Lkb1 deletion in periosteal mesenchymal progenitors induces osteogenic tumors through mTORC1 activation.

Bone osteogenic sarcoma has a poor prognosis, as the exact cell of origin and the signaling pathways underlying tumor formation remain undefined. Here, we report an osteogenic tumor mouse model based on the conditional knockout of liver kinase b1 (Lkb1, also known as Stk11) in Cathepsin K-Cre-expressing (Ctsk-Cre-expressing) cells. Lineage-tracing studies demonstrated that Ctsk-Cre could label a population of periosteal cells. The cells functioned as mesenchymal progenitors with regard to markers and functional properties. LKB1 deficiency increased proliferation and osteoblast differentiation of Ctsk(+) periosteal cells, while downregulation of mTORC1 activity, using a Raptor genetic mouse model or mTORC1 inhibitor treatment, ameliorated tumor progression of Ctsk-Cre Lkb1(fllfl) mice. Xenograft mouse models using human osteosarcoma cell lines also demonstrated that LKB1 deficiency promoted tumor formation, while mTOR inhibition suppressed xenograft tumor growth. In summary, we identified periosteum-derived Ctsk-Cre-expressing cells as a cell of origin-for osteogenic tumor and suggested the LKB1/mTORC1 pathway as a promising target for treatment of osteogenic tumor.