Modeling Inducible Human Tissue Neoplasia Identifies an ECM Interaction Network Involved in Cancer Progression
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE15299 | GEO | 2009/06/02
SECONDARY ACCESSION(S): PRJNA115827
REPOSITORIES: GEO
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Project description:To elucidate mechanisms of cancer progression, we generated inducible human neoplasia in 3-dimensionally intact epithelial tissue. Gene expression profiling of both epithelia and stroma at specific time points during tumor progression revealed sequential enrichment of genes mediating discrete biologic functions in each tissue compartment. A core cancer progression signature was distilled using the increased signaling specificity of downstream oncogene effectors and subjected to network modeling. Network topology predicted that tumor development depends upon specific ECM-interacting network hubs. Blockade of one such hub, the b1 integrin subunit, disrupted network gene expression and attenuated tumorigenesis in vivo. Thus, integrating network modeling and temporal gene expression analysis of inducible human neoplasia provides an approach to prioritize and characterize genes functioning in cancer progression. There are 3 experiments in this study: (1a) a time course of human epidermal tissue transformed by oncogenic ER:H-Ras and IkBaM comprising days 0, 5, 20, and 35 post Ras activation using 4OHT; (1b) a matched time course of adjacent mouse stromal tissue during tumor progression; (2) Arrays comparing 4OHT-induced, Raf-1:ER/IkBaM transformed epidermal tissue and -4OHT controls; and (3) Arrays comparing Ras:ER/IkBaM grafts co-treated with 4OHT and either IgG control antibody or an anti-b1 integrin blocking antibody, P5D2 for 30 days. All arrays were done in biologic duplicate. Epidermal tissue co-expressing ER:H-RasG12V (ER:Ras) and IkBaM was regenerated on female scid/scid mouse recipients. Grafts were allowed to heal for at least 3 weeks before Ras activation via daily i.p. injections of 730ug of 4OHT (in 110ul of a corn oil/ethanol mixture). Duplicate grafts were harvested after 0, 5, 20, and 35 days of 4OHT treatment. Laser capture microdissection was utilized to independently isolate epithelial cells of the basal most layers and adajacent stromal tissue for each time point. RNA was subjected to one round of T7-based linear amplification (Ambion Message Amp II enhanced kit) and hybridized to either HG-U133A 2.0 or MG-430A affymetrix oligonucleotide arrays. Arrays from this experiment are labeled Ras and Stroma, respectively. The second experment was performed on Raf-1:ER/IkBaM expressing grafts with and without 4OHT treament for 30 days. The third experiment was done comparing ER:Ras/IkBaM grafts concomitantly treated with 4OHT and 1.5mg/week of either IgG control antibody or a mouse monoclonal blocking antibody against b1 integrin for 30 days. For experiments 2 and 3, HG-U133A 2.0 GeneChips were used; 4OHT treatment and RNA isolation/amplification was performed as above.
2009-06-02 | E-GEOD-15299 | biostudies-arrayexpress
Project description:Modeling Inducible Human Tissue Neoplasia Identifies an ECM Interaction Network Involved in Cancer Progression
| PRJNA115827 | ENA
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.
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.
2010-09-15 | GSE22382 | 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 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:Many normal tissues undergo age-related DNA methylation drift providing a quantitative measure of tissue age. However this drift has not been demonstrated in neoplastic tissues. Here we identify and validate 781 CpG-islands (CGIs) that undergo significant methylomic drift in normal colorectal tissues continue to drift in neoplasia and remain significantly correlated with one another across tissue samples. However compared with normal colon this drift advances (~3-4 fold) faster in neoplasia consistent with increased cell proliferation during neoplastic progression. Furthermore we show that the observed drift patterns are broadly consistent with modeled adenoma-carcinoma sojourn time distributions from colorectal cancer (CRC) incidence data. These results support the hypothesis that beginning with the founder premalignant cell cancer precursors frequently sojourn for decades before turning into cancer which implies that the founder cell typically arises early in life. We estimate that at least 77-89% of the observed drift variance in distal and rectal tumors is explained by stochastic variability associated with neoplastic progression while only 55% of the variance is explained for proximal tumors. However >50% of identified gene-CGI pairs in the proximal colon that undergo drift are significantly and mainly negatively correlated with cancer gene expression suggesting that methylomic drift participates in the clonal evolution of CRCs. Significance: Methylomic drift advances in colorectal neoplasia consistent with extended sojourn time distributions explaining a significant fraction of epigenetic heterogeneity in CRCs. Importantly the estimated long-duration premalignant sojourn times suggest that early dietary and lifestyle interventions may be more effective than later changes in reducing CRC incidence.
2019-04-19 | GSE113904 | GEO
Project description:Prostate cancer (PCa) is a leading cause of cancer-related deaths. The slow evolution of precancerous lesions to malignant tumors provides a broad time-frame for preventing PCa. To characterize prostatic intraepithelial neoplasia (PIN) progression, we conducted longitudinal studies on Pten(i)pe-/- mice which recapitulate prostate carcinogenesis in humans. We discovered that early PINs are hypoxic and that hypoxia-inducible factor 1 alpha (HIF1A) signaling is activated in luminal cells, which enhances malignant progression. Luminal HIF1A dampens immune surveillance and drives luminal plasticity leading to the emergence of cells with selective Transglutaminase 2 (TGM2) expression and impaired androgen signaling. Importantly, elevated TGM2 levels in PCa patients are associated with shortened progression-free survival after prostatectomy. Finally, we show that pharmacologically inhibiting HIF1A impairs cell proliferation and induces apoptosis in PINs. Therefore, our study demonstrates that HIF1A is a target for PCa prevention, and that TGM2 is a promising prognostic biomarker of early relapse after prostatectomy.
2022-06-07 | GSE189784 | GEO
Project description:Invasive lobular carcinoma (ILC) of the breast accounts for 5-15% of breast cancers and is characterized by loss of E-cadherin and believed to arise via a linear histological progression. Genomic studies have identified a clonal relationship between ILC and concurrent lobular carcinoma in situ (LCIS) lesions, suggesting that LCIS may be a precursor lesion. It has been shown that an LCIS diagnosis confers a 15-20% risk of progression to ILC, over a lifetime. Currently no molecular test or markers can identify LCIS lesions likely to progress to ILC. Since microRNA (miRNA) expression changes have been detected in a number of other cancer types, we explored whether their dysregulation might be detected during progression from LCIS to ILC. Using the Illumina miRNA profiling platform, designed for simultaneous analysis of 470 mature miRNAs, we analyzed the profiles of archived normal breast epithelium, LCIS lesions found alone, LCIS lesions concurrent with ILC, and the concurrent ILCs, as a model of linear histological progression toward ILC. We identified two sets of differentially expressed miRNAs, the first set highly expressed in normal epithelium, including hsa-miR-224, -139, -10b, -450, 140 and -365 and the second set upregulated during lobular neoplasia, including hsa-miR-375, -203, -425-5p, -183, -565 and -182. Using quantitative RT-PCR, we validated a trend of increased expression for hsa-mir-375, hsa-mir-182, and hsa-mir-183 correlating with ILC progression. As we detected increased expression of hsa-miR-375 in LCIS lesions synchronous with ILC, we sought to determine whether hsa-mir-375 might induce phenotypes reminiscent of lobular neoplasia by expressing it in the MCF10A 3D culture model of mammary acinar morphogenesis. Increased expression of hsa-miR-375 resulted in loss of cellular organization and acquisition of a hyperplastic phenotype. These data suggest that dysregulated miRNA expression contributes to lobular neoplastic progression. 6 specimens were analyzed in duplicate. One frozen normal lobular epithelium and the matched FFPE (1 month old) normal lobular epithelium. One lobular carcinoma in situ (LCIS) found alone, one LCIS synchronous with an invasive lobular carcinoma (ILC), the synchronous ILC (from a different archived block), and one ILC found alone without presence of any other breast cancer.
2011-04-11 | E-GEOD-28514 | biostudies-arrayexpress
Project description:Prostate cancer (PCa) is a leading cause of cancer-related deaths. The slow evolution of prostatic precancerous lesions to malignant tumors provides a broad time-frame for strategies targeting disease emergence. To characterize prostatic intraepithelial neoplasia (PIN) progression, we conducted longitudinal studies on prostates of genetically-engineered Pten(i)pe- /- mice. We discovered that early PINs are hypoxic and that hypoxia-inducible factor 1 alpha (HIF1A) signaling is activated in luminal cells during disease progression. Luminal HIF1A enhances glucose metabolism and promotes a PIN-derived secretome that increases the recruitment of myeloid-derived suppressor cells, thus dampening immune surveillance. Moreover, pharmacological inhibition of HIF1A induces apoptosis in early PIN lesions, and slows the proliferation of late ones. Therefore, our study identifies HIF1A as a target for PCa prevention. Importantly, we also demonstrate that HIF1A signaling correlates with the emergence of prostatic luminal cells expressing TGM2, the expression of which predicts early relapse after primary intervention in PCa patients.
2022-06-07 | GSE186419 | GEO