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Lkb1 deletion in periosteal mesenchymal progenitors induces osteogenic tumors through mTORC1 activation
Yujiao Han, … , Tiebang Kang, Weiguo Zou
Yujiao Han, … , Tiebang Kang, Weiguo Zou
Published February 26, 2019
Citation Information: J Clin Invest. 2019;129(5):1895-1909. https://doi.org/10.1172/JCI124590.
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Research Article Bone biology Oncology Article has an altmetric score of 3

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

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Abstract

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 Lkb1fllfl 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.

Authors

Yujiao Han, Heng Feng, Jun Sun, Xiaoting Liang, Zhuo Wang, Wenhui Xing, Qinggang Dai, Yang Yang, Anjia Han, Zhanying Wei, Qing Bi, Hongbin Ji, Tiebang Kang, Weiguo Zou

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Figure 1

Lkb1 deletion in Ctsk-Cre–expressing cells causes osteogenic tumor–like phenotype.

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Lkb1 deletion in Ctsk-Cre–expressing cells causes osteogenic tumor–like...
(A) Body weight plots of Ctsk-Ctrl (n = 10) and Ctsk-CKO (n = 8) male mice. (B) Kaplan-Meier survival plots of Ctsk-Ctrl (n = 31) and Ctsk-CKO (n = 21) mice. (C and D) X-ray images and μCT scans of the spines (C) and tibiae (D) of 20-week-old Ctsk-Ctrl and Ctsk-CKO mice. (E) H&E staining of tibiae from 4-, 20-, 30-, and 40-week-old Ctsk-CKO mice showed a progressive histopathological feature. Scale bar: 1 mm (upper panels); 20 μm (lower panels). (F) Tumor in the tibiae of Ctsk-CKO mice was composed of fibroblastic and osteoblastic cells with abundant blood vessels. It invaded into the adjacent muscle and fat tissues at an age of 40 week. Scale bars: 50 μm. (G) Immunostaining of Ki67 in the tumor osteoid displayed a hyperproliferative characteristic. Scale bar: 50 μm. Similar results were obtained from analyses of both male and female mice for each genotype. (H) Gene expression of human osteosarcoma-related genes in the cortical bone of tibiae from 20-week-old female Ctsk-CKO mice (n = 3) compared with normal Ctsk-Ctrl mice (n = 4). Data are represented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001, unpaired Student’s t test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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