Lipid synthesis, uptake & cholesterol
Dividing cells need membranes, and membranes are fat. Cancers switch on the fat-building enzymes most adult tissues keep off, and in fatty environments (breast, omentum, bone marrow) they also steal lipids from neighbouring fat cells. This links obesity to cancer and offers new drug targets.
Citrate exported from mitochondria is cleaved by ACLY to acetyl-CoA, carboxylated by ACC to malonyl-CoA, and built into palmitate by FASN, then desaturated by SCD1 and elongated; SREBP1/2, activated by mTORC1 and hypoxia and restrained by AMPK and LKB1, is the master transcriptional switch. The mevalonate pathway (HMGCR) makes cholesterol and the isoprenoids needed to anchor RAS to membranes; mutant p53 activates it. Exogenous uptake via CD36, LDLR and lipoprotein lipase supplies fatty acids from adipocytes (omental metastasis of ovarian cancer, prostate cancer in bone) and fatty acid oxidation (CPT1) fuels dormant, metastatic and leukaemia stem cells. Lipid saturation sets ferroptosis sensitivity (PUFAs are the substrate; SCD1 protects). Epidemiologically obesity raises risk of 13 cancers via insulin/IGF-1, oestrogen, inflammation and lipid supply; GLP-1 agonists and bariatric surgery lower incidence. Drugs: FASN inhibitor denifanstat (TVB-2640) in trials, statins repurposed (mostly negative in RCTs), CD36 antibodies preclinical; SCD1 inhibition to sensitise to ferroptosis.
In one picture
A factory that must build its own walls. Normal adult tissue buys wall panels from a supplier (dietary fat); cancer reopens its own panel plant (FASN) and, when it lands in a fat depot, simply strips panels off the buildings next door.
Diagram
top- FASN inhibitor denifanstat and SCD1 inhibitors in trials; statins repurposed with mostly negative randomised data
- Weight management, GLP-1 agonists and bariatric surgery reduce obesity-related cancer incidence
- Exercise and dietary pattern interventions during treatment
- Ferroptosis inducers exploit the lipid composition of mesenchymal and persister cells
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