LIF/LIFR oncogenic signaling is a novel therapeutic target in endometrial cancer.
LIF/LIFR oncogenic signaling is a novel therapeutic target in endometrial cancer.
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DOI：
10.1038/s41420-021-00603-z
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发表时间：
2021-08-16
影响因子：
7
通讯作者：
Viswanadhapalli S
中科院分区：
文献类型：
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作者：
Tang W;Ramasamy K;Pillai SMA;Santhamma B;Konda S;Pitta Venkata P;Blankenship L;Liu J;Liu Z;Altwegg KA;Ebrahimi B;Pratap UP;Li X;Valente PT;Kost E;Sareddy GR;Vadlamudi RK;Nair HB;Tekmal RR;Viswanadhapalli S
子宫内膜癌(EC)是女性第四大常见癌症。晚期食管癌的治疗选择有限，预后差。还有一个尚未得到满足的需求，即确定可操作的驱动因素，以开发EC的靶向治疗。白血病抑制因子受体(LIFR)及其配体LIF在肿瘤的进展、转移、干细胞分化和治疗耐药中起重要作用。然而，对LIF/LIFR轴在EC进展中的功能意义知之甚少。在这项研究中，利用子宫内膜肿瘤组织芯片，我们发现LIF、LIFR在EC中的表达上调。在两种不同的EC细胞中，使用CRISPR/Cas9基因敲除LIFR导致其细胞存活率和细胞存活率显著降低。体内研究表明，LIFR-KO可显著降低EC移植瘤的生长。用一种新型的LIFR抑制剂EC359处理已建立的和原代患者来源的EC细胞，导致细胞活力下降，IC50值在20-100 NM范围内，并诱导细胞凋亡。此外，EC359的治疗减少了EC癌症干细胞的椭圆形形成，并降低了癌症干细胞标记物SOX2、OCT4、NANOG和Axin2的水平。机制研究表明，EC359处理减弱了LIF-LIFR信号通路的激活，包括STAT3和AKT/mTOR信号通路。重要的是，EC359处理显著降低了EC患者来源的体外外植体、EC细胞系来源的异种移植物和患者来源的异种移植物的生长。总之，我们的工作揭示了LIF/LIFR轴在EC中的致癌潜力，并支持LIFR抑制剂EC359作为一种通过抑制LIF/LIFR致癌信号来治疗EC的新的靶向治疗方法。
Endometrial cancer (EC) is the fourth most common cancer in women. Advanced-stage EC has limited treatment options with a poor prognosis. There is an unmet need for the identification of actionable drivers for the development of targeted therapies in EC. Leukemia inhibitory factor receptor (LIFR) and its ligand LIF play a major role in cancer progression, metastasis, stemness, and therapy resistance. However, little is known about the functional significance of the LIF/LIFR axis in EC progression. In this study using endometrial tumor tissue arrays, we identified that expression of LIF, LIFR is upregulated in EC. Knockout of LIFR using CRISPR/Cas9 in two different EC cells resulted in a significant reduction of their cell viability and cell survival. In vivo studies demonstrated that LIFR-KO significantly reduced EC xenograft tumor growth. Treatment of established and primary patient-derived EC cells with a novel LIFR inhibitor, EC359 resulted in the reduction of cell viability with an IC50 in the range of 20–100 nM and induction of apoptosis. Further, treatment with EC359 reduced the spheroid formation of EC cancer stem cells and reduced the levels of cancer stem cell markers SOX2, OCT4, NANOG, and Axin2. Mechanistic studies demonstrated that EC359 treatment attenuated the activation of LIF-LIFR driven pathways, including STAT3 and AKT/mTOR signaling in EC cells. Importantly, EC359 treatment resulted in a significant reduction of the growth of EC patient-derived explants ex vivo, EC cell line-derived xenografts, and patient-derived xenografts in vivo. Collectively, our work revealed the oncogenic potential of the LIF/LIFR axis in EC and support the utility of LIFR inhibitor, EC359, as a novel targeted therapy for EC via the inhibition of LIF/LIFR oncogenic signaling.
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影响因子：
7.7
作者：
Raj, Ganesh V.;Sareddy, Gangadhara Reddy;Vadlamudi, Ratna K.
通讯作者：
Vadlamudi, Ratna K.
白血病抑制因子可以通过PI3K/AKT依赖性MCL-1激活来保护胆管癌细胞免受药物诱导的凋亡。
影响因子：
--
作者：
Morton SD;Cadamuro M;Brivio S;Vismara M;Stecca T;Massani M;Bassi N;Furlanetto A;Joplin RE;Floreani A;Fabris L;Strazzabosco M
通讯作者：
Strazzabosco M
影响因子：
15.9
作者：
Liu, Shu-Chen;Tsang, Ngan-Ming;Chang, Yu-Sun
通讯作者：
Chang, Yu-Sun
影响因子：
4.8
作者：
Gonzalez, RR;Rueda, BR;Leavis, PC
通讯作者：
Leavis, PC
影响因子：
--
作者：
Li X;Yang Q;Yu H;Wu L;Zhao Y;Zhang C;Yue X;Liu Z;Wu H;Haffty BG;Feng Z;Hu W
通讯作者：
Hu W