Journal
MOLECULAR CELL
Volume 69, Issue 4, Pages 699-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2018.01.017
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Funding
- California Institute of Regenerative Medicine [RB5-07356]
- NIH [R01CA188652, R01HG009285, R01CA222826]
- Camille and Henry Dreyfus Teacher-Scholar
- NSF CAREER [1454425]
- Searle Scholar Award
- UCSD Institutional Funds
- Burroughs Wellcome Fund [1013926]
- March of Dimes Foundation [5-FY15-450]
- Kimmel Foundation [SKF-16-150]
- NSF [DGE-1144086]
- Directorate For Engineering
- Div Of Chem, Bioeng, Env, & Transp Sys [1454425] Funding Source: National Science Foundation
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The metabolic pathways fueling tumor growth have been well characterized, but the specific impact of transforming events on network topology and enzyme essentiality remains poorly understood. To this end, we performed combinatorial CRISPR-Cas9 screens on a set of 51 carbohydrate metabolism genes that represent glycolysis and the pentose phosphate pathway (PPP). This high-throughput methodology enabled systems-level interrogation of metabolic gene dispensability, interactions, and compensation across multiple cell types. The metabolic impact of specific combinatorial knockouts was validated using C-13 and H-2 isotope tracing, and these assays together revealed key nodes controlling redox homeostasis along the KEAP-NRF2 signaling axis. Specifically, targeting KEAP1 in combination with oxidative PPP genes mitigated the deleterious effects of these knockouts on growth rates. These results demonstrate how our integrated framework, combining genetic, transcriptomic, and flux measurements, can improve elucidation of metabolic network alterations and guide precision targeting of metabolic vulnerabilities based on tumor genetics.
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