Bone morphogenetic protein and Notch signalling crosstalk in poor‐prognosis, mesenchymal‐subtype colorectal cancer

Abstract

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.

BMP signaling regulates satellite cell-dependent postnatal muscle growth

“…Interestingly, BMP signaling could modulate other signaling cascades, as recently demonstrated for Notch signaling, which becomes activated by BMP-induced Smad1/5 binding to the promoter of the Notch target gene HES1 in colorectal cancer cells (Irshad et al, 2017). Such BMP-Notch signaling crosstalk, being independent of Id1, could contribute to our observed phenotypes as Notch signaling is a crucial regulator of satellite cell function (Fukada et al, 2011).…”

Knockdown GREM1 suppresses cell growth, angiogenesis, and epithelial‐mesenchymal transition in colon cancer

“…[20][21][22] In contrast, GREM1, as an antagonist of BMPs, preferentially shifted the differentiation state of F I G U R E 5 Silencing GREM1 inhibited CRC-induced capillary structure formation and viability of HUVECs. [20][21][22] In contrast, GREM1, as an antagonist of BMPs, preferentially shifted the differentiation state of F I G U R E 5 Silencing GREM1 inhibited CRC-induced capillary structure formation and viability of HUVECs.…”

Colorectal cancer (CRC) as a multifactorial disease and its causal correlations with multiple signaling pathways

“…It is generally accepted that BMP4, a member of the transforming growth factor-β (TGF-β) superfamily, plays a significant role during embryonic development that regulates cell apoptosis, proliferation and differentiation [26]. Regarding the function of BMP4 in cancers, BMP4 has been indicated to mediate the differentiation of cancer stem cells and inhibit the cancer growth of CRC [94].…”

“…The function and interaction of molecular pathways have a significant role in multiple cancer types. Previous studies have indicated that CRC progression is mediated by the dysregulation of many signaling pathways, including Wnt [19], PI3K/Akt [20,21], Hedgehog [22], ErbB [23], RHOA [24], Notch [25], BMP [26], Hippo [27], AMPK [28], NF-κB [29], MAPK [3] and JNK [30]. Moreover, the interaction of these pathways is precise and complicated.…”