Canonical BMP signaling executes epithelial-mesenchymal transition downstream of SNAIL1
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ABSTRACT:
PROVIDER: PRJNA599935 | ENA |
REPOSITORIES: ENA
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Project description:Epithelial-mesenchymal transition (EMT) is a pivotal process in development and disease. In carcinogenesis, various signaling pathways are known to trigger EMT by inducing the expression of EMT transcription factors (EMT-TFs) like SNAIL1, ultimately promoting invasion, metastasis and chemoresistance. However, how EMT is executed downstream of EMT-TFs is incompletely understood. Here, using human colorectal cancer (CRC) and mammary cell line models of EMT, we demonstrate that SNAIL1 critically relies on bone morphogenetic protein (BMP) signaling for EMT execution. This activity requires the transcription factor SMAD4 common to BMP/TGFβ pathways, but is TGFβ signaling-independent. Further, we define a signature of BMP-dependent genes in the EMT-transcriptome which orchestrate EMT-induced invasiveness, and are found to be regulated in human CRC transcriptomes and during EMT in vivo. Collectively, our findings substantially augment the knowledge of mechanistic routes whereby EMT can be effectuated, which is relevant for the conceptual understanding and therapeutic targeting of EMT processes. To identify BMP-dependent genes regulated during EMT, LS174T cells overexpressing Snail1-HA in a doxycycline (Dox)-inducible manner were treated with Dox and inhibitors of BMP signaling (LDN193189/mNoggin) or DMSO as control for different periods of time.
2020-04-22 | GSE143297 | GEO
Project description: Not available
| S-EPMC7226241 | biostudies-literature
Project description:Transforming growth factor beta (TGFβ) superfamily signaling is a prime inducer of epithelial-mesenchymal transitions (EMT) that foster cancer cell invasion and metastasis, a major cause of cancer-related deaths. Yet, TGFβ signaling is frequently inactivated in human tumor entities including colorectal cancer (CRC) and pancreatic adenocarcinoma (PAAD) with a high proportion of mutations incapacitating SMAD4, which codes for a transcription factor (TF) central to canonical TGFβ and bone morphogenetic protein (BMP) signaling. Beyond its role in initiating EMT, SMAD4 was reported to crucially contribute to subsequent gene regulatory events during EMT execution. It is therefore widely assumed that SMAD4-mutant (SMAD4mut) cancer cells are unable to undergo EMT. Here, we scrutinized this notion and probed for potential SMAD4-independent EMT execution using SMAD4mut CRC cell lines. We show that SMAD4mut cells exhibit morphological changes, become invasive, and regulate EMT marker genes upon induction of the EMT-TF SNAIL1. Furthermore, SNAIL1-induced EMT in SMAD4mut cells was found to be entirely independent of TGFβ/BMP receptor activity. Global assessment of the SNAIL1‑dependent transcriptome confirmed the manifestation of an EMT gene regulatory program in SMAD4mut cells highly related to established EMT signatures. Finally, analyses of human tumor transcriptomes showed that SMAD4 mutations are not underrepresented in mesenchymal tumor samples and that expression patterns of EMT‑associated genes are similar in SMAD4mut and SMAD4 wild-type cases. Altogether, our findings reveal considerable plasticity of gene regulatory networks operating in EMT execution and establish that EMT is not categorically precluded in SMAD4mut tumors, which is relevant for their diagnostic and therapeutic evaluation. To identify genes regulated during EMT execution in HT29 cells, two clonal HT29 cell populations (4F5 and 3C2) overexpressing Snail1-HA in a doxycycline (Dox)-inducible manner, as well as control cells were treated with Dox for different periods of time.
2021-11-29 | GSE169735 | GEO
Project description:BMP (bone morphogenetic protein) signaling plays essential roles in the regulation of early tooth development. It is well acknowledged that with binding of extracellular BMP ligands to the type I and type II transmembrane serine/threonine kinase receptor complexes when triggering of the BMP canonical signaling pathway, receptor activated Smad1/5/8 in cytoplasm bind to Smad4, the central mediator of the canonical BMP signaling pathway, to form transfer complexes for entering the nucleus and regulating target gene expression. However, our recent studies reveal the functional operation of a novel BMP mediated signaling pathway named as the atypical BMP canonical signaling pathway in mouse developing tooth, which is Smad1/5/8 dependent but Smad4 independent. In the current study, we investigated whether this atypical BMP canonical signaling is conserved in human odontogenesis. We showed that pSmad1/5/8 is required for expression of MSX1, a well-defined BMP signaling target gene, in human dental mesenchyme, but the typical BMP canonical signaling is indeed not operating in the early human developing tooth, as assessed by the absence of pSMAD1/5/8-SMAD4 complexes in the dental mesenchyme and expression of MSX1 and translocation of pSMAD1/5/8 induced by BMP4 protein is SMAD4-independent in dental mesenchymal cells. Moreover, RNA-Seq data sets comparing the transcriptome profiles of human dental mesenchymal cells with and without SMAD4 knockdown by siRNA displays unchanged expression profiles of pSMAD1/5/8 downstream target genes, further affirming the functional operation of the atypical canonical BMP signaling pathway in a manner of SMAD1/5/8-dependent but SMAD4-independent in the dental mesenchyme during early odontogenesis.
2021-09-30 | GSE179474 | GEO
Project description:SMAD4 is dispensable for execution of epithelial-mesenchymal transition downstream of SNAIL1 in colorectal cancer cells
| PRJNA717772 | ENA
Project description:The transcription factor SNAIL1 is a master regulator of epithelial-to-mesenchymal transition, a process entailing massive gene expression changes. To better understand SNAIL1-induced transcriptional reprogramming we performed time-resolved transcriptome analysis upon conditional SNAIL1 expression in colorectal cancer cells. Bioinformatic analyses indicated that SNAIL1 strongly affected Wnt/β-Catenin pathway activity. This correlated with upregulation of LEF1, a nuclear binding partner of β-Catenin. Several tumour entities, including aggressive mesenchymal colorectal cancers, exhibit positively correlated LEF1 and SNAIL1 expression, and elevated LEF1 levels parallel increased colorectal cancer patient mortality. Comparative gene expression profiling suggested that 35% of Snail1-induced transcriptional changes are attributable to LEF1. LEF1 stimulates Wnt/β-Catenin pathway feedback inhibitor expression, causes cell-cycle arrest in vitro, and retards xenograft tumour growth. Conversely, LEF1-deficiency and preventing the β-Catenin-LEF1 interaction impaired the ability of SNAIL1 to alter Wnt/β-catenin target gene expression and to induce cancer cell invasion. Although LEF1 did not autonomously induce epithelial-mesenchymal transition, LEF1 is a critical factor acting downstream of SNAIL1. Apparently, SNAIL1 employs LEF1 as alternative effector to redirect Wnt/β-catenin pathway activity towards anti-proliferative and pro-invasive gene expression.
2019-08-15 | GSE115716 | GEO
Project description:Cancer cells simultaneously featuring epithelial and mesenchymal traits appear particularly competent to invade and metastasize. However, genetic prerequisites and signaling pathways promoting such partial epithelial-to-mesenchymal transitions (EMT) remain obscure. Here we report that murine intestinal organoids with hyperactive Wnt and MAPK signaling, and mutant Trp53 are purely epithelial and non-invasive in vitro, but initiate a collective invasion program when treated with TGFβ1. Invasive organoids reciprocally interact with the extracellular matrix (ECM), and autonomously deposit and remodel components thereof. Although cells at the organoid/ECM interface shed certain epithelial characteristics, invasive organoids largely maintain epithelial gene expression while concomitantly upregulating a mesenchymal program. TGFβ1-induced phenotypic changes involve canonical, Smad4-dependent signaling, yet, are unimpeded by knockout of Snai1 and Zeb1 - otherwise key regulators of epithelial-to-mesenchymal transitions. The finding of TGFβ1-inducible, Snail1/Zeb1-independent collective invasion of oncogenically transformed intestinal organoids provides novel mechanistic insights and broadens the spectrum of context-dependent manifestations of partial EMT.
2022-01-24 | GSE156553 | GEO
Project description:Operation of the atypical canonical BMP signaling pathway during human odontogenesis
| PRJNA743914 | ENA
Project description:Snail1 transcriptional factor is essential for triggering epithelial-to-mesenchymal transition (EMT) and inducing tumor cell invasion. We report here that Snail1 plays also a key role in tumor associated fibroblasts since is necessary for enhancement by these cells on epithelial cells tumor invasion. Snail1 expression in fibroblast requires signals derived from tumor cells such as TGF-b; reciprocally, in fibroblasts Snail1 organizes a complex program that favors collective invasion of epithelial cells at least in part by the secretion of diffusible signaling molecules, such as prostaglandin E2. The capability of human or murine tumor-derived cancer associated fibroblasts to promote tumor invasion is associated to Snail1 expression and obliterated by Snail1 depletion. In vivo experiments show that tumor cells co-transplanted with Snail1 depleted fibroblasts show lower invasion than those xenografted with control fibroblasts. Finally Snail1 depletion in mice prevents the formation of breast tumors and decreased their invasion. Therefore, these results demonstrate that the role of Snail1 in tumor invasion is not limited to its effect in EMT but dependent on its expression in stromal fibroblasts where it orchestrates its activation and the crosstalk with epithelial cells.
2016-12-22 | GSE74057 | GEO
Project description:Snail1 transcriptional factor is essential for triggering epithelial-to-mesenchymal transition (EMT) and inducing tumor cell invasion. We report here that Snail1 plays also a key role in tumor associated fibroblasts since is necessary for enhancement by these cells on epithelial cells tumor invasion. Snail1 expression in fibroblast requires signals derived from tumor cells such as TGF-b; reciprocally, in fibroblasts Snail1 organizes a complex program that favors collective invasion of epithelial cells at least in part by the secretion of diffusible signaling molecules, such as prostaglandin E2. The capability of human or murine tumor-derived cancer associated fibroblasts to promote tumor invasion is associated to Snail1 expression and obliterated by Snail1 depletion. In vivo experiments show that tumor cells co-transplanted with Snail1 depleted fibroblasts show lower invasion than those xenografted with control fibroblasts. Finally Snail1 depletion in mice prevents the formation of breast tumors and decreased their invasion. Therefore, these results demonstrate that the role of Snail1 in tumor invasion is not limited to its effect in EMT but dependent on its expression in stromal fibroblasts where it orchestrates its activation and the crosstalk with epithelial cells.
2016-12-22 | GSE74056 | GEO