Max-Delbrueck Center for Molecular Medicine, Berlin, Germany.
EMBO J. 2013 Jul 17;32(14):1977-89. doi: 10.1038/emboj.2013.127. Epub 2013 Jun 4.
We show that activation of Wnt/β-catenin and attenuation of Bmp signals, by combined gain- and loss-of-function mutations of β-catenin and Bmpr1a, respectively, results in rapidly growing, aggressive squamous cell carcinomas (SCC) in the salivary glands of mice. Tumours contain transplantable and hyperproliferative tumour propagating cells, which can be enriched by fluorescence activated cell sorting (FACS). Single mutations stimulate stem cells, but tumours are not formed. We show that β-catenin, CBP and Mll promote self-renewal and H3K4 tri-methylation in tumour propagating cells. Blocking β-catenin-CBP interaction with the small molecule ICG-001 and small-interfering RNAs against β-catenin, CBP or Mll abrogate hyperproliferation and H3K4 tri-methylation, and induce differentiation of cultured tumour propagating cells into acini-like structures. ICG-001 decreases H3K4me3 at promoters of stem cell-associated genes in vitro and reduces tumour growth in vivo. Remarkably, high Wnt/β-catenin and low Bmp signalling also characterize human salivary gland SCC and head and neck SCC in general. Our work defines mechanisms by which β-catenin signals remodel chromatin and control induction and maintenance of tumour propagating cells. Further, it supports new strategies for the therapy of solid tumours.
我们证明，通过β-catenin 和 Bmpr1a 的功能获得和缺失突变的联合作用，激活 Wnt/β-catenin 信号并抑制 Bmp 信号，会导致小鼠唾液腺中快速生长、侵袭性强的鳞状细胞癌（SCC）。肿瘤包含可移植和过度增殖的肿瘤起始细胞，这些细胞可通过荧光激活细胞分选（FACS）进行富集。单个突变会刺激干细胞，但不会形成肿瘤。我们发现β-catenin、CBP 和 Mll 可促进肿瘤起始细胞的自我更新和 H3K4 三甲基化。用小分子 ICG-001 阻断 β-catenin-CBP 相互作用，以及用针对β-catenin、CBP 或 Mll 的小干扰 RNA 阻断其功能，可阻断过度增殖和 H3K4 三甲基化，并诱导培养的肿瘤起始细胞分化为类似腺泡的结构。ICG-001 在体外可降低与干细胞相关基因启动子处的 H3K4me3，并减少体内肿瘤的生长。值得注意的是，高 Wnt/β-catenin 和低 Bmp 信号也可作为人类唾液腺癌 SCC 和头颈部 SCC 的特征。我们的工作定义了β-catenin 信号重塑染色质并控制肿瘤起始细胞诱导和维持的机制。此外，它为实体瘤的治疗提供了新的策略。
