Centre de Recherche en Cancérologie de Marseille, CRCM, Aix Marseille University, Institut Paoli-Calmettes, CNRS, INSERM, 'Cell Polarity, Cell Signaling and Cancer'- Equipe Labellisée Ligue Contre le Cancer, Marseille, France.
Centre de Recherche en Cancérologie de Marseille, CRCM, Aix Marseille University, Institut Paoli-Calmettes, CNRS, INSERM, 'Predictive Oncology'- Equipe Labellisée Ligue Contre le Cancer, Marseille, France.
Stem Cell Reports. 2018 Nov 13;11(5):1040-1050. doi: 10.1016/j.stemcr.2018.09.008. Epub 2018 Oct 18.
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.
肿瘤的发生、发展和治疗耐药性被认为起源于肿瘤细胞的一个亚群，即癌症干细胞（CSC）。然而，目前对于其自我更新和肿瘤起始能力的相关机制仍知之甚少。在这里，我们报告称，LANO/LRRC1 的表达与正常和肿瘤乳腺上皮中的干细胞特征相关，它是 SCRIB 肿瘤抑制因子的脊椎动物同源物。通过包括 Lano/Lrrc1 敲除小鼠模型在内的体外和体内实验，我们证明了它参与调节乳腺 CSC（bCSC）的命运。从机制上讲，我们证明了 Lano/LRRC1 耗尽的细胞会分泌更高水平的 WNT 配体，这些配体以旁分泌的方式在 bCSC 中积极地使 WNT/β-catenin 信号通路去调控。除了描述 LANO/LRRC1 的第一个功能外，我们的结果还表明，其表达水平可用作生物标志物来对乳腺癌患者进行分层，以便他们能够从 WNT/β-catenin 信号抑制剂中受益。
