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Gene expression profiles (stroma and epithelium) of prostate cancer mouse models (JOCK1, Pro-Cat × JOCK1, Ubi-Cat × JOCK1)

ABSTRACT: The fibroblast growth factor receptor (FGFR) and canonical Wnt signaling pathways are important regulators of carcinogenesis; however, the interaction between these two pathways in the context of prostate cancer (PCa) has not been fully elucidated. Using novel transgenic mouse models, we describe Wnt-induced synergistic acceleration of FGFR1-driven adenocarcinoma; largely due to pronounced fibroblastic reactive stroma (RS) activation surrounding prostatic intraepithelial neoplasia (PIN) lesions in endogenous and reconstitution assays. Finally, both mouse and human RS are characterized by increases in TGF-β signaling heterogeneity immediately adjacent to PIN lesions; however, heterogeneity is lost during later stages of progression, likely contributing to tissue invasion. These studies confirm the importance of the FGFR1-Wnt-TGF-β signaling axes as driving forces behind reactive stroma and aggressive adenocarcinoma.

ORGANISM(S): Mus musculus

PROVIDER: GSE41344 | GEO | 2014/01/07

SECONDARY ACCESSION(S): PRJNA176665

REPOSITORIES: GEO

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Gene expression profiles (stroma and epithelium) of prostate cancer mouse models (JOCK1, Pro-Cat M-CM-^W JOCK1, Ubi-Cat M-CM-^W JOCK1)

Project description:The fibroblast growth factor receptor (FGFR) and canonical Wnt signaling pathways are important regulators of carcinogenesis; however, the interaction between these two pathways in the context of prostate cancer (PCa) has not been fully elucidated. Using novel transgenic mouse models, we describe Wnt-induced synergistic acceleration of FGFR1-driven adenocarcinoma; largely due to pronounced fibroblastic reactive stroma (RS) activation surrounding prostatic intraepithelial neoplasia (PIN) lesions in endogenous and reconstitution assays. Finally, both mouse and human RS are characterized by increases in TGF-M-NM-2 signaling heterogeneity immediately adjacent to PIN lesions; however, heterogeneity is lost during later stages of progression, likely contributing to tissue invasion. These studies confirm the importance of the FGFR1-Wnt-TGF-M-NM-2 signaling axes as driving forces behind reactive stroma and aggressive adenocarcinoma. To elucidate the mechanism behind the Wnt-accelerated FGFR1 adenocarcinoma, we performed laser capture microdissection (LCM) to separate pre-cancerous (hyperplasia and PIN) epithelia and adjacent reactive-stroma cells. We utilized frozen samples from specific time points (JOCK1, 40 weeks, Pro-Cat M-CM-^W JOCK1 and Ubi-Cat M-CM-^W JOCK1, 24 weeks) and performed gene expression profiling on the respective tissues.

2014-01-07 | E-GEOD-41344 | biostudies-arrayexpress

Microarray analysis of PIN lesions from APT121 mouse prostate

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The contribution of FGFR1 to the development of SCLC is dictated by the cell-of-origin

Project description:Enhanced RAF/MEK/ERK signaling plays an obligatory role in many different types of cancer. Although genetic lesions promoting its aberrant activation are found in lung adenocarcinoma (LADC), the biological role of this pathway is not well documented in small cell lung cancer (SCLC). Here we explored the role of this pathway in SCLC and the broader class of tumors with neuroendocrine (NE) differentiation by introducing a constitutively active form of Fibroblast growth factor receptor 1 (Fgfr1) together with biallelic inactivation of Rb1 and Trp53 in mouse lung. Our data show that FGFR1 expression primarily results in LADC but also in NE tumors depending on the cell-of-origin. FGFR1 activation selectively promoted NE bronchial lesions in a novel lung cell subpopulation, whereas it impaired progression of typical central SCLC initiated from CGRP-expressing NE cells, which is believed to be the most prominent cell-of-origin of SCLC. Strikingly, FGFR1 activation was well tolerated by K14-expressing cells that were efficiently transformed into SCLC and other NE lesions. Taken together, our results indicate that FGFR1 can serve either as driver or suppressor of distinct lung cancer subtypes depending on the cell-of-origin, which should be taken into account when considering FGFR1 as a therapeutic target.

2020-03-27 | GSE132759 | GEO

Next Generation Sequencing of β-cat lox(ex3) (Ctrl) mouse and β-cat lox(ex3);Nex-Cre (β-cat overexpression, β-cat Ovp) mouse Transcriptomes

Project description:Using RNA-seq to sequence the transcriptomes of β-cat lox(ex3) (Ctrl) and β-cat lox(ex3);Nex-Cre (β-cat Ovp) mice, we did not find significant change in the expression level of classical Wnt target genes.

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Genomic profiling of Richter-syndrome Chronic Lymphocytic Leukemia

Project description:Richter syndrome (RS) occurs in up to 15% of patients with chronic lymphocytic leukemia (CLL). While RS, usually represented by the histologic transformation to a diffuse large B-cell lymphoma (DLBCL), is associated with a very poor outcome, especially when clonally related to the pre-existing CLL, mechanisms leading to RS have not been clarified yet. To better understand the pathogenesis of RS, we analyzed a series of cases including: 59 RS, 28 CLL-phase of RS, 315 CLL and 127 de novo DLBCL. RS demonstrated a genomic complexity intermediate between CLL and DLBCL. Cell cycle deregulation via inactivation of TP53 and of CDKN2A was a main mechanism in the histologic transformation from CLL-phase, being present in approximately half of the cases, and affected the outcome of the RS patients. A second major subgroup was characterized by the presence of trisomy 12 and comprised one third of the cases. While RS shared some of the lesions seen in de novo DLBCL, its genomic profile was clearly separate. The CLL-phase preceding RS had not a generalized increase in genomic complexity when compared with untransformed CLL, but it presented clear differences in the frequency of specific genetic lesions.

2013-09-20 | GSE50252 | GEO

Genomic Landscape and Therapeutic Targets of Adenosquamous Carcinoma of the Pancreas [CGH Microarray]

Project description:We applied DNA content flow cytometry to a series of adenosquamous cancer of the pancreas (ASCP) tumor samples and patient derived xenografts (PDXs). We interrogated purified sorted tumor fractions from each sample with whole genome copy number variant (CNV) and whole exome sequencing (WES) analyses. These identified a variety of somatic genomic lesions targeting chromatin regulators in ASCP genomes that were superimposed on well characterized genomic lesions including mutations in KRAS and TP53, homozygous deletion of CDKN2A, and amplification of c-MYC, that are common in PDACs. Furthermore, a comparison of ATAC-seq profiles of ASCP and pancreatic ductal adenocarcinoma (PDAC) genomes using flow sorted PDX models distinguished genes with accessible chromatin in ASCP genomes including the lysine methyltransferase SMYD2, the pancreatic cancer stem cell driver RORγ, and a FGFR1-ERLIN2 fusion associated with focal CNVs in both genes. Organoids derived from these models were used to screen compounds of interest. Notably a FGFR inhibitor had significant activity against the FGFR1-ERLIN2 fusion positive PDX.

2020-01-08 | GSE143256 | GEO

Genomic Landscape and Therapeutic Targets of Adenosquamous Carcinoma of the Pancreas [ATAC-seq]

2020-01-14 | GSE143563 | GEO

Gene expression profiles of reactive stroma in prostate cancer

Project description:This is an analysis of stroma from 17 Grade 3 reactive stroma prostate cancer tissues and matched normal peripheral zone tissues. Keywords: two group comparison Laser capture microdissection and expression array analysis of stroma from 17 Grade 3 reactive stroma prostate cancer tissues and matched normal peripheral zone tissues.

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Genomic profiling of Richter-syndrome Chronic Lymphocytic Leukemia

2013-09-20 | E-GEOD-50252 | biostudies-arrayexpress

Dual-hit strategy for therapeutic targeting of pancreatic cancer in patient-derived xenograft tumors

Project description:Paracrine activation of pro-fibrotic sonic hedgehog (sHH) signaling in pancreatic ductal adenocarcinoma (PDAC) results in stromal amplification that compromises tumor drug delivery, efficacy, and patient survival. Interdiction of sHH-mediated tumor-stroma crosstalk with smoothened inhibitors transiently increases tumor permeability and macromolecule delivery. Using diffusion-weighted magnetic resonance (DW-MR) imaging, we demonstrate in multiple patient-derived xenografts (PDX) that responders to short-term sHH inhibitor exposure show increased permeability with proportionate increases in tumor diffusivity. However, a subset of PDXs fails to respond. Responders show co-induction of epithelial-mesenchymal transition (EMT), elevated FGF drive, and distinctly higher nuclear localization of fibroblast growth factor receptor (FGFR1). A pan-FGFR inhibitor (NVP-BGJ398) reverses EMT and nuclear FGFR1 accumulation without compromising the tumor priming effect. This dual-hit strategy of SMO and FGFR inhibition provides a clinically-translatable approach to compromise the profound impermeability of PDAC tumors. Furthermore, clinical deployment of DW-MR imaging could fulfill the essential clinical requirement for patient stratification

2023-12-12 | GSE159334 | GEO

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