Oncoprotein-specific molecular interaction maps (SigMaps) for cancer network analyses
| Autor: | Barry Honig, Diana Murray, Alexander Lachmann, Peter K. Jackson, David R. Simpson, Andrea Califano, E. Alejandro Sweet-Cordero, Sunny J. Jones, Somnath Tagore, Brennan Chu, Evan O. Paull, Federico M. Giorgi, Joshua Broyde, Aaron T. Griffin |
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| Přispěvatelé: | Broyde J., Simpson D.R., Murray D., Paull E.O., Chu B.W., Tagore S., Jones S.J., Griffin A.T., Giorgi F.M., Lachmann A., Jackson P., Sweet-Cordero E.A., Honig B., Califano A. |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Systems biology
Biomedical Engineering Gene regulatory network Bioengineering Computational biology Biology Small Interfering medicine.disease_cause Applied Microbiology and Biotechnology Article Proto-Oncogene Proteins p21(ras) Mice 03 medical and health sciences 0302 clinical medicine Protein structure Neoplasms Genetics medicine Animals Humans Gene Regulatory Networks RNA Small Interfering Cancer 030304 developmental biology Oncogene Proteins 0303 health sciences Effector Organoids Crosstalk (biology) ROC Curve Mutation RNA Molecular Medicine Rab KRAS Signal transduction Cancer Networks Algorithms 030217 neurology & neurosurgery Signal Transduction Biotechnology |
| Zdroj: | Nature biotechnology, vol 39, iss 2 Nat Biotechnol |
| Popis: | Tumor-specific elucidation of physical and functional oncoprotein interactions could improve tumorigenic mechanism characterization and therapeutic response prediction. Current interaction models and pathways, however, lack context specificity and are not oncoprotein specific. We introduce SigMaps as context-specific networks, comprising modulators, effectors and cognate binding-partners of a specific oncoprotein. SigMaps are reconstructed de novo by integrating diverse evidence sources—including protein structure, gene expression and mutational profiles—via the OncoSig machine learning framework. We first generated a KRAS-specific SigMap for lung adenocarcinoma, which recapitulated published KRAS biology, identified novel synthetic lethal proteins that were experimentally validated in three-dimensional spheroid models and established uncharacterized crosstalk with RAB/RHO. To show that OncoSig is generalizable, we first inferred SigMaps for the ten most mutated human oncoproteins and then for the full repertoire of 715 proteins in the COSMIC Cancer Gene Census. Taken together, these SigMaps show that the cell’s regulatory and signaling architecture is highly tissue specific. Interaction networks for any protein can be generated using a machine learning algorithm. |
| Databáze: | OpenAIRE |
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