Enhanced triacylglycerol catabolism by carboxylesterase 1 promotes aggressive colorectal carcinoma

Enhanced triacylglycerol catabolism by carboxylesterase 1 promotes aggressive colorectal carcinoma

Journal of Clinical Investigation

10.1172/JCI137845

http://dx.doi.org/10.1172/jci137845

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

General Medicine

20 April 2021

Capece, D., D’Andrea, D., Begalli, F., Goracci, L., Tornatore, L., Alexander, J. L., Di Veroli, A., Leow, S.-C., Vaiyapuri, T. S., Ellis, J. K., Verzella, D., Bennett, J., Savino, L., Ma, Y., McKenzie, J. S., Doria, M. L., Mason, S. E., Chng, K. R., Keun, H. C., … Franzoso, G. (2021). Enhanced triacylglycerol catabolism by carboxylesterase 1 promotes aggressive colorectal carcinoma. Journal of Clinical Investigation, 131(11). https://doi.org/10.1172/jci137845

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.

Attribution 4.0 International (CC BY 4.0)

This research / project is supported by the National Research Foundation - Competitive Research Programme
Grant Reference no. : NRF-CRP17-2017-02

This work was supported in part by 1) Cancer Research UK program grant A15115 2) Medical Research Council (MRC) Biomedical Catalyst grant MR/L005069/1 3) Bloodwise project grant 15003 4) NIHR Imperial Biomedical Research Centre (BRC) ITMAT Push for Impact Award P81135 5) NIHR Imperial BRC. the Università degliStudi di Perugia and MIUR for financial support to the project AMIS, through the program “Dipartimenti di Eccellenza 2018-2022”.

https://oar.a-star.edu.sg/communities-collections/articles/18214

1558-8238

Institute of Molecular and Cell Biology

https://doi.org/10.1172/jci137845