Enhanced triacylglycerol catabolism by CES1/TGH promotes aggressive colorectal carcinoma

The recurrence and mortality rates of colorectal cancer (CRC) increase in obese people. It has been proposed that the anatomical proximity of CRC to hypertrophic adipose depots in obese individuals produces an inflammatory state that results in metabolic alterations supportive of tumourigenesis and metastatic spread. Here, we identify carboxylesterase 1 (CES1)/triacylglycerol hydrolase (TGH) as an essential NF-?B-regulated lipase linking inflammation with metabolic adaption to low-nutrient availability in aggressive CRCs. Notably, elevated CES1 expression correlates with poorer clinical outcome in overweight, but not non-overweight CRC patients, and characterises the aggressive consensus molecular subtype (CMS)4, associated with obesity, inflammation and NF-?B-activation. Correspondingly, pharmacologic CES1 inhibition selectively killed glucose-starved CRC cells in vitro and markedly diminished CRC tumourigenesis in vivo. Interestingly, this CRC subtype-specific expression pattern and negative prognostic correlation in CRC patients distinguish CES1 from any other intracellular TAG lipase and could provide an effective route to treat patients with aggressive CRC.