Stromal Liver Kinase B1 [STK11] Signaling Loss Induces Oviductal Adenomas and Endometrial Cancer by Activating Mammalian Target of Rapamycin Complex 1

Germline mutations of the Liver Kinase b1 (LKB1/STK11) tumor suppressor gene have been linked to Peutz-Jeghers Syndrome (PJS), an autosomal-dominant, cancer-prone disorder in which patients develop neoplasms in several organs, including the oviduct, ovary, and cervix. We have conditionally deleted Lkb1 in Müllerian duct mesenchyme-derived cells of the female reproductive tract and observed expansion of the stromal compartment and hyperplasia and/or neoplasia of adjacent epithelial cells throughout the reproductive tract with paratubal cysts and adenomyomas in oviducts and, eventually, endometrial cancer. Examination of the proliferation marker phospho-histone H3 and mammalian Target Of Rapamycin Complex 1 (mTORC1) pathway members revealed increased proliferation and mTORC1 activation in stromal cells of both the oviduct and uterus. Treatment with rapamycin, an inhibitor of mTORC1 activity, decreased tumor burden in adult Lkb1 mutant mice. Deletion of the genes for Tuberous Sclerosis 1 (Tsc1) or Tsc2, regulators of mTORC1 that are downstream of LKB1 signaling, in the oviductal and uterine stroma phenocopies some of the defects observed in Lkb1 mutant mice, confirming that dysregulated mTORC1 activation in the Lkb1-deleted stroma contributes to the phenotype. Loss of PTEN, an upstream regulator of mTORC1 signaling, along with Lkb1 deletion significantly increased tumor burden in uteri and induced tumorigenesis in the cervix and vagina. These studies show that LKB1/TSC1/TSC2/mTORC1 signaling in mesenchymal cells is important for the maintenance of epithelial integrity and suppression of carcinogenesis in adjacent epithelial cells. Because similar changes in the stromal population are also observed in human oviductal/ovarian adenoma and endometrial adenocarcinoma patients, we predict that dysregulated mTORC1 activity by upstream mechanisms similar to those described in these model systems contributes to the pathogenesis of these human diseases.肝激酶B1（Liver Kinase b1, LKB1/STK11）抑癌基因的生殖系突变与波伊茨-耶格综合征（Peutz-Jeghers Syndrome, PJS）密切相关，该疾病为常染色体显性遗传的癌症易感综合征，患者可在输卵管、卵巢、宫颈等多个器官发生肿瘤。本研究在雌性生殖道的米勒管间充质来源细胞中条件性敲除Lkb1，观察到间质组分扩张，整个生殖道内相邻上皮细胞出现增生和/或瘤变，伴随输卵管旁囊肿与腺肌瘤形成，最终诱发子宫内膜癌。通过检测增殖标志物磷酸化组蛋白H3以及哺乳动物雷帕霉素靶蛋白复合物1（mammalian Target Of Rapamycin Complex 1, mTORC1）通路成员，研究人员发现输卵管和子宫间质细胞的增殖水平显著升高，且mTORC1通路发生激活。使用mTORC1活性抑制剂雷帕霉素进行处理，可降低成年Lkb1突变小鼠的肿瘤负荷。在输卵管及子宫间质中敲除LKB1信号下游的mTORC1调控因子——结节性硬化症1（Tuberous Sclerosis 1, Tsc1）或结节性硬化症2（Tsc2）的基因，可重现Lkb1突变小鼠的部分缺陷表型，这证实Lkb1缺失的间质中mTORC1激活失调参与了该表型的发生。同时敲除Lkb1与mTORC1信号通路的上游调控因子PTEN（Phosphatase and tensin homolog），可显著增加子宫的肿瘤负荷，并诱发宫颈与阴道的肿瘤发生。本研究表明，间充质细胞中的LKB1/TSC1/TSC2/mTORC1信号通路对于维持上皮完整性、抑制相邻上皮细胞的癌变进程具有关键作用。鉴于人类输卵管/卵巢腺瘤及子宫内膜腺癌患者中也观察到了类似的间质群体改变，我们推测，与上述模型系统中描述的上游机制类似的、可导致mTORC1活性失调的因素，参与了这些人类疾病的发病过程。