- To improve and focus preclinical testing, we combine tumor models based on a decellularized tissue matrix with bioinformatics to stratify tumors according to stage-specific mutations that are linked to central cancer pathways. We generated tissue models with BRAF-mutant colorectal cancer (CRC) cells (HROC24 and HROC87) and compared treatment responses to two-dimensional (2D) cultures and xenografts. As the BRAF inhibitor vemurafenib is—in contrast to melanoma—not effective in CRC, we combined it with the EGFR inhibitor gefitinib. In general, our 3D models showed higher chemoresistance and in contrast to 2D a more active HGFR after gefitinib and combination-therapy. In xenograft models murine HGF could not activate the human HGFR, stressing the importance of the human microenvironment. In order to stratify patient groups for targeted treatment options in CRC, an in silico topology with different stages including mutations and changes in common signaling pathways was developed. We applied the established topology for in silico simulations to predict new therapeutic options for BRAF-mutated CRC patients in advanced stages. Our in silico tool connects genome information with a deeper understanding of tumor engines in clinically relevant signaling networks which goes beyond the consideration of single drivers to improve CRC patient stratification.
MetadatenAuthor: | Florentin Baur, Sarah Nietzer, Meik Kunz, Fabian Saal, Julian Jeromin, Stephanie Matschos, Michael Linnebacher, Heike Walles, Thomas Dandekar, Gudrun Dandekar |
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URN: | urn:nbn:de:hebis:30:3-527669 |
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DOI: | https://doi.org/10.3390/cancers12010028 |
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ISSN: | 2072-6694 |
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Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/31861874 |
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Parent Title (English): | Cancers |
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Publisher: | MDPI |
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Place of publication: | Basel |
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Document Type: | Article |
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Language: | English |
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Year of Completion: | 2019 |
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Year of first Publication: | 2019 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2020/01/27 |
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Tag: | 3D tissue models; BRAF mutation; colorectal cancer; in silico simulation; stratification; targeted therapy |
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Volume: | 12 |
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Issue: | 1, Art. 28 |
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Page Number: | 27 |
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First Page: | 1 |
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Last Page: | 27 |
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Note: | This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited |
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HeBIS-PPN: | 458522279 |
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Institutes: | Medizin / Medizin |
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Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Licence (German): | Creative Commons - Namensnennung 4.0 |
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