CXCR4 regulates extra-medullary myeloma through epithelial-mesenchymal transition-like transcriptional activation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE68538 | GEO | 2016/10/31
SECONDARY ACCESSION(S): PRJNA283034
REPOSITORIES: GEO
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Project description:Extra-medullary disease (EMD) in multiple myeloma (MM) is associated with poor prognosis and resistance to chemotherapy. However, molecular alterations that lead to EMD have not been well defined. We developed bone marrow (BM)- and EMD-prone MM syngeneic cell lines; identified that epithelial-to-mesenchymal transition (EMT) transcriptional patterns were significantly enriched in both clones compared to parental cells, together with higher levels of CXCR4 protein; and demonstrated that CXCR4 enhanced the acquisition of an EMT-like phenotype in MM cells with a phenotypic conversion for invasion, leading to higher bone metastasis and EMD dissemination in vivo. In contrast, CXCR4 silencing led to inhibited tumor growth and reduced survival. Ulocuplumab, a monoclonal anti-CXCR4 antibody, inhibited MM cell dissemination, supported by suppression of the CXCR4-driven EMT-like phenotype. These results suggest that targeting CXCR4 may act as a regulator of EMD through EMT-like transcriptional modulation, thus representing a potential therapeutic strategy to prevent MM disease progression.
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Project description:The overall description of the project: Epithelial-mesenchymal transition (EMT) is a fundamental cellular process frequently hijacked by cancer cells to promote tumor progression, especially metastasis formation. Molecularly, EMT is orchestrated by various molecular networks acting at different layers of gene regulation. Compared to transcriptional regulation that has been extensively studied in the context of EMT, post-transcriptional mechanisms remain relatively underexplored. Here, by taking advantage of pooled CRISPR screen, we analyzed the influence of 1547 RNA binding proteins (RBPs) on cell motility and identified multiple core P-body (PB) components as negative modulators of cancer cell migration. Further experiments demonstrated that depletion of the PB via silencing DDX6 or EDC4 could activate hallmarks of EMT thereby enhancing cell migration in vitro as well as metastasis formation in vivo. Integrative multi-omics analysis revealed that the PB could repress the translation of its target genes, including an EMT-driver gene, HMGA2. Furthermore, we demonstrated that endoplasmic reticulum (ER) stress is an intrinsic signal that can induce PB disassembly and translational derepression of HMGA2. Finally, we used mouse genetics to demonstrate that knockout of Ddx6 resulted in EMT-related defects in embryonic development. Taken together, our study has put forward a novel function of the PB as an EMT regulator in both pathological and physiological conditions. The description of the MS part: Recent studies have suggested that the PB is mainly involved in translational regulation. Therefore, we performed mass spectrometry analysis on DDX6- and EDC4-KO clones and parental cells to measure changes at the protein level upon PB perturbation. After filtering and normalization, 3,762 and 3,000 peptides corresponding to 3,721 and 2,991 proteins were identified in DDX6- and EDC4-KO cells, respectively, and their abundance was then compared to parental HCT116 cells. A good correlation between two independent gene KO clones was observed in terms of protein level changes. In total, DDX6-KO induced up- and down-regulation of 230 and 291 proteins, respectively, while EDC4-KO induced up- and down-regulation of 73 and 22 proteins, respectively. To assess whether the PB mainly contributes to the RNA degradation or translational repression of its mRNA targets in HCT116 cells, we compared the RNA level and translation efficiency changes of DDX6-bound genes with other genes upon PB loss. As a result, both DDX6 and EDC4 KO led to a lower RNA, but higher translational efficiency of DDX6-bound genes compared to other unbound genes, suggesting PBs mainly function as a translational repressor of stored mRNAs in HCT116 cells.
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Project description:Bone marrow (BM) microenvironment-induced drug resistance in acute lymphoblastic leukemia (ALL) is thought to be mediated by intercellular interaction of leukemic cells with BM niches, but the mechanistic basis of resistance is poorly understood. Here, we genomic and functional analyses, we show that ALL-BM mesenchymal stromal cells (MSC) interactions encompass direct cell-cell adhesion via integrin α4β1, uni-directional secretion of soluble factors from MSC to ALL, and bidirectional transfer of cellular vesicles through tunneling nanotubes. We show that this crosstalk drives an epithelial-mesenchymal transition (EMT)-like program in ALL cells adhering to MSC, thereby triggering stem cell-like features including drug resistance and survival advantage. Moreover, single-cell RNA sequencing of cell line and primary ALL samples identified a hybrid cell state derived from B-ALL adhered to MSC, that exhibits both B-ALL and MSC gene signatures that are orchestrated by an EMT-like program. Multiple EMT-activating pathways including WNT/β-catenin, cytokine/STAT3, TGFβ, NOTCH1, and NF-κB-dependent signaling pathways are activated in MSC-adherent ALL cells; however, only the inhibition of either WNT/β-catenin or cytokine/STAT3 pathway could attenuate the survival and drug resistance of ALL cells adherent to MSC. Notably, we identified that this hybrid cell state exhibited elevated WNT/β-catenin-mediated transcriptional activity. Finally, we show that blocking of the interaction of β-catenin and CBP interaction abrogates the survival and drug resistance of ALL cells adhered to MSC, indicating that targeting of an EMT-like program is potential therapeutic regimen in targeting cell extrinsically acquired drug resistance in ALL.
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Project description:Despite the development of novel therapeutic agents, multiple myeloma (MM) remains incurable, owing mainly to inevitable relapse in almost all patients. Some relapses occur as extramedullary disease (EMD), which is rare but is the most aggressive event in MM patients. Extramedullary myeloma (EMM) has extraordinary heterogeneous biological and clinical features. Previous studies have shown that expression levels of LncRNAs and mRNAs in different stages of MM are different. This study analyzes the expression levels of LncRNAs and mRNAs in primary plasma cells (PCs) from MM and EMM patients.
2023-03-01 | GSE147841 | GEO
Project description:Acquired resistance to trastuzumab, a rationally designed HER-2 targeting antibody, remains a major hurdle in management of HER-2 positive breast cancer (HER-2+ BC) patients. Potential resistance mechanisms are numerous, derived primarily from studies where HER-2 positive cell lines are chronically exposed to trastuzumab. Recent evidence suggests a role for epithelial-mesenchymal transition (EMT) in trastuzumab resistance, but a definitive link between the two has been difficult to establish because relevant model systems are lacking. When sub-populations of trastuzumab sensitive SKBR-3 cells were isolated using cloning rings, an (EMT) occurred spontaneously in several (3/8) clones. SKBR-3 EMT-clones featured increased spindle morphology, expressed N-glycosylated M-NM-21-integrin, and decreased HER-2, all characteristics shared by JIMT-1, a cell lines with intrinsic resistance to trastuzumab. SKBR-3 EMT-clones were characterized by gene expression profiling and mammosphere formation. The N-glycosylated isoform of M-NM-2-itnegrin was targeted with M-NM-2-integrin inhibiting antibody, AIIB2. Transcriptional profiling revealed that SKBR-3 EMT-clones underwent a shift from a luminal molecular subtype to a more aggressive mesenchymal/ basal phenotype. Isolating clones from SKBR-3 cells with enforced expression of a M-NM-2-integrin isoform lacking extensive N-glycosylation failed to increase the likelihood for spontaneous EMT in SKBR-3. However, specific inhibition of the heavily N-glycosylated variant of M-NM-21-integrin expressed by SKBR-3 EMT-clones restored epithelial morphology and impaired mammosphere formation. Furthermore, when SKBR-3 EMT-clones were treated with relevant doses of trastuzumab and lapatinib, they showed M-bM-^@M-^\spontaneousM-bM-^@M-^] resistance. In this study we describe a model of spontaneous EMT following clonal selection in HER-2+ cell line, SKBR-3. Using this model we establish the first direct link between EMT and resistance to HER-2 targeted therapies. We also identify the N-glycosylated isoform of M-NM-2-integrin as a potential biomarker and target in HER-2+ BC refractory to HER-2 targeted therapies. RNA was isolated from 10 breast cancer cell lines in triplicate. Pairwise gene expression differences were compared between each of the SKBR-3 cell lines (SKBR-3/ b1, SK-EV-C4, and SK-B1-C1). Features selected had at least a 2X difference in at least one comparison, with a one-way ANOVA corrected p-value of >0.05. In addition, expression profiles from SKBR-3/ EV and SK-B1-C1 cell were compared and a differential gene list was generated to include genes that differed by at least 1.5X, with a t-test p-value of >0.02 (unpaired, Bonferroni corrected). A total of 1940 entities met these criteria and the expression of these genes was investigated in all breast cancer cell lines.
2015-01-01 | E-GEOD-40152 | biostudies-arrayexpress
Project description:Growing evidence indicates that tumor-associated stroma plays a negative role in human colorectal cancer (CRC). Nature of specific stromal cell populations involved and mechanisms underlying their negative impact remain to be fully understood. In this study we describe the expansion from human primary CRCs of a mesenchymal cell population, referred to as tumor-associated stromal cells (TASCs), resembling bone marrow-derived mesenchymal stem cells (BM-MSCs) in morphology, phenotypes and differentiation potential. We found that, upon co-culture with tumor cells, TASCs acquire membrane-bound TGF-mbTGF-expression, a phenomenon mediated by v6 integrin. MbTGF-expression proved to be critical for triggering epithelial-to-mesenchymal transition (EMT) in tumor cells, eventually leading to enhanced dissemination of circulating tumor cells and increased metastasis formation, in an orthotopic mouse model. Our data identify CRC-associated mesenchymal stem-like cells as critical EMT initiators and suggest mbTGF- as potential novel therapeutic target.
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Project description:One of the hallmarks of multiple myeloma (MM) is a permissive BM microenvironment. Increasing evidence suggest that cell-to-cell communication between myeloma and immune cells via tumor cell-derived extracellular vesicles (EV) plays a key role in the pathogenesis of MM. Hence, we aimed to explore BM immune alterations induced by MM-derived EV. For this, we inoculated immunocompetent BALB/cByJ mice with a myeloma cell line - MOPC315.BM -, inducing a MM phenotype. Upon tumor establishment, characterization of the BM microenvironment revealed the expression of both activation and suppressive markers by lymphocytes, such as Granzyme b and PD-1, respectively. In addition, conditioning of the animals with MOPC315.BM-derived EV, before transplantation of the MOPC315.BM tumor cells, did not anticipate the disease phenotype. However, it induced features of suppression in the BM milieu, such as an increase in PD-1 expression by CD4+ T cells. Overall, our findings reveal the involvement of MOPC315.BM-derived EV protein content as promoters of immune niche remodeling, strengthening the importance of assessing the mechanisms by which MM may impact the immune microenvironment.
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Project description:BackgroundMedullary thyroid carcinoma (MTC) is a rare and challenging endocrine malignancy. Once spread, the therapeutic options are limited and the outcome poor. For these patients, the identification of new druggable biological markers is of great importance. Here, we investigated the prognostic and biological role of the C-X-C chemokine receptors type 4 and 7 (CXCR4/7) in MTC.MethodsEighty-six MTC and corresponding non-neoplastic thyroid specimens were immunohistochemically stained for CXCR4/7 using tissue microarray technology and expression levels correlated with clinicopathological variables. Medullary thyroid carcinoma cell line TT was treated with recombinant human SDF1α/CXCL12 (rh-SDF1α) and CXCR4 antagonists AMD3100 and WZ811. Changes in cell cycle activation, tumour cell invasiveness as well as changes in mRNA expression levels of genes associated with epithelial-mesenchymal transition (EMT) were investigated.ResultsHigh CXCR4 expression was associated with large tumour size and metastatic disease. CXCR4 antagonists significantly reduced tumour cell invasiveness, while the treatment with rh-SDF1α stimulated invasive growth, caused cell cycle activation and induced EMT.ConclusionsThe CXCR4/CXCR7/CXCL12 axis plays an important role in MTC. We provide first evidence that the chemokine receptors might serve as potential therapeutic targets in patients with advanced MTC and offer new valuable insight into the underlying molecular machinery of metastatic MTC.
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2019-03-25 | E-MTAB-6954 | biostudies-arrayexpress