2. Academic Validation
  3. LIPH contributes to glycolytic phenotype in pancreatic ductal adenocarcinoma by activating LPA/LPAR axis and maintaining ALDOA stability

LIPH contributes to glycolytic phenotype in pancreatic ductal adenocarcinoma by activating LPA/LPAR axis and maintaining ALDOA stability

  • J Transl Med. 2023 Nov 21;21(1):838. doi: 10.1186/s12967-023-04702-6.
Lijie Han # 1 2 3,  Yongsheng Jiang # 1 2 3,  Minmin Shi # 1 2 3,  Lina Gan # 1 2 3,  Zhichong Wu 1 2 3,  Meilin Xue 1 2 3,  Youwei Zhu 1 2 3,  Cheng Xiong 1 2 3,  Ting Wang 4,  Xiaozhu Lin 5,  Baiyong Shen 6 7 8 9,  Lingxi Jiang 10 11 12,  Hao Chen 13 14 15 16
Affiliations

Affiliations

  • 1 Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2Nd Road, Shanghai, 200025, China.
  • 2 Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • 3 State Key Laboratory of Oncogenes and Related Genes, Shanghai, China.
  • 4 Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 5 Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2Nd Road, Shanghai, China.
  • 6 Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2Nd Road, Shanghai, 200025, China. shenby@shsmu.edu.cn.
  • 7 Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China. shenby@shsmu.edu.cn.
  • 8 State Key Laboratory of Oncogenes and Related Genes, Shanghai, China. shenby@shsmu.edu.cn.
  • 9 Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China. shenby@shsmu.edu.cn.
  • 10 Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2Nd Road, Shanghai, 200025, China. jlx12120@rjh.com.cn.
  • 11 Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China. jlx12120@rjh.com.cn.
  • 12 State Key Laboratory of Oncogenes and Related Genes, Shanghai, China. jlx12120@rjh.com.cn.
  • 13 Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2Nd Road, Shanghai, 200025, China. haochendr@126.com.
  • 14 Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China. haochendr@126.com.
  • 15 State Key Laboratory of Oncogenes and Related Genes, Shanghai, China. haochendr@126.com.
  • 16 Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China. haochendr@126.com.
  • # Contributed equally.
PMID: 37990271 DOI: 10.1186/s12967-023-04702-6
Abstract

Background: LIPH, a membrane-associated phosphatidic acid-selective Phospholipase A1a, can produce LPA (Lysophosphatidic acid) from PA (Phosphatidic acid) on the outer leaflet of the plasma membrane. It is well known that LIPH dysfunction contributes to lipid metabolism disorder. Previous study shows that LIPH was found to be a potential gene related to poor prognosis with pancreatic ductal adenocarcinoma (PDAC). However, the biological functions of LIPH in PDAC remain unclear.

Methods: Cell viability assays were used to evaluate whether LIPH affected cell proliferation. RNA sequencing and immunoprecipitation showed that LIPH participates in tumor glycolysis by stimulating LPA/LPAR axis and maintaining aldolase A (ALDOA) stability in the cytosol. Subcutaneous, orthotopic xenograft models and patient-derived xenograft PDAC model were used to evaluate a newly developed Gemcitabine-based therapy.

Results: LIPH was significantly upregulated in PDAC and was related to later pathological stage and poor prognosis. LIPH downregulation in PDAC cells inhibited colony formation and proliferation. Mechanistically, LIPH triggered PI3K/Akt/HIF1A signaling via LPA/LPAR axis. LIPH also promoted glycolysis and de novo synthesis of glycerolipids by maintaining ALDOA stability in the cytosol. Xenograft models show that PDAC with high LIPH expression levels was sensitive to gemcitabine/ki16425/aldometanib therapy without causing discernible side effects.

Conclusion: LIPH directly bridges PDAC cells and tumor microenvironment to facilitate aberrant aerobic glycolysis via activating LPA/LPAR axis and maintaining ALDOA stability, which provides an actionable gemcitabine-based combination therapy with limited side effects.

Keywords

ALDOA; Glycolysis; LIPH; LPA/LPAR; Pancreatic cancer.

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