Lkb1 deletion in periosteal mesenchymal progenitors induces osteogenic tumors through mTORC1 activation
Lkb1 deletion in periosteal mesenchymal progenitors induces osteogenic tumors through mTORC1 activation
复制标题
骨膜间充质祖细胞中 Lkb1 缺失通过 mTORC1 激活诱导成骨性肿瘤
DOI：
10.1172/jci124590
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发表时间：
2019-05-01
影响因子：
15.9
通讯作者：
Zou, Weiguo
中科院分区：
文献类型：
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作者：
Han, Yujiao;Feng, Heng;Zou, Weiguo
骨成骨肉瘤的预后很差，因为肿瘤形成的确切起源细胞和信号传导途径尚不清楚。在这里，我们报告了成骨肿瘤小鼠模型的基础上的肝激酶b1（Lkb 1，也称为Stk 11）的组织蛋白酶K-Cre表达（Ctsk-Cre表达）细胞的条件性敲除。谱系追踪研究表明，Ctsk-Cre可以标记骨膜细胞群。这些细胞在标记物和功能特性方面充当间充质祖细胞。LKB 1缺陷增加了Ctsk+骨膜细胞的增殖和成骨细胞分化，而使用Raptor遗传小鼠模型或mTORC 1抑制剂治疗下调mTORC 1活性，改善了Ctsk-Cre Lkb 1fllfl小鼠的肿瘤进展。使用人骨肉瘤细胞系的异种移植小鼠模型也证明LKB 1缺陷促进肿瘤形成，而mTOR抑制抑制异种移植肿瘤生长。总之，我们鉴定了骨膜来源的Ctsk-Cre表达细胞作为成骨肿瘤的起源细胞，并建议LKB 1/mTORC 1通路作为治疗成骨肿瘤的有希望的靶点。
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.