The SCRIB Paralog LANO/LRRC1 Regulates Breast Cancer Stem Cell Fate through WNT/β-Catenin Signaling.
The SCRIB Paralog LANO/LRRC1 Regulates Breast Cancer Stem Cell Fate through WNT/β-Catenin Signaling.
复制标题
Scrib paralog LANO/LRRC1Wnt/β-catenin信号转导调控乳腺癌干细胞命运。
DOI：
10.1016/j.stemcr.2018.09.008
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发表时间：
2018-11-13
影响因子：
5.9
通讯作者：
Santoni MJ
中科院分区：
文献类型：
--
作者：
Lopez Almeida L;Sebbagh M;Bertucci F;Finetti P;Wicinski J;Marchetto S;Castellano R;Josselin E;Charafe-Jauffret E;Ginestier C;Borg JP;Santoni MJ
肿瘤的发生、发展和治疗耐药性被认为源自肿瘤细胞的一个亚群，即癌症干细胞（CSC）。然而，目前对它们自我更新和肿瘤起始能力的机制的理解仍然有限。在这里，我们报告说，LANO/LRRC 1的表达，脊椎动物的SCRIB肿瘤抑制因子，与干细胞的签名在正常和肿瘤乳腺上皮。通过体外和体内实验，包括Lano/Lrrc 1基因敲除小鼠模型，我们证明了它参与乳腺CSC（bCSC）命运的调节。从机制上讲，我们证明了Lano/LRRC 1缺失的细胞分泌增加水平的WNT配体，其以旁分泌方式起作用，以正向解除bCSC中WNT/β-连环蛋白通路的调节。除了描述LANO/LRRC 1的第一个功能外，我们的研究结果表明，其表达水平可用作生物标志物，以分层可能受益于WNT/β-catenin信号传导抑制剂的乳腺癌患者。Lano/LRRC 1表达水平与干细胞转录特征相关Lano/LRRC 1参与乳腺癌干细胞命运的调节Lano/LRRC 1抑制WNT配体分泌在这篇文章中，Santoni和同事报告说，LANO/LRRC 1（SCRIB肿瘤抑制因子的Parkinson）的表达与正常和肿瘤乳腺干细胞特征相关。Lano/LRRC 1通过抑制WNT配体分泌和相关的WNT/β-catenin通路激活来抑制癌症干细胞池的扩增。LANO/LRRC 1可能具有指导患者通过WNT/β-catenin信号传导抑制剂治疗的治疗诊断价值。
Tumor initiation, progression, and therapeutic resistance have been proposed to originate from a subset of tumor cells, cancer stem cells (CSCs). However, the current understanding of the mechanisms involved in their self-renewal and tumor initiation capacity remains limited. Here, we report that expression of LANO/LRRC1, the vertebrate paralog of SCRIB tumor suppressor, is associated with a stem cell signature in normal and tumoral mammary epithelia. Through in vitro and in vivo experiments including a Lano/Lrrc1 knockout mouse model, we demonstrate its involvement in the regulation of breast CSC (bCSC) fate. Mechanistically, we demonstrate that Lano/LRRC1-depleted cells secrete increased levels of WNT ligands, which act in a paracrine manner to positively deregulate the WNT/β-catenin pathway in bCSCs. In addition to describing the first function of LANO/LRRC1, our results suggest that its expression level could be used as a biomarker to stratify breast cancer patients who could benefit from WNT/β-catenin signaling inhibitors. Lano/LRRC1 expression level is associated with stem cell transcription signatures Lano/LRRC1 is involved in the regulation of breast cancer stem cell fate Lano/LRRC1 represses WNT ligand secretion In this article, Santoni and colleagues report that expression of LANO/LRRC1, the paralog of SCRIB tumor suppressor, is associated with normal and tumoral mammary stem cell signature. Lano/LRRC1 represses expansion of cancer stem cell pool through inhibition of WNT ligand secretion and related WNT/β-catenin pathway activation. LANO/LRRC1 might have theranostic value to steer patient treatment by WNT/β-catenin signaling inhibitors.
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影响因子：
3.5
作者：
Nola, Sebastien;Sebbagh, Michael;Santoni, Marie-Josee
通讯作者：
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影响因子：
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4.5
作者：
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影响因子：
64.5
作者：
Zhan L;Rosenberg A;Bergami KC;Yu M;Xuan Z;Jaffe AB;Allred C;Muthuswamy SK
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