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- Title
Lkb1 deletion in periosteal mesenchymal progenitors induces osteogenic tumors through mTORC1 activation.
- 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; Han, Yujiao; Feng, Heng; Sun, Jun; Liang, Xiaoting; Wang, Zhuo; Xing, Wenhui
- Abstract
Bone osteogenic sarcoma has a poor prognosis as the exact cell of origin and the signaling pathways underling 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 (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 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.
- Subjects
OSTEOSARCOMA; TUMOR growth; TUMORS; CANCER cell growth; CELL populations; GENETIC models; OSTEOBLAST metabolism; PERIOSTEUM; DISEASE progression; CELL differentiation; RESEARCH; GENETIC mutation; BONE growth; ANIMAL experimentation; RESEARCH methodology; MACROPHAGES; EVALUATION research; MEDICAL cooperation; BONE tumors; CELLULAR signal transduction; COMPARATIVE studies; TRANSFERASES; KAPLAN-Meier estimator; COMPUTED tomography; SARCOMA; MICE; PHENOTYPES
- Publication
Journal of Clinical Investigation, 2019, Vol 129, Issue 5, p1895
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI124590