Enhanced CXCL12/CXCR4 signaling increases tumor progression in radiation-resistant pancreatic cancer
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ABSTRACT:
PROVIDER: PRJNA796944 | ENA |
REPOSITORIES: ENA
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Project description:Pancreatic cancer (PaCa) has one of the poorest prognoses among gastrointestinal cancers because of rapid development of treatment resistance, which renders chemotherapy and radiotherapy no longer effective. As the mechanism by which PaCa becomes resistant to radiotherapy is unknown, we established radiation-resistant PaCa cell lines to investigate the factors involved in radiation resistance. We investigated the role of the C-X-C motif chemokine 12 (CXCL12)/ C-X-C chemokine receptor type 4 (CXCR4) axis in radiation resistance in PaCa and the effect of a CXCR4 antagonist on radiation-resistant PaCa cell lines. As confirmed by immunofluorescence staining, RT-qPCR, and Western blotting, the expression of CXCR4 was higher in the radiation-resistant PaCa cell lines than in normal PaCa cell lines. The invasion ability of radiation-resistant PaCa cell lines was greater than that of normal cell lines and was enhanced by CXCL12 treatment and co-culture with fibroblasts; this enhanced invasion ability was suppressed by the CXCR4 antagonist AMD070. Irradiation after treatment with the CXCR4 antagonist suppressed the colonization of radiation-resistant PaCa cell lines. In conclusion, the CXCL12/CXCR4 axis may be involved in the radiation resistance of PaCa. We believe this result will help develop treatments for PaCa.
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Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy characterized by infiltration of the bone marrow and other sites with transformed T cell progenitors. The role of tissue microenvironments in the pathogenesis of T-ALL or any other type of acute leukemia is little understood. In delineating interactions between T-ALL cells and their environment, we initially found that T-ALL cells express high surface levels of the chemokine receptor CXCR4. Intravital imaging of an intact tibia revealed T-ALL cells in direct contact with bone marrow stromal cells producing the CXCR4 ligand, CXCL12. Genetic targeting of CXCR4 on T-ALL cells resulted in a marked reduction of leukemia burden and prolonged disease remission, and disruption of the CXCL12/CXCR4 axis using small molecule inhibitors prevented T-ALL progression in a primary xenograft model. Finally, we were able to show that CXCR4 inhibition significantly decreased expression of Myc and its target genes. Myc expression is a key regulator of T-ALL leukemia initiating cell (LIC) activity, suggesting that CXCR4 inhibition can suppress LIC activity by silencing the Myc response in T-ALL cells. Our data suggest that targeting of CXCL12/CXCR4 signaling could be a powerful new tool for combating T-ALL, a disease with no current targeted therapies. Mouse T-ALL cells were treated ex vivo with Cxcr4 inhibitor AMD3100 or vehicle control. Additionally, mouse T-ALL primary tumors were isolated from control (Cxcr4+/+) or knockout (Cxcr4-/-) animals. Total RNA was extracted from samples using the RNeasy Plus Mini Kit (Qiagen). Samples were then subject to PolyA selection using oligo-dT beads (Life Technologies, Carlsbad, CA) according to the manufacturer's instructions. The resulting RNA samples were then used as input for library construction using the dUTP method as described by Parkhomchuck et al., 2009. RNA libraries were then sequenced on the Illumina HiSeq 2500 using 50bp single-end reads.
2015-08-12 | E-GEOD-60367 | biostudies-arrayexpress
Project description:It has been reported that mesenchymal stem cells (MSC) derived from adult tissues are effective in promoting wound healing. However, the cell quality varies and cell number is limited as both depend on donations. Moreover, dissociated MSC delivered to an inflammatory lesion are subject to challenges to their survival and functions. Here we demonstrate that dropping of spheres of MSC derived from human embryonic stem cells (EMSC) onto murine dermal wound had much higher survival and efficacy than topical application of dissociated EMSC. RNA sequencing on cells isolated from the wound highlights the CXCL12-CXCR4 signalling in the EMSC sphere-mediated efficacy, which was verified via CXCL12 knockdown in EMSC and CXCR4 inhibition in target cells such as vascular endothelial cells, epithelial keratinocytes, and macrophage. Finally, we enhanced the biosafety of EMSC spheres by engineering the cells with an inducible suicide gene. Together, we propose topical application of EMSC spheres as an unlimited, quality-assured, safety-enhanced, and noninvasive therapy for wound healing and the CXCL12-CXCR4 axis as a key player in the treatment.
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Project description:Analysis of genes in DNA damage induced senescence using BrdU as a DNA damaging agent in HeLa cells which can trigger cellular senescence and identifying effect of CXCL12-CXCR4 axis during this process.
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Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy characterized by infiltration of the bone marrow and other sites with transformed T cell progenitors. The role of tissue microenvironments in the pathogenesis of T-ALL or any other type of acute leukemia is little understood. In delineating interactions between T-ALL cells and their environment, we initially found that T-ALL cells express high surface levels of the chemokine receptor CXCR4. Intravital imaging of an intact tibia revealed T-ALL cells in direct contact with bone marrow stromal cells producing the CXCR4 ligand, CXCL12. Genetic targeting of CXCR4 on T-ALL cells resulted in a marked reduction of leukemia burden and prolonged disease remission, and disruption of the CXCL12/CXCR4 axis using small molecule inhibitors prevented T-ALL progression in a primary xenograft model. Finally, we were able to show that CXCR4 inhibition significantly decreased expression of Myc and its target genes. Myc expression is a key regulator of T-ALL leukemia initiating cell (LIC) activity, suggesting that CXCR4 inhibition can suppress LIC activity by silencing the Myc response in T-ALL cells. Our data suggest that targeting of CXCL12/CXCR4 signaling could be a powerful new tool for combating T-ALL, a disease with no current targeted therapies.
2015-08-12 | GSE60367 | GEO
Project description:CXCR4 cDNA transcripts were subcloned into plenti-IRES-GFP vectors, and stably transduced using a lentiviral system In addition to wild-type CXCR4, vectors with the mutations c.1013C>G (p.Ser338*), c.932_933insT (p.Thr311fs), and c.1030_1041delinsGT (p.Ser344fs) were generated. Cell lines were stimulated with 50nM of the CXCR4 ligand CXCL12 (SDF1A) (R&D Systems, Minneapolis MN) for two hours. RNA from each sample was extracted at baseline and at 2 hours. At baseline and following stimulation, RNA was extracted and processed for analysis using Affymetrix Human Gene ST 2.0 arrays (Affymetrix, Santa Clara, CA). Data was analyzed using Oligo and Limma bioconductor packages in R using TMM normalization.
2016-06-10 | E-GEOD-83150 | biostudies-arrayexpress
Project description:CXCR4 cDNA transcripts were subcloned into plenti-IRES-GFP vectors, and stably transduced using a lentiviral system In addition to wild-type CXCR4, vectors with the mutations c.1013C>G (p.Ser338*), c.932_933insT (p.Thr311fs), and c.1030_1041delinsGT (p.Ser344fs) were generated. Cell lines were stimulated with 50nM of the CXCR4 ligand CXCL12 (SDF1A) (R&D Systems, Minneapolis MN) for two hours. RNA from each sample was extracted at baseline and at 2 hours.
2016-06-10 | GSE83150 | GEO
Project description:Acute myeloid leukemia (AML) is defined by an accumulation of immature myeloid blasts in the bone marrow. To identify key dependencies of AML stem cells in vivo, here we use a CRISPR-Cas9 screen targeting cell surface genes in a syngeneic MLL-AF9 AML mouse model and show that CXCR4 is a top cell surface regulator of AML cell growth and survival. Deletion of Cxcr4 in AML cells eradicates leukemia cells in vivo without impairing their homing to the bone marrow. In contrast, the CXCR4- ligand CXCL12 is dispensable for leukemia development in recipient mice. Moreover, expression of mutated Cxcr4 variants reveals that CXCR4 signaling is essential for leukemia cells. Notably, loss of CXCR4 signaling in leukemia cells leads to oxidative stress and differentiation in vivo. Taken together, our results identify CXCR4 signaling as essential for AML stem cells by protecting them from differentiation independent of CXCL12 stimulation.
2019-11-15 | GSE135275 | GEO
Project description:The chemokine CXCL12 and its receptor CXCR4 play important roles in signaling and migration of T-cells, but little is known about the transcriptional events involved in CXCL12-mediated T-cell migration. In this study we performed microarray analysis on CXCL12- treated T-cells, and found that the Wnt family of proteins was significantly upregulated during CXCL12 treatment. Confirmation of these results by real-time PCR and Western analysis indicated that the non-canonical Wnt pathway was specifically upregulated during CXCL12 treatment. In vitro and in vivo knockdown studies confirm that b-catenin (the key mediator of canonical Wnt signaling) is not involved in the CXCL12-mediated migration of T-cells. However, Wnt5A, a non-canonical Wnt protein, increases signaling through the CXCL12/ CXCR4 axis via Protein Kinase C (PKC). Our results demonstrated that CXCL12 required Wnt5A to mediate T-cell migration, and the treatment of T-cells with recombinant Wnt5A sensitized T-cells to CXCL12 induced migration. Additionally, Wnt5A expression was required for the sustained expression of CXCR4, both transcriptionally and translationally. These results could be translated in vivo, using EL4 thymoma metastasis as a model of T-cell migration. Taken together our data indicate, for the first time, that Wnt5A is a critical mediator of the CXCL12/ CXCR4 signaling axis. Keywords: Wnt5A, CXCL12, CXCL12, CXCR4, T-cell Migration
2009-01-01 | GSE12449 | GEO
Project description:Chemotaxis is an essential physiological process, often harnessed by tumors for metastasis. CXCR4, its ligand CXCL12 and the atypical receptor ACKR3 are overexpressed in many human cancers. Interfering with this axis by ACKR3 deletion impairs lymphoma cell migration towards CXCL12. Here, we propose a model of how ACKR3 controls the migration of the diffused large B-cell lymphoma VAL cells in vitro and in vivo in response to CXCL12. VAL cells expressing full-length ACKR3, but not a truncated version missing the C-terminus, can support the migration of VAL cells lacking ACKR3 (VAL-ko) when allowed to migrate together. This migration of VAL-ko cells is pertussis toxin-sensitive suggesting the involvement of a Gi-protein coupled receptor. RNAseq analysis indicate the expression of chemotaxis-mediating LTB4 receptors in VAL cells. We found that LTB4 acts synergistically with CXCL12 in stimulating the migration of VAL cells. Pharmacologic or genetic inhibition of BLT1R markedly reduces chemotaxis towards CXCL12 suggesting that LTB4 enhances in a contact-independent manner the migration of lymphoma cells. The results unveil a novel mechanism of cell-to-cell-induced migration of lymphoma.
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