Enhanced triacylglycerol catabolism by carboxylesterase 1 promotes aggressive colorectal carcinoma
Daria Capece, … , Gabriele Cruciani, Guido Franzoso
Daria Capece, … , Gabriele Cruciani, Guido Franzoso
Published April 20, 2021
Citation Information: J Clin Invest. 2021;131(11):e137845. https://doi.org/10.1172/JCI137845.
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Research Article Metabolism Oncology

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 patients with CRC. 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 patients with CRC 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 cell-autonomous 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 patients with CRC. Accordingly, NF-κB drove CES1 expression in CRC consensus molecular subtype 4 (CMS4), which is 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 unfavorable prognostic correlation distinguished CES1 from other intracellular triacylglycerol lipases and suggest CES1 could provide a route to treat aggressive CRC.

Authors

Daria Capece, Daniel D’Andrea, Federica Begalli, Laura Goracci, Laura Tornatore, James L. Alexander, Alessandra Di Veroli, Shi-Chi Leow, Thamil S. Vaiyapuri, James K. Ellis, Daniela Verzella, Jason Bennett, Luca Savino, Yue Ma, James S. McKenzie, Maria Luisa Doria, Sam E. Mason, Kern Rei Chng, Hector C. Keun, Gary Frost, Vinay Tergaonkar, Katarzyna Broniowska, Walter Stunkel, Zoltan Takats, James M. Kinross, Gabriele Cruciani, Guido Franzoso

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Figure 5

CES1 is upregulated in CMS2 and CMS4 CRCs and denotes aggressive disease in obese/overweight patients.

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CES1 is upregulated in CMS2 and CMS4 CRCs and denotes aggressive disease...
(A) TAG abundance in CRCs (n = 57) stratified based on CES1 expression. Shown are the mean (horizontal lines), mean ± SEM (box outlines), or mean ± SD (vertical lines). Significance was calculated by 2-tailed Student’s t test. (B) DSS in patients from A stratified based on tumor-associated CES1 expression. (C) DSS in obese/overweight (left; n = 30) and normal weight (right; n = 23) patients from A stratified as in B. (D) DSS in obese/overweight (left; n = 157) and normal weight (right; n = 272) patients with CRC from the TCGA data set (n = 427) stratified based on tumor-associated CES1 expression using the 25th or 50th percentile as thresholds. (E) PFI in obese/overweight (left; n = 161) and normal weight (right; n = 275) patients from D stratified as in D. (F) Median z scores of the obesity-gene signatures in each CMS CRC subtype from Figure 1, A and B. (G) Percentage of overweight patients with CMS subtypes from F. Samples in each subtype were compared with all other CRC samples using Fisher’s exact test. *P = 0.03. (H and I) CES1 (H) and HNF4A (I) mRNA expression in CMS subtypes from F. (B–E) Significance was calculated using the log-rank test. (F, H, and I) Shown are the medians (horizontal lines), 25th to 75th percentiles (box outlines), and highest and lowest values within 1.5 times the interquartile range (vertical lines). Notches denote the 95% confidence interval of the medians. Samples in each CMS subtype were compared with all other CRC samples using 2-tailed Student’s t test. Significance for multiple comparisons was calculated using the Kruskal-Wallis test (P < 2.2 × 10–16). *P < 0.05; ***P < 0.001.