Sequencing Facilitates Quantitative Analysis of gene expression among 3 stromal cell populations: NAF, CAF, CAF_HiP
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE99744 | GEO | 2019/06/01
REPOSITORIES: GEO
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Project description:Prostate cancer-associated stroma (CAS) plays an active role in malignant transformation, tumor progression, and metastasis. Molecular analyses of CAS have demonstrated significant changes in gene expression; however, conflicting evidence exists on whether genomic alterations in benign cells comprising the tumor microenvironment (TME) underlie gene expression changes and oncogenic phenotypes. This study evaluates the nuclear and mitochondrial DNA integrity of prostate carcinoma cells, CAS, matched benign epithelium and benign epithelium-associated stroma by whole genome copy number analyses, targeted sequencing of TP53, and fluorescence in situ hybridization. Comparative genomic hybridization (aCGH) of CAS revealed a copy-neutral diploid genome with only rare and small somatic copy number aberrations (SCNAs). In contrast, several expected recurrent SCNAs were evident in the adjacent prostate carcinoma cells, including gains at 3q, 7p, and 8q, and losses at 8p and 10q. No somatic TP53 mutations were observed in CAS. Mitochondrial DNA (mtDNA) extracted from carcinoma cells and stroma identified 23 somatic mtDNA mutations in neoplastic epithelial cells but only one mutation in stroma. Finally, genomic analyses identified no SCNAs, no loss of heterozygosity (LOH) or copy-neutral LOH in cultured cancer-associated fibroblasts (CAFs), which are known to promote prostate cancer progression in vivo. Agilent whole human genome aCGH oligonucleotide microarrays were used to assess copy number aberrations in 79 specimens from 20 patients as well as two pairs of cancer-associated fibroblasts (CAF) and benign/normal associated fibroblasts (NAF). 3 CAF/NAF sample pairs were also assessed for DNA copy number aberrations and copy-neutral LOH using the Infinium HumanOmniExpressExome BeadChip Kit.
2016-02-12 | E-GEOD-76456 | biostudies-arrayexpress
Project description:Interactions between epithelial cells and their associated stroma, mainly the fibroblasts therein have been implicated in breast malignancy. Our aim was to verify the effect of soluble factors resulting from the co-culture of normal (NAF) or associated breast cancer fibroblasts (CAF) with a normal (MCF-10A) or a metastatic (MDA-MB231) breast epithelial cell line on fibroblast gene expression profiles. Fibroblast primary cultures were established and co-culture of these cell types separated by inserts, which allow the passage of soluble factors, was performed. Total RNA was extracted, amplified and subjected to microarray gene expression profiling using microarrays in which 4,608 ORESTES (open reading frame expressed sequence tags) were spotted. Differentially expressed genes, at a False Discovery Ratio (FDR) less then 0.01 and fold variation greater than 2, were selected. CAF molecular signature was characterized by down regulation of 62% (29/47) of genes as compared to NAF, represented mainly by those related to vesicular transport, cytoskeleton plasticity and cell motility. CAF responded to co-culture with MCF-10A cells by up regulation of 63.5% (89/140) of genes, including those involved with cytoskeleton remodelling, lipid synthesis and members of the PI3K pathway. Contrarywise, MDA-MB231 cells affected the gene expression profile of CAF by down regulation of 65% (102/156) of genes, including those associated to tumor suppression and antiangiogenic potential. Up regulated genes, were mainly implicated with cell cycle progression and proliferation. NAF signature was altered by MDA-MB231 presence resulting in down regulation of suppressor genes, integrins and angiogenic factors, but it was modestly affected by MCF-10A. Keywords: Fibroblasts transcriptome altered by breast cell lines
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Project description:We obtained fibroblast cultures from fresh surgical specimen ressected from patients with primary colorectal carcinoma: normal colonic fibroblasts (NCF=9) from the normal colonic mucosa at least 5-10cm from the surgical margin, carcinoma-associated fibroblasts from the primary tumor (CAF-PT=14) and carcinoma-associated fibroblasts (CAF-LM=11) from fresh surgical specimens of liver metastases. We identified 277 probes, in common between the three types of fibroblasts, whose expression level is sequentially deregulated according to cancer progression (NCF→CAF-PT→CAF-LM; fold change Log2 normalized expression>1.5 in each step). Prediction Analysis of Microarrays was applied to obtain a 25-gene signature that better characterizes each fibroblast class. The signature is able to classify patients carrying primary tumors according to prognosis. This fact was exploited to obtain a 19-gene signature (from the 277 deregulated probes) predicting recurrence with high accuracy in stage II/III colorectal cancer patients. Signature validation has been carried out in two independent datasets and in a meta-cohort of 336 stage II/III patients. Since the 25-gene signature was obtained regardless of gene expression data of tumor specimens or patient’s clinical data, the prognostic power of this signature provides strong evidence of the link between the tumor stroma and cancer progression. Furthermore, the 19-gene signature was able to identify low-risk patients with very high accuracy, especially relevant for those high-risk stage-II patients. We hybridised fibroblast RNA in Affymetrix GeneChip 1.0 st arrays
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Project description:The pro-inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β) are expressed simultaneously and have tumor-promoting roles in breast cancer. In parallel, mesenchymal stem cells (MSCs) undergo transition at the tumor site to cancer-associated fibroblasts (CAFs), which are generally connected to enhanced tumor progression. Here, we determined the impact of consistent inflammatory stimulation on stromal cell plasticity. MSCs that were persistently stimulated by TNFα+IL-1β (2-3 weeks) gained a CAF-like morphology, accompanied by prominent changes in gene expression, including in stroma/fibroblast-related genes. These CAF-like cells expressed elevated levels of vimentin and fibroblast activation protein (FAP) and demonstrated significantly increased ability to contract collagen gels. Moreover, they have gained the phenotype of inflammatory CAFs, as indicated by reduced expression of α smooth muscle actin (αSMA), increased proliferation and elevated expression of inflammatory genes and proteins, primarily inflammatory chemokines. These inflammatory CAFs released factors that enhanced tumor cell detachment, spreading and migration; the inflammatory CAF-derived factors elevated cancer cell migration by stimulating the chemokine receptors CCR2, CCR5 and CXCR1/2 and Ras-activating receptors, expressed by the cancer cells. Together, these novel findings demonstrate that chronic inflammation, per se, can induce MSC-to-CAF transition, leading to generation of tumor-promoting inflammatory CAFs.
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Project description:Although cancer associated fibroblasts (CAF) play a critical role in cancer progression, their identities are still unknown. Because cells’ own identity is determined by core regulatory circuit (CRC) comprising master transcription factors (TFs), it is critical to find CAF’s master TF. Therefore, we attempt to find master TF of CAF through the extensive screening of single cell RNA-seq database of cancer tissues, and discovered Prrx1, master regulator of embryonic mesenchymal cells, as candidate for master TF of CAF. Prrx1 was abundantly expressed in CAFs with significant correlation with unfavorable clinical outcomes. Furthermore, Prrx1 in fibroblasts dramatically enhanced tumor progression and metastasis in fibroblast-specific Prrx1 inducible mice. On the other hand, tumor formation was severely inhibited in conditional Prrx1 knock-down mice. Finally, we confirmed that Prrx1 is a master TF of CAF and normal fibroblast executing wound healing program using ChIP-SEQ, CRC modeling, and in vivo validation. Furthermore we also revealed that targeting Prrx1 in fibroblast alone induced complete remission of chemotherapy-resistant cancer in preclinical mouse experiments.
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Project description:Although cancer associated fibroblasts (CAF) play a critical role in cancer progression, their identities are still unknown. Because cells’ own identity is determined by core regulatory circuit (CRC) comprising master transcription factors (TFs), it is critical to find CAF’s master TF. Therefore, we attempt to find master TF of CAF through the extensive screening of single cell RNA-seq database of cancer tissues, and discovered Prrx1, master regulator of embryonic mesenchymal cells, as candidate for master TF of CAF. Prrx1 was abundantly expressed in CAFs with significant correlation with unfavorable clinical outcomes. Furthermore, Prrx1 in fibroblasts dramatically enhanced tumor progression and metastasis in fibroblast-specific Prrx1 inducible mice. On the other hand, tumor formation was severely inhibited in conditional Prrx1 knock-down mice. Finally, we confirmed that Prrx1 is a master TF of CAF and normal fibroblast executing wound healing program using ChIP-SEQ, CRC modeling, and in vivo validation. Furthermore we also revealed that targeting Prrx1 in fibroblast alone induced complete remission of chemotherapy-resistant cancer in preclinical mouse experiments.
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Project description:Although cancer associated fibroblasts (CAF) play a critical role in cancer progression, their identities are still unknown. Because cells’ own identity is determined by core regulatory circuit (CRC) comprising master transcription factors (TFs), it is critical to find CAF’s master TF. Therefore, we attempt to find master TF of CAF through the extensive screening of single cell RNA-seq database of cancer tissues, and discovered Prrx1, master regulator of embryonic mesenchymal cells, as candidate for master TF of CAF. Prrx1 was abundantly expressed in CAFs with significant correlation with unfavorable clinical outcomes. Furthermore, Prrx1 in fibroblasts dramatically enhanced tumor progression and metastasis in fibroblast-specific Prrx1 inducible mice. On the other hand, tumor formation was severely inhibited in conditional Prrx1 knock-down mice. Finally, we confirmed that Prrx1 is a master TF of CAF and normal fibroblast executing wound healing program using ChIP-SEQ, CRC modeling, and in vivo validation. Furthermore we also revealed that targeting Prrx1 in fibroblast alone induced complete remission of chemotherapy-resistant cancer in preclinical mouse experiments.
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Project description:Although cancer associated fibroblasts (CAF) play a critical role in cancer progression, their identities are still unknown. Because cells’ own identity is determined by core regulatory circuit (CRC) comprising master transcription factors (TFs), it is critical to find CAF’s master TF. Therefore, we attempt to find master TF of CAF through the extensive screening of single cell RNA-seq database of cancer tissues, and discovered Prrx1, master regulator of embryonic mesenchymal cells, as candidate for master TF of CAF. Prrx1 was abundantly expressed in CAFs with significant correlation with unfavorable clinical outcomes. Furthermore, Prrx1 in fibroblasts dramatically enhanced tumor progression and metastasis in fibroblast-specific Prrx1 inducible mice. On the other hand, tumor formation was severely inhibited in conditional Prrx1 knock-down mice. Finally, we confirmed that Prrx1 is a master TF of CAF and normal fibroblast executing wound healing program using ChIP-SEQ, CRC modeling, and in vivo validation. Furthermore we also revealed that targeting Prrx1 in fibroblast alone induced complete remission of chemotherapy-resistant cancer in preclinical mouse experiments.
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Project description:Although cancer associated fibroblasts (CAF) play a critical role in cancer progression, their identities are still unknown. Because cells’ own identity is determined by core regulatory circuit (CRC) comprising master transcription factors (TFs), it is critical to find CAF’s master TF. Therefore, we attempt to find master TF of CAF through the extensive screening of single cell RNA-seq database of cancer tissues, and discovered Prrx1, master regulator of embryonic mesenchymal cells, as candidate for master TF of CAF. Prrx1 was abundantly expressed in CAFs with significant correlation with unfavorable clinical outcomes. Furthermore, Prrx1 in fibroblasts dramatically enhanced tumor progression and metastasis in fibroblast-specific Prrx1 inducible mice. On the other hand, tumor formation was severely inhibited in conditional Prrx1 knock-down mice. Finally, we confirmed that Prrx1 is a master TF of CAF and normal fibroblast executing wound healing program using ChIP-SEQ, CRC modeling, and in vivo validation. Furthermore we also revealed that targeting Prrx1 in fibroblast alone induced complete remission of chemotherapy-resistant cancer in preclinical mouse experiments.
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