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DDR1 regulates RUNX1-CBFβ to control breast stem cell differentiation

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE272979 | GEO | 2024/07/31

REPOSITORIES: GEO

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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

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

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

Comparative transcriptome of proliferative cells, dormant cells and awaken cells throught a DDR1 depletion

Project description:The goal of this study is to compare the trancriptome of proliferative THEP3 cells to their dormant counterpart DHEP3 and an awaken version through DDR1 receptor depletion (shRNA control verus shRNA DDR1) to identify target genes involved in the dormancy state and the awakening process from where metatsiss will arise.

2021-10-20 | GSE182890 | GEO

Transcription profiling of human lobular and ductal invasive carcinomas vs normal breast tissue from the same patient to identify gene expression profiles of ductal and lobular carcinomas in relation to normal ductal and lobular cells

Project description:The aim of our study was to identify gene expression profiles of ductal and lobular carcinomas in relation to normal ductal and lobular cells. We examined ten mastectomy specimens from postmenopausal breast cancer patients. Ductal and lobular tumor and normal cells were microdissected from cryosections. Fifty nanograms of total RNA were amplified and labeled by PCR and in vitro transcription. GCOS pairwise comparison algorithm and rank products have identified multiple genes that are differentially expressed in comparisons between ductal and lobular tumor and normal cell types. The results suggest that these genes are involved in epithelial-mesenchymal transition, TGFbeta and Wnt signaling. These changes are present in both tumor types but appear to be more prominent in lobular carcinomas. Ten surgical specimens obtained by mastectomy from postmenopausal patients with invasive ductal (IDC) and lobular breast (ILC) carcinomas were investigated. Of these, 5 were IDCs and 5 were ILCs. Tumor and normal tissues from the same mammary gland were identified by an experienced pathologist, snap-frozen in liquid nitrogen and stored at -80ÂºC for further analysis. Microdissection, RNA isolation, amplification, labeling and microarray analysis are described in sample definitions. Samples from particular cell types (normal ductal, normal lobular, tumor ductal, tumor lobular - 10, 10, 5, 5 samples, respectively) were considered as biological replicates and were compared in between.

2007-11-01 | E-GEOD-5764 | biostudies-arrayexpress

Gene expression profileing of DDR1 overexpression and control T24 human bladder cancer cell line

Project description:We performed RNA-seq analysis on xenograft mouse model generated by T24 human bladder cancer cell line with enforced expression of DDR1 or controls.

2022-10-19 | GSE191097 | GEO

In vivo 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 | PXD008546 | Pride

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

2018-01-31 | PXD008582 | Pride

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