Engelmann, Julia C. and Amann, Thomas and Ott-Roetzer, Birgitta and Nuetzel, Margit and Reinders, Yvonne and Reinders, Joerg and Thasler, Wolfgang E. and Kristl, Theresa and Teufel, Andreas and Huber, Christian G. and Oefner, Peter J. and Spang, Rainer and Hellerbrand, Claus (2015) Causal Modeling of Cancer-Stromal Communication Identifies PAPPA as a Novel Stroma-Secreted Factor Activating NF kappa B Signaling in Hepatocellular Carcinoma. PLOS COMPUTATIONAL BIOLOGY, 11 (5): e1004293. ISSN 1553-7358,
Full text not available from this repository. (Request a copy)Abstract
Inter-cellular communication with stromal cells is vital for cancer cells. Molecules involved in the communication are potential drug targets. To identify them systematically, we applied a systems level analysis that combined reverse network engineering with causal effect estimation. Using only observational transcriptome profiles we searched for paracrine factors sending messages from activated hepatic stellate cells (HSC) to hepatocellular carcinoma (HCC) cells. We condensed these messages to predict ten proteins that, acting in concert, cause the majority of the gene expression changes observed in HCC cells. Among the 10 paracrine factors were both known and unknown cancer promoting stromal factors, the former including Placental Growth Factor (PGF) and Periostin (POSTN), while Pregnancy-Associated Plasma Protein A (PAPPA) was among the latter. Further support for the predicted effect of PAPPA on HCC cells came from both in vitro studies that showed PAPPA to contribute to the activation of NF kappa B signaling, and clinical data, which linked higher expression levels of PAPPA to advanced stage HCC. In summary, this study demonstrates the potential of causal modeling in combination with a condensation step borrowed from gene set analysis [Model-based Gene Set Analysis (MGSA)] in the identification of stromal signaling molecules influencing the cancer phenotype.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HEPATIC STELLATE CELLS; GROWTH-FACTOR RECEPTOR; PLASMA-PROTEIN; EXPRESSION; PROMOTE; MIGRATION; TUMOR; MICROENVIRONMENT; INHIBITORS; INVASION; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) Medicine > Lehrstuhl für Innere Medizin I Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Statistische Bioinformatik (Prof. Spang) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 18 Jul 2019 09:31 |
| Last Modified: | 18 Jul 2019 09:31 |
| URI: | https://pred.uni-regensburg.de/id/eprint/5531 |
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