A cellular taxonomy of the bone marrow stroma in homeostasis and leukemia demonstrates cancer-crosstalk with stroma to impair normal tissue function
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE128423 | GEO | 2019/05/23
REPOSITORIES: GEO
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Project description:A cellular taxonomy of the bone marrow stroma in homeostasis and leukemia demonstrates cancer-crosstalk with stroma to impair normal tissue function
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Project description:Tissue of the breast is heterogeneous, consisting of a variety of cell types and connective tissue. This heterogeneity is also present in breast tumors and will complicate proteomic analysis, as it is not always clear whether a signal originates from the stromal environment, from normal epithelial or tumor cells. Here we microdissected a variety of cell types and stroma from benign and malignant breast tissues. We compared proteomic differences between these tissues, both from cells of epithelial origin and the stromal environment. Differences in protein abundances corresponded with several hallmarks of cancer, including loss of cell adhesion, transformation to a migratory phenotype, and enhanced energy metabolism. Furthermore, despite enriching for (tumor) epithelial cells, many changes to the extracellular matrix were detected in microdissected cells of epithelial origin. The stromal compartment was heterogeneous and richer in the number of fibroblast and immune cells in malignant sections, compared to benign tissue sections. Although this heterogeneity complicated detection of differentially abundant proteins, several markers were exclusively detected in stroma. However, as heterogeneity in the stroma is more difficult to be reduced through microdissection, comparative analysis was most informative in microdissected cells of epithelial origin, and provided a relatively complete picture of malignant transformations.
2017-01-11 | PXD003632 | Pride
Project description:Restoration of hematopoiesis upon bone marrow (BM) transplantation relies on the engraftment, expansion and function of transplanted hematopoietic stem cells (HSC). However, the number of donorâderived HSC typically remain much below that present in normal individuals and this likely limits and delays hematopoietic recovery. HSC depend on supportive stromal niches, however, whether the preâconditioning required for BM transplantation damages this stromal niche has not been evaluated extensively. Using mouse models, we now find that that BM stroma cells (BMSC) are severely and permanently damaged by preâconditioning. Transplantation of primary but not cultured BMSC quantitatively reconstitutes stroma function in vivo, which is mediated by a multipotent CD73+ CD105â Sca1+ BMSC subpopulation. BMSC coâtransplantation significantly ameliorates clinical side effects of BM transplantation and doubles expansion of functional, donorâ derived HSC, demonstrating the potential of stroma transplantation to improve HSC transplantation. Purified CD45âTer119âCD73+ CD105â and CD45âTer119âCD73+ CD105+ cells were directly sorted on lysis buffer with FACS Aria 2 in triplicate.
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Project description:Matrix induced effects on gene expression in HeLa and MDA-MB-231 cells Tissue homeostasis is dependent on the spatially controlled localization of specific cell types and the correct composition of the extracellular stroma. While the role of the cancer stroma in tumor progression has been well characterized, the specific contribution of the matrix itself is unknown. Furthermore, the mechanisms enabling normal – not cancer – stroma to provide tumor suppressive signals and act as an anti-tumorigenic barrier are poorly understood. Here, we show that extracellular matrix (ECM) generated by normal fibroblasts (NFs) is softer than CAF-matrix and it is the physical and structural features of NF-generated matrix that regulate cancer cell proliferation . We find that normal stromal ECM triggers downregulation and nuclear exit of the histone demethylase JMJD1a resulting in the epigenetic growth restriction of carcinoma cells. Interestingly, JMJD1a positively regulates transcription of many target genes, including YAP/TAZ, and thus therefore gene expression in stiffness-dependent manner. Thus normal stromal restricts cancer cell proliferation through JMJD1a-dependent modulation of gene expression.
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Project description:Gene expression profiling by cDNA microarray of bone marrow stromal cells from three healthy donors treated as follows: vehicle control; or stimulated with 10 nM substance P. Hematopoiesis is tightly regulated by the bone marrow (BM) niche. The niche is robust, allowing for the return of hematopoietic homeostasis after insults such as infection. Hematopoiesis is partly regulated by soluble factors such as neuropeptides, substance P (SP) and neurokinin A (NK-A), which mediate hematopoietic stimulation and inhibition, respectively. The hematopoietic effects of SP and NK-A are mostly mediated via BM stroma. Array analyses with 2400 genes indicated distinct changes in SP-stimulated BM stroma.
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Project description:Intrahepatic cholangiocarcinoma (ICC) is the second most common type of primary cancer in the liver. ICC is an aggressive cancer with poor prognosis and limited therapeutic strategies. The identification of new drug targets and prognostic biomarkers is an important clinical challenge for ICC. The presence of an abundant stroma is a histological hallmark of ICC. Given the well established role of the stromal compartment in the progression of cancer diseases, we hypothesized that relevant biomarkers could be identified by analyzing the stroma of ICC. By combining laser capture microdissection and gene expression profiling we demonstrated that ICC stromal cells exhibit dramatic genomic changes. We identified a signature of 1,073 non-redundant genes that significantly discriminate the tumor stroma from non tumor fibrous tissue. Functional analysis of differentially expressed genes demonstrated that up-regulated genes in the stroma of ICC were related to cell cycle, extracellular matrix and Transforming Growth Factor beta (TGFM-NM-2) pathways. Tissue microarray analysis using an independent cohort of 40 ICC patients validated at a protein level the increase expression of Collagen 4, Laminin, Osteopontin/SPP1, KIAA0101 and TGFM-NM-22 genes in the stroma of ICC. Statistical analysis of clinical and pathological features demonstrated that the expression of Osteopontin, TGFM-NM-22 and Laminin in the stroma of ICC was significantly correlated with patient overall survival. More importantly, multivariate analysis demonstrated that the stromal expression of Osteopontin was an independent prognostic marker for overall and disease-free survival. Conclusion: The study identifies clinically relevant genomic alterations in the stroma of ICC, including candidates biomarkers for prognosis, supporting the idea that tumor stroma is an important factor for ICC onset and progression. 20 RNA samples were analyzed, from 10 patients with ICC. For each patient, RNA were isolated from laser capture microdissected (LCM) stroma from tumor and non tumor areas.
2013-06-21 | E-GEOD-45001 | biostudies-arrayexpress
Project description:The objectives of this study were to measure effects of an aspirin intervention on gene expression in normal colonic epithelial and stromal tissue in healthy humans and to determine whether response differed by UGT1A6*2 genotype. We also sought to characterize gene expression differences within colonic tissue microenvironments by identifying genes that were differentially expressed between epithelial and stromal tissue. No statistically significant differences in gene expression were observed in response to aspirin or UGT1A6 genotype, but tissue PGE2 levels were lower with aspirin compared to placebo (p <0.001). Transcripts differentially expressed between epithelium and stroma (N = 4916, P <0.01, false discovery rate <0.001), included a high proportion of genes involved in cell signaling, cellular movement, and cancer. Genes preferentially expressed in epithelium were involved in drug and xenobiotic metabolism, fatty acid and lipid metabolism, apoptosis signaling, and ion transport. Genes preferentially expressed in stroma included those involved in inflammation, cellular adhesion, and extracellular matrix production. Wnt-Tcf4 pathway genes were expressed in both epithelium and stroma but differed by subcellular location. Our results suggest that, in healthy individuals, subtle effects of aspirin on gene expression in normal colon tissue are likely overwhelmed by inter-individual variability in microarray analyses. Differential expression of critical genes between colonic epithelium and stroma suggest that these tissue types need to be considered separately.
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Project description:Pancreatic cancer is characterized by abundant desmoplastic stroma. Despite numerous theoretical and experimental efforts, therapeutic approaches targeting pancreatic cancer stroma have been largely unsuccessful, highlighting the need for more comprehensive assessment of inter- and intratumoral stromal heterogeneity in a large series of clinical tumors. Quantitative computation of FAP-dominant fibroblasts, ACTA2-dominant fibroblasts, and intratumoral collagen in whole-tissue sections from 215 treatment-naïve pancreatic cancers allowed us to identify three distinct stroma types (FAP-dominant fibroblast-rich stroma [F-stroma], ACTA2-dominant fibroblast-rich stroma [A-stroma], and collgen-rich stroma [C-stroma]), which were differentially associated with patient outcomes, molecular characteristics and the immunosuppressive tumor microenvironment. We explored differentially expressed genes between three distinct stroma types (F-stroma, A-stroma, and C-stroma) using frozen samples from 20 patients with pancreatic cancer.
2020-09-03 | GSE157353 | GEO
Project description:The objectives of this study were to measure effects of an aspirin intervention on gene expression in normal colonic epithelial and stromal tissue in healthy humans and to determine whether response differed by UGT1A6*2 genotype. We also sought to characterize gene expression differences within colonic tissue microenvironments by identifying genes that were differentially expressed between epithelial and stromal tissue. No statistically significant differences in gene expression were observed in response to aspirin or UGT1A6 genotype, but tissue PGE2 levels were lower with aspirin compared to placebo (p <0.001). Transcripts differentially expressed between epithelium and stroma (N = 4916, P <0.01, false discovery rate <0.001), included a high proportion of genes involved in cell signaling, cellular movement, and cancer. Genes preferentially expressed in epithelium were involved in drug and xenobiotic metabolism, fatty acid and lipid metabolism, apoptosis signaling, and ion transport. Genes preferentially expressed in stroma included those involved in inflammation, cellular adhesion, and extracellular matrix production. Wnt-Tcf4 pathway genes were expressed in both epithelium and stroma but differed by subcellular location. Our results suggest that, in healthy individuals, subtle effects of aspirin on gene expression in normal colon tissue are likely overwhelmed by inter-individual variability in microarray analyses. Differential expression of critical genes between colonic epithelium and stroma suggest that these tissue types need to be considered separately. In a randomized, cross-over, placebo-controlled trial of 44 healthy men and women, homozygous for UGT1A6*1 or UGT1A6*2, we explored differences between global epithelial and stromal expression, using Affymetrix U133 + 2.0 microarrays and tested effects of 60-day aspirin supplementation (325 mg/d) on epithelial and stromal gene expression and colon prostaglandin E2 (PGE2) levels Participants were randomly assigned, blocked on sex and genotype, to the order in which they received treatment A or treatment B. (Note: The type of treatment i.e., pill type active or placebo is masked. Please contact the study authors directly if you would like access to this information). The washout period between intervention periods was three months. A sigmoidoscopy was performed at least 60 days after day 1 of each intervention period. Therefore, two biopsies were obtained from each participant and then processed, where by, epithelial and stromal fractions were separated and analyzed using Affymetrix U133+2.0 microarrays. This resulted in obtaining total RNA from 88 epithelial and and 88 matched stromal samples. A total of 176 gene arrays were measured. Participants were labeled consecutively. There are 4 samples from each person designated A1-A4 (participant 1); A5-A6 (participant 2); B1-B4 (participant 3) etc. to W1-W4 (participant 44). Within each person, odd numbers (1 & 3) are epithelial tissue and even numbers (2 & 4) are stromal tissue. The epithelial and stroma from each intervention period are paired together (e.g., A1 & A2 are from the first treatment Participant 1 received; A3 & A4 are from the second treatment Participant 1 received).
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