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DDR1 regulates RUNX1-CBFβ to control breast stem cell differentiation

ABSTRACT: Understanding epithelial stem cell differentiation and morphogenesis during breast tissue development is essential, as disruption in these processes underlie breast cancer formation. Recent work has shown that epithelial stem and progenitor cells use the collagen receptor Discoidin Domain Receptor 1 (DDR1) for differentiation into both basal and luminal cell lineages, which together are necessary for complex ductal-lobular morphogenesis. Here, we used a next-generation single cell derived organoid model that generates miniaturized breast tissue, to study how single stem cells can give rise to multiple cell types and compound tissue structures. We show that DDR1inhibition traps cells in a bipotent state, blocking alveolar morphogenesis and luminal cell expansion necessary for complex epithelium formation. Disrupting RUNX1 function produced nearly identical phenotypes, underscoring its critical role downstream of DDR1. Mechanistically, DDR1 affects the interaction and expression of RUNX1 and its cofactor CBFβ, thereby regulating its activity. Mutational analyses in breast cancer patients reveal frequent alterations in the DDR1-RUNX1 signaling axis, particularly co-occurring mutations. Together, these findings uncover DDR1-RUNX1 as a central signaling pathway driving breast epithelial differentiation, whose dysregulation may contribute fundamentally to breast cancer pathogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE298818 | GEO | 2025/06/09

REPOSITORIES: GEO

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DDR1 regulates RUNX1-CBFβ to control breast stem cell differentiation

Project description:The human breast is complex and comprised of multi-lineage and multi-structural elements. Recent work has shown that epithelial stem and progenitor cells use the collagen receptor Discoidin Domain Receptor 1 (DDR1) for differentiation into both basal and luminal cell lineages, which together are necessary for complex ductal-lobular morphogenesis. We developed a next-generation single cell derived organoid model that generates miniaturized breast tissue, to study how single stem cells can give rise to multiple cell types and compound tissue structures. We show that DDR1 activation triggers stem cell differentiation via RUNX1, in turn driving multilineage differentiation as well as complex ductal-lobular development. Mechanistically, DDR1 affects the interaction and expression of RUNX1 and its cofactor CBFβ, thereby regulating its activity. Together, these findings contribute to the current understanding of how the extracellular matrix component within the stem cell niche drives organogenesis and tissue regeneration.

2024-07-31 | GSE272979 | GEO

Breast tissue regeneration is driven by cell-matrix interactions that coordinate multi-lineage stem cell differentiation through DDR1

Project description:Mammary morphogenesis is an orchestrated process involving differentiation, proliferation and organization of cells to form a bi-layered epithelial network of ducts and lobules embedded in storm tissue. We have engineered a 3D biomimetic human breast that makes it possible to study how stem cell fate decisions translate to tissue-level structure and functions. Using this advancement, we describe the mechanism by which breast epithelial cells build a complex three-dimensional, multi-lineage tissue by signaling through the collagen receptor DDR1. DDR1 induces stem cells to differentiate into basal cells, which in turn stimulate luminal progenitor cells to differentiate and form lobules via Notch signaling. These findings demonstrate how human breast tissue regeneration is triggered by transmission of signals from the extracellular matrix through an epithelial bilayer to coordinate structural changes that form a complex ductal-lobular network. More broadly, these findings suggest that DDR1 may coordinate collagen and Notch signaling to regulate multi-lineage differentiation and morphogenesis across diverse tissues.

2021-10-25 | GSE162296 | GEO

DDR1 regulates RUNX1-CBFβ to control breast stem cell differentiation

Project description:DDR1 regulates RUNX1-CBFβ to control breast stem cell differentiation

| PRJNA1271425 | ENA

DDR1 regulates RUNX1-CBFβ to control breast stem cell differentiation

Project description:DDR1 regulates RUNX1-CBFβ to control breast stem cell differentiation

| PRJNA1139738 | ENA

DDR1 knockdown in BXPC3 cell line

Project description:Examination of effect of stable DDR1 knockdown by shRNA on transcriptional profile in BXPC3 cell line to understand role of DDR1 in tumorigenesis. Transcriptional profiles of parental BXPC3 cell line was compared to BXPC3 cells stably transfected with non-target shRNA or DDR1 shRNA, N=3 for each condition.

2014-05-01 | E-GEOD-39207 | biostudies-arrayexpress

DDR1 knockdown in BXPC3 cell line

Project description:Examination of effect of stable DDR1 knockdown by shRNA on transcriptional profile in BXPC3 cell line to understand role of DDR1 in tumorigenesis.

2014-05-01 | GSE39207 | GEO

DDR1 plays a distinctive role in mammary tumour growth

Project description:Purpose: The goals of this study are to compare mammary tumor transcriptome profiling with or without DDR1 in immunocompetent mice in an unbiased way. Methods: In vitro samples: DDR1 WT or KO in vitro cultured E0771 cells were sequenced. Rag1-/- samples: DDR1 WT or KO E0771 cells were injected in Rag1-/- mice, and tumors were harvested and sequenced. C57BL/6 samples: DDR1 WT or KO E0771 cells were firstly inoculated into Rag1-/- mice. When tumor volume reached approximately 200~300 mm3 (usually 20 days after inoculation), 60 mg of tumor organoid were transplanted to WT C57BL/6 mice. Tumor samples were collected on day 4 after transplantation for RNA-seq. Antibody treatment samples: DDR1 KO E0771 cells were reconstituted with human DDR1, then injected into C57BL/6 mice. Isotype control IgG or anti-hDDR1 ECD antibody treatment (10mg/kg intrutumural) started when tumor volume reached approximately 100 mm3. Tumor samples were collected on day 6 after treatment for RNA-seq. Results: Approximately 50 million sequence reads were obtained per sample and identified more than 20,000 transcript isoforms. Conclusions: The RNA-seq results represents the detailed analysis of DDR1 WT/KO mammary tumor transcriptomes in immunocompetent mice C57BL/6.

2021-09-07 | GSE139239 | GEO

In vitro DDR1 signalling - Inhibition of DDR1-BCR signalling by nilotinib as a new therapeutic strategy for metastatic colorectal cancer

Project description:The clinical management of metastatic colorectal cancer (mCRC) faces major challenges. For instance, patients harbouring oncogenic mutations in RAS signalling do not respond to anti-EGFR targeted treatment. Therefore, RAS-independent therapies are needed. Interestingly nilotinib, a clinically approved drug for chronic myeloid leukaemia, inhibits human CRC cell invasion in vitro and reduces their metastatic potential in intrasplenic tumour mouse models. Nilotinib acts by inhibiting the kinase activity of DDR1, a receptor tyrosine kinase for collagens, which we identified as a RAS-independent inducer of CRC metastasis. Using quantitative phosphoproteomics, we identified BCR as a new DDR1 substrate and demonstrated that nilotinib prevents DDR1-mediated BCR phosphorylation on Tyr177, which is important for maintaining -catenin transcriptional activity necessary for tumour cell invasion. DDR1 kinase inhibition also reduced the invasion of patient-derived metastatic and circulating CRC cell lines.

2018-01-31 | PXD008582 | Pride

In vivo DDR1 signalling - Inhibition of DDR1-BCR signalling by nilotinib as a new therapeutic strategy for metastatic colorectal cancer

2018-01-31 | PXD008546 | Pride

Collagenolysis dependent DDR1 signaling dictates pancreatic cancer outcome

Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic, aggressive cancer, frequently progressing and spreading by liver metastasis. Cancer-associated fibroblasts (CAF), extracellular matrix (ECM), and type I collagen (Col I) support or restrain PDAC progression and may impede blood supply and nutrient availability. The dichotomous role of the stroma in PDAC, and the mechanisms through which it influences patient survival and enables desmoplastic cancers to escape nutrient limitation remain poorly understood. Here we show that matrix metalloprotease (MMP)-cleaved or intact Col I (cCol I and iCol I, respectively) exert opposing effects on PDAC bioenergetics, macropinocytosis (MP), tumor growth and metastasis. While cCol I activates DDR1 (discoidin domain receptor-1)-NF-kB-p62-NRF2 signaling to promote PDAC growth, iCol I triggers DDR1 degradation and restrains PDAC growth. Patients whose tumors are iCol I enriched and DDR1 and NRF2 low have improved median survival compared to those with high cCol I, DDR1 and NRF2. Inhibition of DDR1-stimulated NF-kB or mitochondrial biogenesis blocked tumorigenesis in wildtype mice but not in mice expressing MMP-resistant Col I. The diverse effects of the tumor stroma on PDAC growth, metastasis, and patient survival are mediated through the Col I-DDR1-NF-kB-NRF2-mitochondrial biogenesis pathway, presenting new therapeutic opportunities.

2022-07-13 | GSE206218 | GEO

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