Metabolic programming of distinct cancer stem cells promotes metastasis of pancreatic ductal adenocarcinoma

Oncogene. 2021 Jan;40(1):215-231. doi: 10.1038/s41388-020-01518-2. Epub 2020 Oct 27.


Pancreatic ductal adenocarcinoma (PDAC) metastasizes to distant organs, which is the primary cause of mortality; however, specific features mediating organ-specific metastasis remain unexplored. Emerging evidence demonstrates that cancer stem cells (CSCs) and cellular metabolism play a pivotal role in metastasis. Here we investigated the role of distinct subtypes of pancreatic CSCs and their metabolomic signatures in organ-specific metastatic colonization. We found that PDAC consists of ALDH+/CD133+ and drug-resistant (MDR1+) subtypes of CSCs with specific metabolic and stemness signatures. Human PDAC tissues with gemcitabine treatment, autochthonous mouse tumors from KrasG12D; Pdx1-Cre (KC) and KrasG12D; Trp53R172H; Pdx-1 Cre (KPC) mice, and KPC- Liver/Lung metastatic cells were used to evaluate the CSC, EMT (epithelial-to-mesenchymal transition), and metabolic profiles. A strong association was observed between distinct CSC subtypes and organ-specific colonization. The liver metastasis showed drug-resistant CSC- and EMT-like phenotype with aerobic glycolysis and fatty acid β-oxidation-mediated oxidative (glyco-oxidative) metabolism. On the contrary, lung metastasis displayed ALDH+/CD133+ and MET-like phenotype with oxidative metabolism. These results were obtained by evaluating FACS-based side population (SP), autofluorescence (AF+) and Alde-red assays for CSCs, and Seahorse-based oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and fatty acid β-oxidation (FAO)-mediated OCR assays for metabolic features along with specific gene signatures. Further, we developed in vitro human liver and lung PDAC metastasis models by using a combination of liver or lung decellularized scaffolds, a co-culture, and a sphere culture methods. PDAC cells grown in the liver-mimicking model showed the enrichment of MDR1+ and CPT1A+ populations, whereas the PDAC cells grown in the lung-mimicking environment showed the enrichment of ALDH+/CD133+ populations. In addition, we observed significantly elevated expression of ALDH1 in lung metastasis and MDR1/LDH-A expression in liver metastasis compared to human primary PDAC tumors. Our studies elucidate that distinct CSCs adapt unique metabolic signatures for organotropic metastasis, which will pave the way for the development of targeted therapy for PDAC metastasis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AC133 Antigen / metabolism
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • Aldehyde Dehydrogenase 1 Family / metabolism*
  • Animals
  • Carcinoma, Pancreatic Ductal / drug therapy
  • Carcinoma, Pancreatic Ductal / metabolism*
  • Cell Line, Tumor
  • Coculture Techniques
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Deoxycytidine / therapeutic use
  • Drug Resistance, Neoplasm
  • Epithelial-Mesenchymal Transition
  • Gemcitabine
  • Gene Expression Regulation, Neoplastic
  • Glycolysis
  • Humans
  • L-Lactate Dehydrogenase / metabolism*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / secondary*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary*
  • Metabolomics / methods
  • Mice
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / metabolism*
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / metabolism*
  • Retinal Dehydrogenase / metabolism*


  • ABCB1 protein, human
  • AC133 Antigen
  • ATP Binding Cassette Transporter, Subfamily B
  • PROM1 protein, human
  • Deoxycytidine
  • L-Lactate Dehydrogenase
  • LDHA protein, human
  • Aldehyde Dehydrogenase 1 Family
  • ALDH1A1 protein, human
  • Retinal Dehydrogenase
  • Gemcitabine