An automated network-based tool to search for metabolic vulnerabilities in cancer
The development of computational tools for the systematic prediction of metabolic vulnerabilities of cancer cells constitutes a central question in systems biology. Here, we present gmctool, a freely accessible online tool that allows us to accomplish this task in a simple, efficient and intuitive environment. gmctool exploits the concept of genetic Minimal Cut Sets (gMCSs), a theoretical approach to synthetic lethality based on genome-scale metabolic networks, including a unique database of synthetic lethals computed from Human1, the most recent metabolic reconstruction of human cells. gmctool introduces qualitative and quantitative improvements over our previously developed algorithms to predict, visualize and analyze metabolic vulnerabilities in cancer, demonstrating a superior performance than competing algorithms. A detailed illustration of gmctool is presented for multiple myeloma (MM), an incurable hematological malignancy. We provide in vitro experimental evidence for the essentiality of CTPS1 (CTPS synthase) and UAP1 (UDP-N-Acetylglucosamine Pyrophosphorylase 1) in specific MM patient subgroups.
Authors
- Francisco J. Planes (ORCID: https://orcid.org/0000-0003-1155-3105)
- Felipe Prósper (ORCID: https://orcid.org/0000-0001-6115-8790)
- Jesús F. San Miguel (ORCID: https://orcid.org/0000-0002-9183-4857)
- Raquel Ordóñez (ORCID: https://orcid.org/0000-0002-6924-5175)
- Danel Olaverri-Mendizabal (ORCID: https://orcid.org/0000-0003-1740-6616)
- Luis V. Valcárcel (ORCID: https://orcid.org/0000-0003-3769-5419)
- Edurne San José‐Eneriz (ORCID: https://orcid.org/0000-0001-5786-5273)
- Xabier Agirre (ORCID: https://orcid.org/0000-0002-6558-9560)
- Leire Gárate
- Antonio Pineda‐Lucena (ORCID: https://orcid.org/0000-0002-3532-8781)
- Naroa Barrena (ORCID: https://orcid.org/0000-0003-4324-3371)
- Iñigo Apaolaza (ORCID: https://orcid.org/0000-0002-8961-4513)
- Ana Valcárcel
Institutions
- Centro de Estudios e Investigaciones Técnicas de Gipuzkoa (ES)
- Tecnalia (ES)
- Gobierno de Navarra (ES)
- Clinica Universidad de Navarra (ES)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- Universidad de Navarra (ES)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-10-11
- DOI
- https://doi.org/10.1038/s41467-024-52725-4
- Citations
- 7
- Primary Topic
- Microbial Metabolic Engineering and Bioproduction
- Type
- article
- Field-Weighted Citation Impact
- 1.64
Funders
- Cancer Research UK
- European Commission
- Eusko Jaurlaritza
- Ministerio de Economía y Competitividad
- Centro de Investigación Biomédica en Red de Cáncer
- Instituto de Salud Carlos III