Enhanced triacylglycerol catabolism by carboxylesterase 1 promotes aggressive colorectal carcinoma

Abstract

The ability to adapt to low-nutrient microenvironments is essential for tumor-cell survival and progression in solid cancers, such as colorectal carcinoma (CRC). Signaling by the NF-κB transcription-factor pathway associates with advanced disease stages and shorter survival in CRC patients. NF-κB has been shown to drive tumor-promoting inflammation, cancer-cell survival and intestinal epithelial cell (IEC) dedifferentiation in mouse models of CRC.However, whether NF-κB affects the metabolic adaptations that fuel aggressive disease in CRC patients is unknown. Here, we identified carboxylesterase 1 (CES1) as an essential NF-κB-regulated lipase linking obesity-associated inflammation with fat metabolism and adaptation to energy stress in aggressive CRC. CES1 promoted CRC-cell survival via cellautonomous mechanisms that fuel fatty-acid oxidation (FAO) and prevent the toxic build-up of triacylglycerols. We found that elevated CES1 expression correlated with worse outcomes in overweight CRC patients. Accordingly, NF-κB drove CES1 expression in CRC consensus molecular subtype (CMS)4, associated with obesity, stemness and inflammation.CES1 was also upregulated by gene amplifications of its transcriptional regulator, HNF4A, in CMS2 tumors, reinforcing its clinical relevance as a driver of CRC. This subtype-based distribution and unfavourable prognostic correlation distinguished CES1 from other intracellular triacylglycerol lipases and suggest CES1 could provide a route to treat aggressive CRC.

Rewired lipid metabolism as an actionable vulnerability of aggressive colorectal carcinoma

“…Mechanistically, we found that Ces1d/CES1 promotes CRC cell survival via at least two cell-autonomous mechanisms: 1) It increases TAG and CE breakdown to mobilize endogenous FFAs and produce ATP by FAO during starvation, thus enabling CRC cells to meet their energy demand; 2) it prevents the toxic buildup of neutral lipids that results in ROS production and phospholipid peroxidation, triggering apoptosis and ferroptosis 16 ( Figure 1 ). Accordingly, CES1 inhibition by knockdown or small molecules resulted in CRC cell death upon starvation in vitro and suppression of CRC growth in mouse xenograft models in vivo .…”

“…Using the Consensus Molecular Subtype (CMS) CRC classification, 15 we discovered an intrinsic linkage of obesity with constitutive activation of NF-κB transcription factors, tumor-based inflammation, and fat catabolism in the mesenchymal CMS4 subtype, associated with stemness, stromal infiltration, EMT, and shorter overall survival (OS) and relapse-free survival (RFS) in CRC patients. 16 By conducting a combined metabonomic and gene expression profiling, we identified carboxylesterase 1 (CES1) as an essential NF-κB-regulated TAG and CE lipase promoting tumor cell survival and metabolic adaptation in aggressive CRC. 16 Increased CES1 expression correlated with worse clinical outcomes in overweight, but not non-overweight CRC patients and was enriched downstream of NF-κB in CMS4 tumors, thus providing a mechanism for the aggressive clinical behavior of obesity-associated CRC and a potential therapeutic route that relates to the core biological underpinnings of tumor subtypes ( Figure 1 ).…”

“… 16 By conducting a combined metabonomic and gene expression profiling, we identified carboxylesterase 1 (CES1) as an essential NF-κB-regulated TAG and CE lipase promoting tumor cell survival and metabolic adaptation in aggressive CRC. 16 Increased CES1 expression correlated with worse clinical outcomes in overweight, but not non-overweight CRC patients and was enriched downstream of NF-κB in CMS4 tumors, thus providing a mechanism for the aggressive clinical behavior of obesity-associated CRC and a potential therapeutic route that relates to the core biological underpinnings of tumor subtypes ( Figure 1 ). Interestingly, CES1 was alternatively upregulated by prognostically unfavorable amplifications of the gene encoding its transcriptional regulator, Hepatocyte nuclear factor 4 alpha ( HNF4A ), in the canonical CMS2 subtype, 16 underscoring how different oncogenic pathways converge on CES1 to drive CRC ( Figure 1 ).…”

“… 16 Increased CES1 expression correlated with worse clinical outcomes in overweight, but not non-overweight CRC patients and was enriched downstream of NF-κB in CMS4 tumors, thus providing a mechanism for the aggressive clinical behavior of obesity-associated CRC and a potential therapeutic route that relates to the core biological underpinnings of tumor subtypes ( Figure 1 ). Interestingly, CES1 was alternatively upregulated by prognostically unfavorable amplifications of the gene encoding its transcriptional regulator, Hepatocyte nuclear factor 4 alpha ( HNF4A ), in the canonical CMS2 subtype, 16 underscoring how different oncogenic pathways converge on CES1 to drive CRC ( Figure 1 ). Notably, this tumor subtype-based distribution and unfavorable prognostic correlation distinguished CES1 from all other human intracellular TAG lipases, 16 suggesting that CES1 plays a unique role in the etiopathogenesis of CRC.…”

“…Interestingly, CES1 was alternatively upregulated by prognostically unfavorable amplifications of the gene encoding its transcriptional regulator, Hepatocyte nuclear factor 4 alpha ( HNF4A ), in the canonical CMS2 subtype, 16 underscoring how different oncogenic pathways converge on CES1 to drive CRC ( Figure 1 ). Notably, this tumor subtype-based distribution and unfavorable prognostic correlation distinguished CES1 from all other human intracellular TAG lipases, 16 suggesting that CES1 plays a unique role in the etiopathogenesis of CRC.

Figure 1.

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