Editors' ChoiceCancer

In PDAC, “bad” cholesterol is good

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Science Signaling  10 Nov 2020:
Vol. 13, Issue 657, eabf5642
DOI: 10.1126/scisignal.abf5642

LDL-lowering statins can promote the development of an aggressive subtype of pancreatic cancer.

Obesity and increased serum cholesterol are risk factors for various cancers, including pancreatic ductal adenocarcinoma (PDAC). However, cholesterol-lowering statins, often prescribed to manage heart disease in these patients, have not had the added benefit of preventing tumor growth. Rather, Gabitova-Cornell et al. found a positive correlation between statin treatment and more aggressive PDAC in patients (see also coverage by Kugel and Hingorani). In KRAS-mutant/p53-deficient mouse models, disruption of cholesterol synthesis with statins or conditional gene deletion promoted the development and accelerated the growth of basal (rather than glandular) PDAC, which resulted in decreased animal survival. This phenotypic switch was mediated by induction of the gene encoding the lipid homeostasis protein SREBP1 and, consequently, that encoding transforming growth factor–β (TGF-β). Secreted TGF-β then activated its receptors in an autocrine manner, which mediated an epithelial-to-mesenchymal transition (EMT). This SREBP1–TGF-β–EMT axis was suppressed by the addition of low-density lipoproteins. Notably, despite—or perhaps because of—induced SREBP1–TGF-β signaling, statins blocked malignant progression of precursor lesions in a p53-proficient mouse model. These findings indicate that statins are counterproductive to preventing and treating PDAC, except potentially in patients with p53-proficient tumors.

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