In silico models of biomolecular regulation in cancer, annotated with patient-specific gene expression data, can aid in the development of novel personalized cancer therapeutic strategies. Drosophila melanogaster is a well-established animal model that is increasingly being employed to evaluate such preclinical personalized cancer therapies. Here, we report five Boolean network models of biomolecular regulation in cells lining the Drosophila midgut epithelium and annotate them with colorectal cancer patient-specific mutation data to develop an in silico Drosophila Patient Model (DPM). We employed cell-type-specific RNA-seq gene expression data from the FlyGut-seq database to annotate and then validate these networks. Next, we developed three literature-based colorectal cancer case studies to evaluate cell fate outcomes from the model. Results obtained from analyses of the proposed DPM help: (i) elucidate cell fate evolution in colorectal tumorigenesis, (ii) validate cytotoxicity of nine FDA-approved CRC drugs, and (iii) devise optimal personalized treatment combinations. The personalized network models helped identify synergistic combinations of paclitaxel-regorafenib, paclitaxel-bortezomib, docetaxel-bortezomib, and paclitaxel-imatinib for treating different colorectal cancer patients. Follow-on therapeutic screening of six colorectal cancer patients from cBioPortal using this drug combination demonstrated a 100% increase in apoptosis and a 100% decrease in proliferation. In conclusion, this work outlines a novel roadmap for decoding colorectal tumorigenesis along with the development of personalized combinatorial therapeutics for preclinical translational studies.
Plants employ photosynthesis to produce sugars for supporting their growth. During photosynthesis, an enzyme Ribulose 1,5 bisphosphate carboxylase/oxygenase (Rubisco) combines its substrate Ribulose 1,5 bisphosphate (RuBP) with CO2 to produce phosphoglycerate (PGA). Alongside, Rubisco also takes up O2 and produce 2-phosphoglycolate (2-PG), a toxic compound broken down into PGA through photorespiration. Photorespiration is not only a resource-demanding process but also results in CO2 loss which affects photosynthetic efficiency in C3 plants. Here, we propose to circumvent photorespiration by adopting the cyanobacterial glycolate decarboxylation pathway into C3 plants. For that, we have integrated the cyanobacterial glycolate decarboxylation pathway into a kinetic model of C3 photosynthetic pathway to evaluate its impact on photosynthesis and photorespiration. Our results show that the cyanobacterial glycolate decarboxylation bypass model exhibits a 10% increase in net photosynthetic rate (A) in comparison with C3 model. Moreover, an increased supply of intercellular CO2 (Ci) from the bypass resulted in a 54.8% increase in PGA while reducing photorespiratory intermediates including glycolate (− 49%) and serine (− 32%). The bypass model, at default conditions, also elucidated a decline in phosphate-based metabolites including RuBP (− 61.3%). The C3 model at elevated level of inorganic phosphate (Pi), exhibited a significant change in RuBP (+ 355%) and PGA (− 98%) which is attributable to the low availability of Ci. Whereas, at elevated Pi, the bypass model exhibited an increase of 73.1% and 33.9% in PGA and RuBP, respectively. Therefore, we deduce a synergistic effect of elevation in CO2 and Pi pool on photosynthesis. We also evaluated the integrative action of CO2, Pi, and Rubisco carboxylation activity (Vcmax) on A and observed that their simultaneous increase raised A by 26%, in the bypass model. Taken together, the study potentiates engineering of cyanobacterial decarboxylation pathway in C3 plants to bypass photorespiration thereby increasing the overall efficiency of photosynthesis.
Multi-scale models integrating biomolecular data from genetic, transcriptional, and translational levels, coupled with extracellular microenvironments can assist in decoding the complex mechanisms underlying system-level diseases such as cancer. To investigate the emergent properties and clinical translation of such cancer models, we present Theatre for in silico Systems Oncology (TISON, https://tison.lums.edu.pk), a next-generation web-based multi-scale modeling and simulation platform for in silico systems oncology. TISON provides a “zero-code” environment for multi-scale model development by seamlessly coupling scale-specific information from biomolecular networks, microenvironments, cell decision circuits, in silico cell lines, and organoid geometries. To compute the temporal evolution of multi-scale models, a simulation engine and data analysis features are also provided. Furthermore, TISON integrates patient-specific gene expression data to evaluate patient-centric models towards personalized therapeutics. Several literature-based case studies have been developed to exemplify and validate TISON’s modeling and analysis capabilities. TISON provides a cutting-edge multi-scale modeling pipeline for scale-specific as well as integrative systems oncology that can assist in drug target discovery, repositioning, and development of personalized therapeutics.
Rapid advancements in high-throughput omics technologies and experimental protocols have led to the generation of vast amounts of scale-specific biomolecular data on cancer that now populates several online databases and resources. Cancer systems biology models built using this data have the potential to provide specific insights into complex multifactorial aberrations underpinning tumor initiation, development, and metastasis. Furthermore, the annotation of these single- and multi-scale models with patient data can additionally assist in designing personalized therapeutic interventions as well as aid in clinical decision-making. Here, we have systematically reviewed the emergence and evolution of (i) repositories with scale-specific and multi-scale biomolecular cancer data, (ii) systems biology models developed using this data, (iii) associated simulation software for the development of personalized cancer therapeutics, and (iv) translational attempts to pipeline multi-scale panomics data for data-driven in silico clinical oncology. The review concludes that the absence of a generic, zero-code, panomics-based multi-scale modeling pipeline and associated software framework, impedes the development and seamless deployment of personalized in silico multi-scale models in clinical settings.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.