Irshad Shazia, Bansal Mukesh, Guarnieri Paolo, Davis Hayley, Al Haj Zen Ayman, Baran Brygida, Pinna Claudia Maria Assunta, Rahman Haseeb, Biswas Sujata, Bardella Chiara, Jeffery Rosemary, Wang Lai Mun, East James Edward, Tomlinson Ian, Lewis Annabelle, Leedham Simon John
Gastrointestinal Stem-cell Biology Laboratory, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Department of Systems Biology, Columbia University Medical Center, New York, NY, USA.
J Pathol. 2017 Jun;242(2):178-192. doi: 10.1002/path.4891. Epub 2017 May 3.
The functional role of bone morphogenetic protein (BMP) signalling in colorectal cancer (CRC) is poorly defined, with contradictory results in cancer cell line models reflecting the inherent difficulties of assessing a signalling pathway that is context-dependent and subject to genetic constraints. By assessing the transcriptional response of a diploid human colonic epithelial cell line to BMP ligand stimulation, we generated a prognostic BMP signalling signature, which was applied to multiple CRC datasets to investigate BMP heterogeneity across CRC molecular subtypes. We linked BMP and Notch signalling pathway activity and function in human colonic epithelial cells, and normal and neoplastic tissue. BMP induced Notch through a γ-secretase-independent interaction, regulated by the SMAD proteins. In homeostasis, BMP/Notch co-localization was restricted to cells at the top of the intestinal crypt, with more widespread interaction in some human CRC samples. BMP signalling was downregulated in the majority of CRCs, but was conserved specifically in mesenchymal-subtype tumours, where it interacts with Notch to induce an epithelial-mesenchymal transition (EMT) phenotype. In intestinal homeostasis, BMP-Notch pathway crosstalk is restricted to differentiating cells through stringent pathway segregation. Conserved BMP activity and loss of signalling stringency in mesenchymal-subtype tumours promotes a synergistic BMP-Notch interaction, and this correlates with poor patient prognosis. BMP signalling heterogeneity across CRC subtypes and cell lines can account for previous experimental contradictions. Crosstalk between the BMP and Notch pathways will render mesenchymal-subtype CRC insensitive to γ-secretase inhibition unless BMP activation is concomitantly addressed. © 2017 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
骨形态发生蛋白（BMP）信号传导在结直肠癌（CRC）中的功能作用尚不清楚，癌细胞系模型中的矛盾结果反映了评估一个依赖于背景且受遗传限制的信号通路所固有的困难。通过评估二倍体人结肠上皮细胞系对BMP配体刺激的转录反应，我们生成了一个预后性BMP信号特征，并将其应用于多个CRC数据集，以研究CRC分子亚型之间的BMP异质性。我们将BMP和Notch信号通路的活性及功能与人结肠上皮细胞、正常组织和肿瘤组织联系起来。BMP通过一种不依赖γ-分泌酶的相互作用诱导Notch，这种相互作用受SMAD蛋白调控。在稳态下，BMP/Notch共定位局限于肠隐窝顶部的细胞，而在一些人类CRC样本中有更广泛的相互作用。BMP信号在大多数CRC中下调，但在间充质亚型肿瘤中特异性保留，在那里它与Notch相互作用以诱导上皮-间质转化（EMT）表型。在肠道稳态中，BMP-Notch通路的串扰通过严格的通路分离局限于分化细胞。间充质亚型肿瘤中保守的BMP活性和信号严格性的丧失促进了BMP-Notch的协同相互作用，这与患者预后不良相关。CRC亚型和细胞系之间的BMP信号异质性可以解释先前的实验矛盾。BMP和Notch通路之间的串扰将使间充质亚型CRC对γ-分泌酶抑制不敏感，除非同时解决BMP激活问题。© 2017作者。《病理学杂志》由约翰·威利父子有限公司代表大不列颠及爱尔兰病理学会出版。
