, Iris PL Wong, Kari Vaahtomeri, Gustavo Leone, Benoit Viollet, Makela P. Tomi. Investigating mechanisms of gastrointestinal polyposis and osteoblastic tumor formation induced by mesenchymal Lkb1 deficiency. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr C55.