Personalized logical models to investigate cancer response to BRAF treatments in melanomas and colorectal cancers
| Autor: | Laurence Calzone, Lorenzo Pantolini, Vincent Noël, Jonas Béal, Emmanuel Barillot |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Patient-Specific Modeling Cell signaling Skin Neoplasms Colorectal cancer Computer science Cell Cancer Treatment Signal transduction Synthetic Genome Editing Genome Engineering Omics data Machine Learning 0302 clinical medicine Medicine and Health Sciences CRISPR Logical data model Biology (General) Melanoma Skin Tumors Ecology Mathematical model Simulation and Modeling Crispr Signaling cascades Response to treatment medicine.anatomical_structure Computational Theory and Mathematics Oncology 030220 oncology & carcinogenesis Modeling and Simulation Engineering and Technology Synthetic Biology Colorectal Neoplasms Research Article Proto-Oncogene Proteins B-raf Cell biology MAPK signaling cascades Signal Inhibition QH301-705.5 Bioengineering Antineoplastic Agents Computational biology Dermatology Research and Analysis Methods 03 medical and health sciences Cellular and Molecular Neuroscience Cell Line Tumor Genetics medicine Humans In patient Protein kinase A Molecular Biology Ecology Evolution Behavior and Systematics Colorectal Cancer Biology and life sciences Cancer Cancers and Neoplasms Computational Biology Genetic Therapy Synthetic Genomics medicine.disease Omics 030104 developmental biology Cell culture CRISPR-Cas Systems Transcriptome Signalling pathways |
| Zdroj: | PLoS Computational Biology PLoS Computational Biology, Vol 17, Iss 1, p e1007900 (2021) |
| ISSN: | 1553-7358 1553-734X |
| Popis: | The study of response to cancer treatments has benefited greatly from the contribution of different omics data but their interpretation is sometimes difficult. Some mathematical models based on prior biological knowledge of signaling pathways facilitate this interpretation but often require fitting of their parameters using perturbation data. We propose a more qualitative mechanistic approach, based on logical formalism and on the sole mapping and interpretation of omics data, and able to recover differences in sensitivity to gene inhibition without model training. This approach is showcased by the study of BRAF inhibition in patients with melanomas and colorectal cancers who experience significant differences in sensitivity despite similar omics profiles. We first gather information from literature and build a logical model summarizing the regulatory network of the mitogen-activated protein kinase (MAPK) pathway surrounding BRAF, with factors involved in the BRAF inhibition resistance mechanisms. The relevance of this model is verified by automatically assessing that it qualitatively reproduces response or resistance behaviors identified in the literature. Data from over 100 melanoma and colorectal cancer cell lines are then used to validate the model’s ability to explain differences in sensitivity. This generic model is transformed into personalized cell line-specific logical models by integrating the omics information of the cell lines as constraints of the model. The use of mutations alone allows personalized models to correlate significantly with experimental sensitivities to BRAF inhibition, both from drug and CRISPR targeting, and even better with the joint use of mutations and RNA, supporting multi-omics mechanistic models. A comparison of these untrained models with learning approaches highlights similarities in interpretation and complementarity depending on the size of the datasets. This parsimonious pipeline, which can easily be extended to other biological questions, makes it possible to explore the mechanistic causes of the response to treatment, on an individualized basis. Author summary We constructed a logical model to study, from a dynamical perspective, the differences between melanomas and colorectal cancers that share the same BRAF mutations but exhibit different sensitivities to anti-BRAF treatments. The model was built from the literature and completed from existing pathway databases. The model encompasses the key proteins of the MAPK pathway and was made specific to each cancer cell line (100 melanoma and colorectal cell lines from public database) using available omics data, including mutations and RNAseq data. It can simulate the effect of drugs and show high correlation with experimental results. Moreover, the structure of the network confirms both the importance of the reactivation of the MAPK pathway through CRAF and the involvement of PI3K/AKT pathway in the mechanisms of resistance to BRAF inhibition. The study shows that, because of the low number of samples, the mechanistic approach that we propose provides different insights than powerful standard machine learning methodologies would, showing the complementarity between the two approaches. An important aspect to mention is that the mechanistic approach presented here does not rely on training datasets but directly interprets and maps data on the model to simulate drug responses. |
| Databáze: | OpenAIRE |
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