CXCL12 and IGF1 select for cancer cell populations with enhanced bone metastasis ability
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE39102 | GEO | 2012/12/10
SECONDARY ACCESSION(S): PRJNA170054
REPOSITORIES: GEO
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Project description:CXCL12 and IGF1 confer on cancer cells survival advantage. Src potentiates cancer cells' reponse to CXCL12 and IGF1 by strengthening AKT activation. Long-term incubation of CXCL12 and IGF1 select for cancer cells with enhanced Src activity and bone metastasis potential. MDA-MB-231 cells were incubated for three weeks in growth medium of reduced serum concentration (0.2%) with or without CXCL12 (30 ng/ml) and IGF1 (10 ng/ml). Cell populations survive under these condidtions are expanded by regular growth medium with 10% serum. Two biological replicates were profiled for each condition.
2012-12-10 | E-GEOD-39102 | biostudies-arrayexpress
Project description:CXCL12 and IGF1 are key secreting molecules produced by cancer-associated fibroblasts in breast cancer. These factors promote the survival of disseminated cancer cells in the bone marrow. To assess the combined responses elicited by CXCL12 and IGF1, we examined the translating transcriptome of cancer cells in response to these two factors by Translating Ribosome Affinity Purification (TRAP)-RNAseq. MDA-MB-231 cells were engineered to express an EGFP-tagged version of ribosomal protein L10a. This allows the retrieval of polysome-associated mRNA by anti-GFP pull down (TRAP) and profiling the translating transcriptome by RNAseq. EGFP-L10a+ cancer cells were serum starved (0.2% serum) for 24 hours, and then treated with CXCL12 (30ng/mL) + IGF1 (10ng/mL) or CXCL12 (300ng/mL) + IGF1 (100ng/mL) for 6hrs. Two biological replicates were profiled for each condition.
2013-11-01 | E-GEOD-43296 | biostudies-arrayexpress
Project description:CXCL12 and IGF1 are key secreting molecules produced by cancer-associated fibroblasts in breast cancer. These factors promote the survival of disseminated cancer cells in the bone marrow. To assess the combined responses elicited by CXCL12 and IGF1, we examined the translating transcriptome of cancer cells in response to these two factors by Translating Ribosome Affinity Purification (TRAP)-RNAseq.
2013-11-01 | GSE43296 | GEO
Project description:Decline in hematopoietic function in aged individuals is associated with expansion of phenotypic hematopoietic stem cells (HSCs) and a shift in their lineage potential toward production of myeloid cells. Both HSC-intrinsic changes, and extrinsic changes in the bone marrow (BM) microenvironment, have been identified in old mice and humans. However, to extend healthy and robust hematopoietic function from youth into older age, we need to understand and effectively target the processes that initiate functional hematopoietic decline. We recently identified decline in Insulin-Like Growth Factor 1 (IGF1) in the BM microenvironment as early as middle age to be an HSC-extrinsic initiating driver of HSC aging (Young et al., Cell Stem Cell 2021). As systemic IGF1 administration has significant undesirable side effects, we sought to comprehensively interrogate the cell population(s) in the BM microenvironment that are responsible for IGF1 decline, towards the goal of cell type-specific targeted therapy. We performed single cell RNA-seq to comprehensively profile hematopoietic and non-hematopoietic fractions of the BM in young (2-4mo; n = 5 biological replicates) and middle-aged (12-14mo; n = 10) mice. In young mice, we find Igf1 to be nearly entirely detected in the mesenchymal stromal cell populations Adipo-CAR and Osteo-CAR, and Igf1 is significantly reduced in expression in both populations in middle-aged mice. Using two independent mesenchymal stromal cell Cre mouse lines, Lepr-Cre and Prx1-CreERT2, we found that knockout of Igf1 resulted in myeloid-biased hematopoiesis that replicated aging phenotypes. This result was similar to our published work showing that knockout of Igf1 using Nestin-CreER causes myeloid-biased hematopoiesis. While these Cre models generally do not mark similar cell types, it has been shown that Lepr-Cre-expressing perisinusoidal stromal cells include cells that express certain Nestin transgenes. Using fluorescent reporters, we find that all three lines (Lepr-Cre, Prx1-CreERT2, and Nestin-CreER) overlap in expression in the CAR populations that abundantly express Igf1 in young mice. Taken together, our work identifies a new role for Cxcl12-abundant reticular cells in sustaining hematopoietic function through local IGF1 production and suggests that specifically targeting CAR cells to maintain or restore Igf1 expression during aging will have beneficial effects on lymphoid cell production and adaptive immunity.
2023-01-01 | GSE210584 | GEO
Project description:Defects in cell-cell contacts have been proposed to participate in early steps of tumor metastasis1 but little is known about the signals from the cancer cell niche that influence this process. Here, we show that the lack of adherens junctions caused by genetic loss of the adhesion molecule NECTIN1 in melanoma promotes tumor dissemination specifically under growth factor deprivation. We found that NECTIN1 was deleted in 53% of human melanomas and that its loss was enriched in metastases. NECTIN1 inactivation in zebrafish melanomas stimulated cancer cell spreading in vivo, while in human cell lines, it increased cell migration specifically in response to serum starvation. We further identified IGF1 as the serum component responsible for this effect. Serum withdrawal or IGF1 inhibition induced formation of strong adherens junctions between NECTIN1-wild-type melanoma cells. In contrast, NECTIN1-deficient cells were unable to establish adherens junctions and instead activated integrin-mediated motility through a FAK/SRC axis. During melanoma dissemination, NECTIN1 loss thus causes a cellular phenotypic switch from cell-cell adhesion to cell-matrix adhesion triggered by IGF1 signaling. Our study uncovers a mechanism by which cancer cells integrate information from the tumor microenvironment and cell-cell contacts to regulate their migratory behavior during spreading.
2022-05-26 | GSE149481 | GEO
Project description:How organ-specific metastatic traits accumulate in primary tumors remains unknown. We identified a role of the primary tumor stroma in selecting breast cancer cells that are primed for metastasis in the bone. A fibroblast-rich stroma in breast tumors creates a microenvironment that is similar to that of bone metastases in its abundance of the cytokines CXCL12 and IGF1. Heterogeneous breast cancer cell populations growing in such mesenchymal environment evolve towards a preponderance of clones that thrive on CXCL12 and IGF1. Fibroblast-driven selection of bone metastatic clones in mammary tumors is suppressed by CXCL12 and IGF1 receptor inhibition. Thus, a fibroblast-rich stroma in breast tumors can pre-select bone metastatic seeds, promoting the evolution of metastatic traits and the interplay between a primary tumor and its distant metastases. Affymetrix U133 Plus2 arrays were hybridized according to the manufacturer's procedure using RNA extracted from 47 primary breast tumors. Specific gene sets were evaluated in this cohort.
2013-11-01 | E-GEOD-47389 | biostudies-arrayexpress
Project description:We revealed the unique molecular signature characterizing CXCL12-deficient Cxcl12-GFP+ bone marrow stromal cells.
2020-10-27 | GSE160158 | GEO
Project description:Insight into the role of Insulin-like Growth Factor (IGF) in development of lungs has come from the study of genetically modified mice. IGF1 is a key factor during lung development. IGF1 deficiency in the neonatal mouse causes respiratory failure collapsed alveoli and altered alveolar septa. To further characterize IGF1 function during lung development we analyzed Igf1-/- mouse prenatal lungs in a C57Bl/6 genetic background. Mutant lungs showed disproportional hypoplasia, disorganized extracellular matrix and dilated alveolar capillaries. IGF1 target genes during lung maturation were identified by analyzing RNA differential expression in Igf1-/- lungs using microarrays. Lungs from E18.5 were isolated from both Igf1+/+ wild type and Igf1-/- null mice and pooled to obtain RNA. Heterozygous male and female with a genetic background C57BL/6J were mated to obtain embryos at embrionic (E) stage 18.5 days post coitum (E18.5). 3 biological replicates per genotype.
2014-03-31 | E-GEOD-17157 | biostudies-arrayexpress
Project description:Comparative bulk RNAseq analysis of CXCL12-deficient bone marrow stromal cells (BMSCs), Cxcl12-GFP+ BMSCs versus CXCL12-deficient Cxcl12-GFP+ BMSCs.
| PRJNA672120 | ENA
Project description:How organ-specific metastatic traits accumulate in primary tumors remains unknown. We identified a role of the primary tumor stroma in selecting breast cancer cells that are primed for metastasis in the bone. A fibroblast-rich stroma in breast tumors creates a microenvironment that is similar to that of bone metastases in its abundance of the cytokines CXCL12 and IGF1. Heterogeneous breast cancer cell populations growing in such mesenchymal environment evolve towards a preponderance of clones that thrive on CXCL12 and IGF1. Fibroblast-driven selection of bone metastatic clones in mammary tumors is suppressed by CXCL12 and IGF1 receptor inhibition. Thus, a fibroblast-rich stroma in breast tumors can pre-select bone metastatic seeds, promoting the evolution of metastatic traits and the interplay between a primary tumor and its distant metastases.
2013-11-01 | GSE47389 | GEO