Organotypic Human Epithelial Neoplasia
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE22382 | GEO | 2010/09/15
SECONDARY ACCESSION(S): PRJNA127637
REPOSITORIES: GEO
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Project description:Refined cancer models are required to assess the burgeoning number of potential targets for cancer therapeutics within a rapid and clinically relevant context. Here we utilize tumor-associated genetic pathways to transform primary human epithelial cells from epidermis, oropharynx, esophagus, and cervix into genetically defined tumors within an entirely human 3-dimensional (3-D) tissue environment incorporating cell-populated stroma and intact basement membrane (BM). These engineered organotypic tissues recapitulated natural features of tumor progression, including epithelial invasion through the BM, a complex process critically required for biologic malignancy in 90% of human cancers. Invasion was rapid, and potentiated by stromal cells. Oncogenic signals in 3-D tissue, but not 2-D culture, resembled gene expression profiles from spontaneous human cancers. Screening well-characterized signaling pathway inhibitors in 3-D organotypic neoplasia helped distil a clinically faithful cancer gene signature. Multi-tissue 3-D human tissue cancer models may provide an efficient and relevant complement to current approaches to characterize cancer progression.
2010-10-15 | GSE22573 | GEO
Project description:Refined cancer models are required to assess the burgeoning number of potential targets for cancer therapeutics within a rapid and clinically relevant context. Here we utilize tumor-associated genetic pathways to transform primary human epithelial cells from epidermis, oropharynx, esophagus, and cervix into genetically defined tumors within an entirely human 3-dimensional (3-D) tissue environment incorporating cell-populated stroma and intact basement membrane (BM). These engineered organotypic tissues recapitulated natural features of tumor progression, including epithelial invasion through the BM, a complex process critically required for biologic malignancy in 90% of human cancers. Invasion was rapid, and potentiated by stromal cells. Oncogenic signals in 3-D tissue, but not 2-D culture, resembled gene expression profiles from spontaneous human cancers. Screening well-characterized signaling pathway inhibitors in 3-D organotypic neoplasia helped distil a clinically faithful cancer gene signature. Multi-tissue 3-D human tissue cancer models may provide an efficient and relevant complement to current approaches to characterize cancer progression. Organotypic human cervical epithium expressing LacZ, cdk4 and Ras, or cdk and Ras with U0126 mediated MEK inhibition were harvested for RNA extraction and hybridization on Affymetrix microarrays. There are 2 biologic replicates for each group.
2010-09-15 | E-GEOD-22382 | biostudies-arrayexpress
Project description:Refined cancer models are required to assess the burgeoning number of potential targets for cancer therapeutics within a rapid and clinically relevant context. Here we utilize tumor-associated genetic pathways to transform primary human epithelial cells from epidermis, oropharynx, esophagus, and cervix into genetically defined tumors within an entirely human 3-dimensional (3-D) tissue environment incorporating cell-populated stroma and intact basement membrane (BM). These engineered organotypic tissues recapitulated natural features of tumor progression, including epithelial invasion through the BM, a complex process critically required for biologic malignancy in 90% of human cancers. Invasion was rapid, and potentiated by stromal cells. Oncogenic signals in 3-D tissue, but not 2-D culture, resembled gene expression profiles from spontaneous human cancers. Screening well-characterized signaling pathway inhibitors in 3-D organotypic neoplasia helped distil a clinically faithful cancer gene signature. Multi-tissue 3-D human tissue cancer models may provide an efficient and relevant complement to current approaches to characterize cancer progression. Organotypic human epidermal epithium expressing LacZ, cdk4 and Hras, or cdk and Ras with U0126 mediated MEK inhibition were harvested for RNA extraction and hybridization on Affymetrix microarrays. There are 8 biologic replicates for the LacZ, and cdk4 Ras groups, and 2 biologic replicates for the U0126 treated samples.
2010-10-15 | E-GEOD-22573 | biostudies-arrayexpress
Project description:The first step in metastasis is dissemination of tumor cells into the surrounding tissue, or stroma. In carcinomas, cancers of epithelial origin, tumor cells must first breach the basement membrane (BM), a network that encapsulates the tumor. As tumor progresses, other cell types that reside in the stroma, such as carcinoma-associated fibroblasts (CAFs) accumulate around the tumor. Whether CAFs can help cancer cells to breach the BM remains an open question. Here we show that CAFs promote cancer cell invasion by physically remodeling the BM. Using a novel 3D in vitro model we observed that primary CAFs isolated from colon cancer patients stimulate cancer cell invasion through a native mesenteric BM. This stimulated invasion is the result of the physical presence of CAFs rather than an increased invasive potential of cancer cells. In the presence of CAFs, cancer cells can invade the BM in a matrix metalloproteinase-independent manner. Using live imaging, we found that CAFs actively pull and stretch the BM, leading to the formation of gaps through which cancer cells can migrate. Notably, CAF-mediated gap-widening is independent of proteolysis but relies on actomyosin contractility. We propose that CAFs exert mechanical forces that alter the organization and the physical properties of the BM, making it permissive for cancer cell invasion.
2017-09-18 | PXD003670 | Pride
Project description:Human squamous cell cancers are the most common epithelially derived malignancies. One example is esophageal squamous cell carcinoma (ESCC), which is associated with a high mortality rate that is related to a propensity for invasion and metastasis. We report that periostin, a highly expressed cell adhesion molecule, is a key component of a novel tumor invasive signature obtained from an organotypic culture model of engineered ESCC. This tumor invasive signature classifies with human ESCC microarrays, underscoring its utility in human cancer. Genetic modulation of periostin promotes tumor cell migration and invasion as revealed in gain of and loss of function experiments. Inhibition of EGFR signaling and restoration of wild-type p53 function were each found to attenuate periostin, suggesting interdependence of two common genetic alterations with periostin function. Our studies reveal periostin as an important mediator of ESCC tumor invasion and they indicate that organotypic (3D) culture can offer an important tool to discover novel biologic effectors in cancer. Invading and non-invading genetically engineered human esophageal cells with hTERT and EGFR overexpression and p53 mutations were grown in organotypic culture. These invading and non-invading cells were excised using laser-capture microdissection. RNA was isolated and amplified for Affymetrix U133 microarrays. Subsequent microarray analysis & comparison with 2 independent cohorts of primary ESCC tumors revealed upregulation of periostin as gene with highest upregulation found in novel tumor invasive signature in esophageal cancer.
2010-07-08 | E-GEOD-21293 | biostudies-arrayexpress
Project description:The mammalian target of rapamycin (mTOR) kinase is a master regulator of protein synthesis that couples nutrient sensing to cell growth and cancer. However, the downstream translationally regulated nodes of gene expression that may direct cancer development are poorly characterized. Employing ribosome profiling we uncover specialized translation of the prostate cancer genome by oncogenic mTOR signaling, revealing a remarkably specific repertoire of genes involved in cell proliferation, metabolism, and invasion. We extend these findings by functionally characterizing a class of translationally controlled pro-invasion mRNAs that we show direct prostate cancer invasion and metastasis downstream of oncogenic mTOR signaling. We further develop a clinically relevant ATP site inhibitor of mTOR, INK128, which reprograms this gene expression signature with therapeutic benefit for prostate cancer metastasis, for which there is presently no cure. Together, these findings significantly extend our understanding of how the M-bM-^@M-^\cancerousM-bM-^@M-^] translation machinery steers specific cancer cell behaviors and may be therapeutically targeted. Examination of mRNA translation in human prostate cancer upon differential inhibition of the mTOR signaling pathway.
2012-02-28 | E-GEOD-35469 | biostudies-arrayexpress
Project description:Human squamous cell cancers are the most common epithelially derived malignancies. One example is esophageal squamous cell carcinoma (ESCC), which is associated with a high mortality rate that is related to a propensity for invasion and metastasis. We report that periostin, a highly expressed cell adhesion molecule, is a key component of a novel tumor invasive signature obtained from an organotypic culture model of engineered ESCC. This tumor invasive signature classifies with human ESCC microarrays, underscoring its utility in human cancer. Genetic modulation of periostin promotes tumor cell migration and invasion as revealed in gain of and loss of function experiments. Inhibition of EGFR signaling and restoration of wild-type p53 function were each found to attenuate periostin, suggesting interdependence of two common genetic alterations with periostin function. Our studies reveal periostin as an important mediator of ESCC tumor invasion and they indicate that organotypic (3D) culture can offer an important tool to discover novel biologic effectors in cancer.
2010-06-22 | GSE21293 | GEO
Project description:Tumor microenvironment (TME) is an active player in malignant growth and spread. Changes in the composition and structure of TME and extracellular matrix can result in either suppression or facilitation of malignant tumor growth. Carcinoma‐associated fibroblasts, bone marrow-derived multipotent mesenchymal stromal cells (BMMSCs), tumor associated macrophages and other inflammatory cells all affect the composition of TME, proliferation and survival of cancer cells, angiogenesis, invasion and metastasis. The objective of this work was to investigate the effect of the interaction between bone marrow-derived BMMSCs and human oral tongue squamous cell carcinoma (OTSCC) cells in the processes of invasion and gene expression. Co-cultures of OTSCC cancer cells and BMMSCs in 3D organotypic invasion assay were used in addition to cell culture, immunological, microarray, and RNA interference techniques. Total number of 4 samples were analyzed. 2 replicates of cultured human oral tongue squamous cell carcinoma (OTSCC) cells, and 2 replicates of OTSCC cells co-cultured with bone marrow-derived multipotent mesenchymal stromal cells
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Project description:Brain metastases are an increasing burden among breast cancer patients, particularly for those with HER2+ and triple negative (TN) subtypes. Mechanistic insight into the pathophysiology of brain metastases and preclinical validation of therapies has relied almost exclusively on intracardiac injection of brain-homing cells derived from highly aggressive TN MDA-MB-231 and HER2+ BT474 breast cancer cell lines. Yet, these well characterized models are far from representing the tumor heterogeneity observed clinically and, due to their fast progression in vivo, their suitability to validate therapies for established brain metastasis remains limited. The goal of this study was to develop and characterize novel human brain metastasis breast cancer patient-derived xenografts (BM-PDXs) to study the biology of brain metastasis and to serve as tools for testing novel therapeutic approaches. We obtained freshly resected brain metastases from consenting donors with breast cancer. Tissue was immediately implanted in the mammary fat pad of female immunocompromised mice and expanded as BM-PDXs. Brain metastases from 3/4 (75%) TN, 1/1 (100%) estrogen receptor positive (ER+), and 5/9 (55.5%) HER2+ clinical subtypes were established as transplantable BM-PDXs. To facilitate tracking of metastatic dissemination using BM-PDXs, we labeled PDX-dissociated cells with EGFP-luciferase followed by re-implantation in mice, and generated a BM-derived cell line (F2-7). Immunohistologic analyses demonstrated that parental and labeled BM-PDXs retained expression of critical clinical markers such as ER, progesterone receptor (PR), epidermal growth factor receptor (EGFR), HER2 and the basal cell marker cytokeratin 5 (CK5). Similarly, RNA sequencing analysis showed clustering of parental, labeled BM-PDXs and their corresponding cell line derivative. Intracardiac injection of dissociated cells from BM-E22-1, resulted in MRI-detectable macrometastases in 4/8 (50%) and micrometastases (8/8) (100%) mice, suggesting that BM-PDXs remain capable of colonizing the brain at high frequencies. Brain metastases developed 8 to 12 weeks after ic injection, located to the brain parenchyma, grew around blood vessels and elicited astroglia activation characteristic of breast cancer brain metastasis. These novel BM-PDXs represent heterogeneous and clinically relevant models to study mechanisms of brain metastatic colonization, with the added benefit of a slower progression rate that makes them suitable for preclinical testing of drugs in therapeutic settings.
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Project description:Cell motility and invasion initiate metastasis. However, only a subpopulation of cancer cells within a tumor will ultimately become invasive. Due to this stochastic and transient nature, in an experimental setting, migrating and invading cells need to be isolated from the general population in order to study the gene expression profiles linked to these processes. This report describes microarray analysis on RNA derived from migrated or invaded subpopulations of triple negative breast cancer cells in a Transwell set-up, at two different time points during motility and invasion, pre-determined as M-bM-^@M-^\earlyM-bM-^@M-^] and M-bM-^@M-^\lateM-bM-^@M-^] in real-time kinetic assessments. Invasion- and migration-related gene expression signatures were generated through comparison with non-invasive cells, remaining at the upper side of the Transwell membranes. Late-phase signatures of both invasion and migration indicated poor prognosis in a series of breast cancer data sets. Furthermore, evaluation of the genes constituting the prognostic invasion-related gene signature revealed KruM-LM-^Hppel-like factor 9 (KLF9) as a putative suppressor of invasive growth in breast cancer. Next to loss in invasive vs non-invasive cell lines, KLF9 also showed significantly lower expression levels in the M-bM-^@M-^\earlyM-bM-^@M-^] invasive cell population, in several public expression data sets and in clinical breast cancer samples when compared to normal tissue. Overexpression of EGFP-KLF9 fusion protein significantly altered morphology and blocked invasion and growth of MDA-MB-231 cells in vitro. In addition, KLF9 expression correlated inversely with mitotic activity in clinical samples, indicating anti-proliferative effects. After selection of two time points (M-bM-^@M-^\earlyM-bM-^@M-^] and M-bM-^@M-^\lateM-bM-^@M-^]), RNA from invasive and migratory MDA-MB-231 cells was isolated from Transwell membranes and hybridized onto an Illumina HumanHT-12 v4 Expression beadchip. Gene expressions of migrated/invaded subpopulations vs non-motile cells were compared.
2014-01-29 | E-GEOD-54465 | biostudies-arrayexpress