Statins affect cancer cell plasticity with distinct consequences for tumor progression and metastasis

Statins are among the most commonly prescribed drugs, and around every fourth person above the age of 40 is on statin medication. Therefore, it is of utmost clinical importance to understand the effect of statins on cancer cell plasticity and its consequences to not only patients with cancer but also patients who are on statins. Here, we find that statins induce a partial epithelial-to-mesenchymal transition (EMT) phenotype in cancer cells of solid tumors. Using a comprehensive STRING network analysis of transcriptome, proteome, and phosphoproteome data combined with multiple mechanistic in vitro and functional in vivo analyses, we demonstrate that statins reduce cellular plasticity by enforcing a mesenchymal-like cell state that increases metastatic seeding ability on one side but reduces the formation of (secondary) tumors on the other due to heterogeneous treatment responses. Taken together, we provide a thorough mechanistic overview of the consequences of statin use for each step of cancer development, progression, and metastasis. [Display omitted] •Statins induce a partial EMT phenotype in PDAC, lung cancer, and colon cancer•Partial EMT and reduced cellular plasticity can drive apoptosis or block MET•Cancer cells overcome statin-induced apoptosis by activating ERK•Statins increase metastatic seeding but reduce tumor formation and metastatic growth Dorsch et al. identify statins as potent modulators of cancer cell plasticity and demonstrate that cholesterol pathway inhibition induces a mesenchymal cell shift in cancer cells. They show that statin-induced EMT promotes metastatic seeding on one hand but unexpectedly counteracts tumor and metastasis formation on the other hand.