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High-throughput sequencing of matched colorectal normal, tumor and metastasis tissues and proof-of principal bioinformatics modeling of therapeutic consequences of miRNA applications

ABSTRACT: MiRNAs are discussed as diagnostic and therapeutic molecules. However, effective miRNA drug treatments with miRNAs are so far hampered by the complexity of the miRNA networks. To identify potential miRNA drugs in colorectal cancer, we profiled miRNA and mRNA expression in matching normal, tumor and metastasis tissues of eight patients by Illumina sequencing. We identified miRNA-1 as top candidate differentially expressed in tumor and metastasis. Furthermore, miRNA-1 was de-regulated in 16 additional tumor entities underscoring its central role in tumor pathogenesis. Functional analyses showed an additive effect of miRNA-1 with camptothecin treatment. We used a systems-biology simulation of cellular cancer models implemented in PyBios to investigate miRNA-1 function and assessed the effects of depletion as well as overexpression in terms of miRNA-1 as a potential treatment option. In this system miRNA-1 treatment reverted the disease phenotype with different effectiveness among the patients. Scoring the gene expression changes obtained through mRNA-Seq from the same patients we show that the combination of deep sequencing and systems biological modeling can help to identify patient-specific responses to miRNA treatments. We present this data as guideline for future pre-clinical assessments of new and personalized therapeutic options.

ORGANISM(S): Homo sapiens

PROVIDER: GSE46622 | GEO | 2013/09/18

SECONDARY ACCESSION(S): PRJNA201245

REPOSITORIES: GEO

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High-throughput sequencing of matched colorectal normal, tumor and metastasis tissues and proof-of principal bioinformatics modeling of therapeutic consequences of miRNA applications

Project description:MiRNAs are discussed as diagnostic and therapeutic molecules. However, effective miRNA drug treatments with miRNAs are so far hampered by the complexity of the miRNA networks. To identify potential miRNA drugs in colorectal cancer, we profiled miRNA and mRNA expression in matching normal, tumor and metastasis tissues of eight patients by Illumina sequencing. We identified miRNA-1 as top candidate differentially expressed in tumor and metastasis. Furthermore, miRNA-1 was de-regulated in 16 additional tumor entities underscoring its central role in tumor pathogenesis. Functional analyses showed an additive effect of miRNA-1 with camptothecin treatment. We used a systems-biology simulation of cellular cancer models implemented in PyBios to investigate miRNA-1 function and assessed the effects of depletion as well as overexpression in terms of miRNA-1 as a potential treatment option. In this system miRNA-1 treatment reverted the disease phenotype with different effectiveness among the patients. Scoring the gene expression changes obtained through mRNA-Seq from the same patients we show that the combination of deep sequencing and systems biological modeling can help to identify patient-specific responses to miRNA treatments. We present this data as guideline for future pre-clinical assessments of new and personalized therapeutic options. Examination of miRNA expression values by Illumina sequencing of matched benign, tumor and metastasis tissues of 8 colorectal cancer patients. For 4 of these patients all tissues have been resequenced to obtain mRNA expression values.

2013-09-18 | E-GEOD-46622 | biostudies-arrayexpress

Deregulated microRNAs in triple-negative breast cancer revealed by deep sequencing

Project description:Twenty-four triple-negative breast cancer and 14 adjacent normal tissues were collected from breast cancer patients during surgeries at National Taiwan University Hospital (NTUH, Taipei, Taiwan). All triple-negative breast cancer samples were invasive ductal carcinomas (IDC) and were negative in immunohistochemical statuses of ER, PR, and HER2 receptors, as confirmed by professional pathologists. Treatment procedure of all patients followed the National Comprehensive Cancer Network (NCCN) guideline. All samples were neoadjuvant-free and were collected before systemic chemotherapy treatments. Written informed consent was obtained from all patients who participated in this study. Using human tissues for research in this study was approved by the institutional review board at NTUH. A novel set of 25-miRNA signature identified in this study was able to effectively distinguish between triple-negative breast cancer and adjacent normal tissues. Moreover, we documented the first evidence of seven polycistronic miRNA clusters preferentially harboring deregulated miRNA genes in triple-negative breast cancer.

2015-03-01 | GSE40049 | GEO

Antagonizing miR-128 abrogates chemoresistance-associated metastasis and is therapeutic in non-small cell lung cancer [miRNA]

Project description:This experiment is designed to screen miRNAs that are deregulated during chemoresistance-associated metastasis of lung cancer cells. Chemoresistant metastatic in vivo tumor model of A549-luc-Vector cells was established after four rounds of cisplatin (CDDP) treatments compared to corresponding control solvent treatments. Upon examining profiles of miRNA expression differential between tumor-derived cultured cells from the Ctrl-4th and CDDP-4th treatments, most markedly upregulated and downregulated miRNAs in chemoresistant, metastatic A549-luc-CDDP-4th cells were identified. In order to establish a chemoresistant in vivo tumor model, after inoculation of A549-luc-Vector cells, cisplatin (CDDP) or control solvent was intraperitoneally (i.p.) injected six rounds in a two-week period and cells were isolated from corresponding resultant tumors, cultured and re-transplanted into syngeneic mice to receive the next round of treatment. In our experimental model, human lung cancer xenografts developed chemoresistance in the third round of CDDP treatment (CDDP-3rd) and chemoresistance-associated metastases following the fourth round of treatment. Tumor-derived cultured cells from Ctrl-4th and CDDP (cisplatin)-4th treatment were subjected to miRNA array (Agilent-031181 human miRNA (8*60k) V16.0) analysis, with two biological replications for each treatment.

2015-04-10 | E-GEOD-67727 | biostudies-arrayexpress

Unique MicroRNA Expression Signature Predicts Survival, Metastases and Recurrence of HCC

Project description:In this study we investigated the miRNA expression profile of Hepatocellular carcinoma (HCC) specimens from radical resection. We developed a unique 20 miRNA signature that could significantly distinguish HCC venous metastasis from metastasis-free HCC. In contrast to HCC staging systems, this signature was capable of predicting survival and recurrence of HCC patients with multinodular or solitary tumors, including those with early-stage disease. Moreover, the signature was an independent and significant predictor of patient prognosis and relapse when compared to other available clinical parameters. Our study suggests that these 20 miRNAs can enable HCC prognosis and may have clinical utility for the advance identification of HCC patients with a propensity towards metastasis/recurrence. Keywords: disease state design Gene expression profiles were conducted in primary HCC and corresponding noncancerous hepatic tissues from 244 Chinese HCC patients. A total of 134 well-defined cases were used as a training group. Among them, 30 had primary HCC lesions accompanied by tumor emboli and 104 had solitary HCC with no metastasis/recurrence found at follow-up (3 yr). We used a testing group of 110 independent cases. The testing cases included 43 multinodular and 67 solitary HCC. In addition, eight normal liver tissues from disease-free patients were included as normal controls. In the analysis of the 244 HCC cases, RNA was isolated in a pairwise fashion from tumor or non-tumor tissue and samples were selected in random order for miRNA analysis to avoid grouping bias.

2008-01-14 | E-GEOD-6857 | biostudies-arrayexpress

microRNA epxression patterns can discriminate between patients with oligometastatic and polymetastatic progression: tissues

Project description:Background Cancer staging and treatment presumes a division into localized or metastatic disease. We proposed an intermediate state defined by ≤5 cumulative metastasis(es), termed oligometastases. In contrast to widespread polymetastases, oligometastatic patients may benefit from metastasis-directed local treatments. However, many patients who initially present with oligometastases progress to polymetastases. Predictors of progression could improve patient selection for metastasis-directed therapy. Methods Here, we identified patterns of microRNA expression of tumor samples from oligometastatic patients treated with high-dose radiotherapy. Results Patients who failed to develop polymetastases are characterized by unique prioritized features of a microRNA classifier that includes the microRNA-200 family. We created an oligometastatic-polymetastatic xenograft model in which the patient-derived microRNAs discriminated between the two metastatic outcomes. MicroRNA-200c enhancement in an oligometastatic cell line resulted in polymetastatic progression. Conclusions These results demonstrate a biological basis for oligometastases and a potential for using microRNA expression to identify patients most likely to remain oligometastatic after metastasis-directed treatment.

2010-11-25 | GSE25552 | GEO

Antagonizing miR-128 abrogates chemoresistance-associated metastasis and is therapeutic in non-small cell lung cancer [miRNA]

2015-04-10 | GSE67727 | GEO

Breast Cancer Cell Secretome Analysis to Decipher miRNA Tumor Biology and Discover Potential Biomarkers

Project description:MicroRNA (miRNA/miR) miR526b and miR655 overexpressed tumor cell-free secretions promote breast cancer phenotypes in the tumor microenvironment (TME). However, the mechanisms of miRNA regulating TME have never been investigated. With mass spectrometry analysis of MCF7-miRNA-overexpressed versus miRNA-low MCF7-Mock tumor cell secretomes, we identified 34 novel secretory proteins coded by eight genes YWHAB, TXNDC12, MYL6B, SFN, FN1, PSMB6, PRDX4, and PEA15 those are differentially regulated. We used bioinformatic tools and systems biology approaches to identify these markers’ role in breast cancer. Gene ontology analysis showed that the top functions are related to apoptosis, oxidative stress, membrane transport, and motility, supporting miRNA-induced phenotypes. These secretory markers expression is high in breast tumors, and a strong positive correlation exists between upregulated markers’ mRNA expressions with miRNA cluster expression in luminal A breast tumors. Gene expression of secretome markers is higher in tumor tissues compared to normal samples, and immunohistochemistry data supported gene expression data. Moreover, both up and downregulated marker expressions are associated with breast cancer patient survival. miRNA regulates these marker protein expressions by targeting transcription factors of these genes. Premature miRNA (pri-miR526b and pri-miR655) are established breast cancer blood biomarkers. Here we report novel secretory markers upregulated by miR526b and miR655 (YWHAB, MYL6B, PSMB6, and PEA15) are significantly upregulated in breast cancer patients’ plasma, and are potential breast cancer biomarkers.

2023-05-10 | PXD031771 | Pride

Wilson2012 - tumor vaccine efficacy

Project description:The paper describes a model of antitumor vaccine therapy. Created by COPASI 4.25 (Build 207) This model is described in the article: A Mathematical Model of the Enhancement of Tumor Vaccine Efficacy by Immunotherapy Shelby Wilson and Doron Levy Bull Math Biol. 2012 July ; 74(7) Abstract: TGF-β is an immunoregulatory protein that contributes to inadequate antitumor immune responses in cancer patients. Recent experimental data suggests that TGF-β inhibition alone, provides few clinical benefits, yet it can significantly amplify the anti-tumor immune response when combined with a tumor vaccine. We develop a mathematical model in order to gain insight into the cooperative interaction between anti-TGF-β and vaccine treatments. The mathematical model follows the dynamics of the tumor size, TGF-β concentration, activated cytotoxic effector cells, and regulatory T cells. Using numerical simulations and stability analysis, we study the following scenarios: a control case of no treatment, anti-TGF-β treatment, vaccine treatment, and combined anti-TGF-β vaccine treatments. We show that our model is capable of capturing the observed experimental results, and hence can be potentially used in designing future experiments involving this approach to immunotherapy. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

2021-03-12 | BIOMD0000000791 | BioModels

Small Molecule Inhibitors that Disrupt the MTDH-SND1 Complex Suppress Breast Cancer Progression and Metastasis

Project description:Previous studies discovered that MTDH frequently amplifies and overexpresses in breast cancer in human patients and is strongly associated with higher metastasis and treatment failure and thereby leads to poor prognosis. In mouse mammary tumor models, knockout of Mtdh substantially reduces tumor incidence and suppresess metastasis. Furthermore, Mtdh interact with Snd1 and the interaction appears essential for its tumor promoting function. To develop novel therapeutics targeting Mtdh function, small molecular compound to disrupt the Mtdh-Snd1 interaction was identified by high throughput screen. To further elucidate the mechanism of MTDH targeting caused anti-tumor activity and to confirm the action mode of the small molecular compound C26A6 as a Mtdh-Snd1 disruptor, transcriptome changes in mouse mammary tumors following treatments of C26A6 and acute induction of Mtdh knockout by Tamoxifen treatment were investigated using next generation sequencing.

2021-09-07 | GSE159764 | GEO

microRNA epxression patterns can discriminate between patients with oligometastatic and polymetastatic progression: cell lines

Project description:Cancer staging and treatment frequently assume a binary division of tumors into localized or metastatic cancers. We proposed a state of metastatic disease defined by the number of metastases termed oligometastases. Patients with oligometastatic disease may be cured with localized methods of cancer treatment. We analyzed miRNA expression from paraffin blocks of primary or metastatic tumor samples derived from oligometastatic (? 5 metastases) patients treated with high dose localized radiotherapy. We report patterns of miRNA expression in the metastatic and primary tumor samples that identify patients who failed to progress to widespread polymetastases. We created a model of oligometastases of human tumors in immune compromised mice. The miRNA patterns of gene expression derived from patients accurately identified oligometastatic patterns in the mouse model as compared to animals that developed widespread metastases. MiRNA signatures may identify patients most likely to benefit from aggressive curative treatment of limited metastatic disease. Injection of MDA-MB-435-GFP cancer cells into the mammary fat pad of female athymic mice to develop spontaneous macroscopic lung metastasis. Tail vein experimental lung colonization assay was performed to model the development of MDA-MB-435-GFP Oligo- or Poly-metastases in the lung in vivo.

2010-12-09 | GSE25967 | GEO

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