Unified tumor growth mechanisms from multimodel inference and dataset integration.
PLoS Comput Biol
; 19(7): e1011215, 2023 07.
Article
em En
| MEDLINE
| ID: mdl-37406008
ABSTRACT
Mechanistic models of biological processes can explain observed phenomena and predict responses to a perturbation. A mathematical model is typically constructed using expert knowledge and informal reasoning to generate a mechanistic explanation for a given observation. Although this approach works well for simple systems with abundant data and well-established principles, quantitative biology is often faced with a dearth of both data and knowledge about a process, thus making it challenging to identify and validate all possible mechanistic hypothesis underlying a system behavior. To overcome these limitations, we introduce a Bayesian multimodel inference (Bayes-MMI) methodology, which quantifies how mechanistic hypotheses can explain a given experimental datasets, and concurrently, how each dataset informs a given model hypothesis, thus enabling hypothesis space exploration in the context of available data. We demonstrate this approach to probe standing questions about heterogeneity, lineage plasticity, and cell-cell interactions in tumor growth mechanisms of small cell lung cancer (SCLC). We integrate three datasets that each formulated different explanations for tumor growth mechanisms in SCLC, apply Bayes-MMI and find that the data supports model predictions for tumor evolution promoted by high lineage plasticity, rather than through expanding rare stem-like populations. In addition, the models predict that in the presence of cells associated with the SCLC-N or SCLC-A2 subtypes, the transition from the SCLC-A subtype to the SCLC-Y subtype through an intermediate is decelerated. Together, these predictions provide a testable hypothesis for observed juxtaposed results in SCLC growth and a mechanistic interpretation for tumor treatment resistance.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Carcinoma de Pequenas Células do Pulmão
/
Neoplasias Pulmonares
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article