Transcriptome and Lipidomic Analysis Suggests Lipid Metabolism Reprogramming and Upregulating SPHK1 Promotes Stemness in Pancreatic Ductal Adenocarcinoma Stem-like Cells

Jinzhi Xu; Lina Zhou; Xiaojing Du; Zhuoran Qi; Sinuo Chen; Jian Zhang; Xin Cao; Jinglin Xia

doi:10.3390/metabo13111132

Transcriptome and Lipidomic Analysis Suggests Lipid Metabolism Reprogramming and Upregulating SPHK1 Promotes Stemness in Pancreatic Ductal Adenocarcinoma Stem-like Cells

Metabolites. 2023 Nov 4;13(11):1132. doi: 10.3390/metabo13111132.

Authors

Jinzhi Xu¹, Lina Zhou², Xiaojing Du³, Zhuoran Qi¹, Sinuo Chen¹, Jian Zhang¹, Xin Cao^{1

4}, Jinglin Xia^{1

5}

Affiliations

¹ National Medical Center and National Clinical Research Center for Interventional Medicine, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China.
² CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
³ Endoscopy Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
⁴ Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
⁵ Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.

Abstract

Cancer stem cells (CSCs) are considered to play a key role in the development and progression of pancreatic ductal adenocarcinoma (PDAC). However, little is known about lipid metabolism reprogramming in PDAC CSCs. Here, we assigned stemness indices, which were used to describe and quantify CSCs, to every patient from the Cancer Genome Atlas (TCGA-PAAD) database and observed differences in lipid metabolism between patients with high and low stemness indices. Then, tumor-repopulating cells (TRCs) cultured in soft 3D (three-dimensional) fibrin gels were demonstrated to be an available PDAC cancer stem-like cell (CSLCs) model. Comprehensive transcriptome and lipidomic analysis results suggested that fatty acid metabolism, glycerophospholipid metabolism, and, especially, the sphingolipid metabolism pathway were mostly associated with CSLCs properties. SPHK1 (sphingosine kinases 1), one of the genes involved in sphingolipid metabolism and encoding the key enzyme to catalyze sphingosine to generate S1P (sphingosine-1-phosphate), was identified to be the key gene in promoting the stemness of PDAC. In summary, we explored the characteristics of lipid metabolism both in patients with high stemness indices and in novel CSLCs models, and unraveled a molecular mechanism via which sphingolipid metabolism maintained tumor stemness. These findings may contribute to the development of a strategy for targeting lipid metabolism to inhibit CSCs in PDAC treatment.

Keywords: SPHK1; cancer stem-like cells; lipid metabolism reprogramming; pancreatic ductal adenocarcinoma; sphingolipid metabolism.

Grants and funding

This study was funded by the Natural Science Foundation of Shanghai (20ZR1410400), National Natural Science Foundation of China (81972233, 82173662, 81772590 and 81572395).