Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA374356 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Protective interactions with bystander cells in micro-environmental niches such as lymph nodes (LNs) contribute to survival and therapy resistance of chronic lymphocytic leukemia (CLL) cells. This is caused by a shift in expression of BCL-2 family members. Pro-survival proteins BCL-XL, BFL-1, and MCL-1 are upregulated by LN-residing T cells through CD40L interaction, presumably via NF-κB signaling. Macrophages also reside in the LN, and are assumed to provide important supportive functions for CLL cells. However, if and how macrophages are able to induce survival is incompletely known. We first established that macrophages induced survival due to an exclusive upregulation of MCL-1. Next, we investigated the mechanism underlying MCL-1 induction by macrophages in comparison with CD40L. Genome-wide expression profiling of in vitro macrophage- and CD40L-stimulated CLL cells indicated activation of the PI3K-AKT-mTOR pathway, which was confirmed in ex vivo CLL LN material. Inhibition of PI3K-AKT-mTOR signaling abrogated MCL-1 upregulation and survival by macrophages as well asCD40 stimulation. MCL-1 can be regulated at multiple levels, and we established that AKT leads to increased MCL-1 translation, but does not affect MCL-1 transcription or protein stabilization. Furthermore, among macrophage-secreted factors that could activate AKT, we found that induction of MCL-1 and survival critically depended on C-C Motif Chemokine Receptor-1 (CCR1). In conclusion, this study indicates that two distinct micro-environmental factors, CD40L and macrophages, signal via CCR1 to induce AKT activation resulting in translational stabilization of MCL-1, and hence can contribute to CLL cell survival.
2017-02-11 | GSE94801 | GEO
Project description:We demonstrated that the microenvironment-dependent secretion of IL32β was controlled by the CD40L/NFKB2 axis whereas its tumor specificity was the consequence of IL32 promoter hypomethylation in MCL. Through the secretion of IL32β, the tumor was able to corrupt its microenvironment through the polarization of monocytes into specific MCL-associated macrophages, which in turn favor tumor survival. We next highlighted that while IL32β-stimulated macrophages secreted several protumoral factors, they supported tumor survival through a soluble dialog, mostly driven by BAFF. Finally, we demonstrated the efficacy of selective NIK/alternative-NFkB inhibition to counteract both microenvironment-dependent induction of IL32β and BAFF-dependent survival of MCL cells.
2022-12-06 | GSE179766 | GEO
Project description:We demonstrated that the microenvironment-dependent secretion of IL32β was controlled by the CD40L/NFKB2 axis whereas its tumor specificity was the consequence of IL32 promoter hypomethylation in MCL. Through the secretion of IL32β, the tumor was able to corrupt its microenvironment through the polarization of monocytes into specific MCL-associated macrophages, which in turn favor tumor survival. We next highlighted that while IL32β-stimulated macrophages secreted several protumoral factors, they supported tumor survival through a soluble dialog, mostly driven by BAFF. Finally, we demonstrated the efficacy of selective NIK/alternative-NFkB inhibition to counteract both microenvironment-dependent induction of IL32β and BAFF-dependent survival of MCL cells.
2022-12-06 | GSE179636 | GEO
Project description:Immunotherapy approaches have been ineffective in pancreatic ductal adenocarcinoma (PDA), pointing to the need for additional avenues to target in the pancreatic cancer microenvironment. We previously discovered that tumor educated bone marrow derived macrophages express high levels of C-C Motif Chemokine Receptor 1 (CCR1). By single-cell RNA sequencing, we found CCR1 to be expressed predominantly by tumor associated macrophages (TAMs) and granulocytes in both human and mouse PDA. Thus, we sought to investigate the functional role of CCR1 in pancreatic cancer. Using KC; Ccr1-/- mice (Ptf1a-Cre; LSL-KrasG12D; Ccr1-/-), we determined that CCR1 is dispensable during pancreatic cancer initiation, although we observed increased CD8 T cell infiltration in KC; Ccr1-/- pancreata. Using syngeneic orthotopic PDA mouse models we discovered that CCR1 ablation in Ccr1-/- mice or pharmaceutical inhibition of CCR1 both resulted in reduced tumor growth. Further, CCR1 ablation prolonged the overall survival of KPC mice. Through mass cytometry (CyTOF) and co-immunofluorescence staining we showed CCR1 ablation elevated CD8 T cell cytotoxic activity in the orthotopic PDA model. Mechanistically we found TAMs lacking CCR1 expressed less Arginase 1 and CD206 -both immunosuppressive markers of macrophages- compared to wild type TAMs. Further, targeting both CCR1 and Arginase 1 synergized with immune checkpoint blockade anti-PD-L1 to enhance antitumor efficacy in orthotopic model of PDA. Together, our data is consistent with the notion that tumor associated macrophages lacking CCR1 expression are less immunosuppressive, consequently allowing increased CD8 T cell mediated anti-tumor immunity. Targeting CCR1 in combination with immune checkpoint blockade improves antitumor efficacy in pancreatic cancer.
2024-06-26 | GSE269182 | GEO
Project description:The two B-cell non-Hodgkin lymphoma (NHL) entities chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) show recurrent chromosomal gains of 3q25 q29, 12q13 q14 and 18q21-q22. The pathomechanisms affected by these aberrations are not understood. The aim of this study was to identify genes, located within these gained regions, which control cell death and cell survival of MCL and CLL cancer cells. Blood samples from 24 CLL and 6 MCL patients as well as 6 cell lines representing both malignancies were analyzed by gene expression profiling. By comparison of genomic DNA and gene expression, 72 candidate genes were identified. We performed a limited RNAi screen with these candidates in order to identify genes affecting cell survival. CCDC50, SERPINI2 and SMARCC2 mediated a reduction of cell viability in primary CLL cells as well as in cell lines. Gene knock down and a NFkB reporter gene assay revealed that CCDC50 is required for survival in MCL and CLL cells and controls NFkB signaling. This SuperSeries is composed of the SubSeries listed below.
2010-06-03 | GSE16413 | GEO
Project description:CD38 and CD49d are associated negative prognosticators in chronic lymphocytic leukemia (CLL). Despite evidence that both molecules are involved in interactions occurring between CLL and normal cells in the context of CLL-involved tissues, a functional link is still missing. Using gene expression profiles comparing CD38+CD49d+ vs. CD38-CD49d- CLL cells, we demonstrated overexpression of the CCL3 and CCL4 chemokines in cells from the former group. These chemokines were also upregulated by CD38 signals in CLL; moreover, CCL3 was expressed by CLL cells from bone marrow biopsies (BMB) of CD38+CD49d+ but not CD38-CD49d- cases. High levels of CCR1 and, to a lesser extent, CCR5, the receptors for CCL3 and CCL4, were found in CLL-derived monocyte-macrophages. Consistently, CCL3 increased monocyte migration, and CD68+ macrophage infiltration was particularly high in BMB from CD38+CD49d+ CLL. Conditioned media from CCL3-stimulated macrophages induced endothelial cells to express VCAM-1, the CD49d ligand, likely through TNFα over-production. These effects were apparent in BMB from CD38+CD49d+CLL, where lymphoid infiltrates were characterized by a prominent meshwork of VCAM-1+ stromal/endothelial cells. Lastly, CD49d engagement by VCAM-1-transfectants increased viability of CD38+CD49d+ CLL cells. Altogether, CD38 and CD49d can be thought of as a part of a consecutive chain of events ultimately leading to improved survival of CLL cells.
2009-03-03 | GSE14560 | GEO
Project description:Background:A subset of hematological cancer patients is refractory to treatment or suffer relapse, due in part to minimal residual disease, whereby some cancer cells survive treatment via microenvironment interaction. Cell-adhesion mediated drug resistance is an important mechanism, whereby cancer cells receive survival signals via interaction with e.g. stromal cells. No genome-wide studies of in vitro systems have yet been performed to compare gene expression in different cell subsets within a co-culture and cells grown separately. Results: Using RNAseq and species-specific read mapping, we compared transcript levels in human Jeko-1 mantle cell lymphoma (MCL) cells stably adhered to stromal cells or in suspension within a co-culture and in separate culture as well as mouse MS-5 stromal cells in co-culture or in separate culture. 1050 differentially expressed transcripts in adherent MCL cells identified 24 functional categories that together represent four main functional themes, anti-apoptosis, B-cell signaling, cell adhesion/migration and early mitosis. Comparison with previous MCL and chronic lymphocytic leukemia (CLL) patient data identified 116 genes that are differentially regulated in all three studies. From these genes we suggest a gene signature (CCL3, CCL4, DUSP4, ETV5, ICAM1, IL15RA, IL21R, IL4I1, MFSD2A, NFKB1, NFKBIE, SEMA7A, TMEM2) characteristic of cells undergoing cell-adhesion mediated microenvironment signaling in MCL/ CLL cells. Conclusions: The model system developed and characterized here together with suggested signature genes can be used in future studies of pathways that mediate increased cancer cell survival and drug resistance mechanisms.
2018-06-12 | GSE99501 | GEO
Project description:This dataset includes chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL) cases reviewed for pathology consensus at the University Health Network. Also included are challenging cases of small B-cell lymphomas without pathology consensus. Methylation array profiling was performed using the Infinium MethylationEPIC array platform. Unprocessed IDAT files and matrix with beta values (beta_TGL51_illumina_annot_geo.txt) are provided.
2021-09-02 | GSE171424 | GEO
Project description:The microenvironment strongly influences mantle cell lymphoma (MCL) survival, proliferation and chemoresistance. However, little is known regarding the molecular characterization of lymphoma niches. We focused on the interplay between MCL cells and associated monocytes/macrophages.
2019-08-27 | GSE124931 | GEO
Project description:The functional consequences of many of the genetic changes, or combinations of genetic changes, in chronic lymphocytic leukaemia (CLL) are not known, but it is essential to discover these in order to understand the biology of the disease and the causes of individual variation in response to novel and conventional treatments. In this proof-of-principle study the translational landscape of CLL was determined for the first time by ribosome profiling. Individual variation in response to stimuli from the tumour microenvironment has not been systematically explored previously, but is likely to influence response to treatment and survival.
2018-08-07 | E-MTAB-6196 | biostudies-arrayexpress