2. Academic Validation
  3. CES2 sustains HNF4α expression to promote pancreatic adenocarcinoma progression through an epoxide hydrolase-dependent regulatory loop

CES2 sustains HNF4α expression to promote pancreatic adenocarcinoma progression through an epoxide hydrolase-dependent regulatory loop

  • Mol Metab. 2022 Feb;56:101426. doi: 10.1016/j.molmet.2021.101426.
Yihui Chen 1,  Michela Capello 1,  Mayrim V Rios Perez 2,  Jody V Vykoukal 1,  David Roife 2,  Ya'an Kang 2,  Laura R Prakash 2,  Hiroyuki Katayama 1,  Ehsan Irajizad 1,  Alia Fleury 1,  Sammy Ferri-Borgogno 3,  Dodge L Baluya 4,  Jennifer B Dennison 1,  Kim-Anh Do 5,  Oliver Fiehn 6,  Anirban Maitra 7,  Huamin Wang 8,  Paul J Chiao 9,  Matthew H G Katz 2,  Jason B Fleming 10,  Samir M Hanash 1,  Johannes F Fahrmann 11
Affiliations

Affiliations

  • 1 Departments of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 2 Departments of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 3 Departments of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 4 Departments of Center for Radiation Oncology Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 5 Departments of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 6 UC Davis Genome Center - Metabolomics, University of California, Davis, 95616, CA, USA.
  • 7 Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, USA; Departments of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 8 Departments of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 9 Departments of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 10 Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
  • 11 Departments of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: jffahrmann@mdanderson.org.
PMID: 34971802 DOI: 10.1016/j.molmet.2021.101426
Abstract

Objective: Intra-tumoral expression of the serine hydrolase carboxylesterase 2 (CES2) contributes to the activation of the pro-drug irinotecan in pancreatic ductal adenocarcinoma (PDAC). Given other potential roles of CES2, we assessed its regulation, downstream effects, and contribution to tumor development in PDAC.

Methods: Association between the mRNA expression of CES2 in pancreatic tumors and overall survival was assessed using The Cancer Genome Atlas. Cell viability, clonogenic, and anchorage-independent growth assays as well as an orthotopic mouse model of PDAC were used to evaluate the biological relevance of CES2 in pancreatic Cancer. CES2-driven metabolic changes were determined by untargeted and targeted metabolomic analyses.

Results: Elevated tumoral CES2 mRNA expression was a statistically significant predictor of poor overall survival in PDAC patients. Knockdown of CES2 in PDAC cells reduced cell viability, clonogenic capacity, and anchorage-independent growth in vitro and attenuated tumor growth in an orthotopic mouse model of PDAC. Mechanistically, CES2 was found to promote the catabolism of Phospholipids resulting in HNF4α activation through a soluble Epoxide Hydrolase (sEH)-dependent pathway. Targeting of CES2 via siRNA or small molecule inhibitors attenuated HNF4α protein expression and reduced gene expression of classical/progenitor markers and increased basal-like markers. Targeting of the CES2-sEH-HNF4α axis using small molecule inhibitors of CES2 or sEH reduced cell viability.

Conclusions: We establish a novel regulatory loop between CES2 and HNF4α to sustain the progenitor subtype and promote PDAC progression and highlight the potential utility of CES2 or sEH inhibitors for the treatment of PDAC as part of non-irinotecan-containing regimens.

Keywords

CES2; Classical/progenitor subtype; HNF4α; PDAC; Phospholipid catabolism.

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