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Frontiers of Medicine

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Front. Med.    2024, Vol. 18 Issue (2) : 375-393    https://doi.org/10.1007/s11684-023-1020-z
Multi-omics joint analysis revealed the metabolic profile of retroperitoneal liposarcoma
Fu’an Xie1,2,3, Yujia Niu2, Lanlan Lian4, Yue Wang1, Aobo Zhuang1, Guangting Yan1, Yantao Ren1, Xiaobing Chen5, Mengmeng Xiao5, Xi Li6, Zhe Xi1, Gen Zhang1, Dongmei Qin1, Kunrong Yang7, Zhigang Zheng8, Quan Zhang9, Xiaogang Xia10, Peng Li10, Lingwei Gu1, Ting Wu2,3(), Chenghua Luo5(), Shu-Hai Lin2(), Wengang Li1,2,3,10()
1. Cancer Research Center, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, China
2. State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China
3. Xiamen University Research Center of Retroperitoneal Tumor Committee of Oncology Society of Chinese Medical Association, Xiamen University, Xiamen 361102, China
4. Department of Laboratory Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, China
5. Department of Retroperitoneal Tumor Surgery, Peking University International Hospital, Beijing 102206, China
6. School of Public Health, Harvard University, Boston, MA 02115, USA
7. Laboratory of Biochemistry and Molecular Biology Research, Department of Clinical Laboratory, Fujian Medical University Cancer Hospital, Fuzhou 350014, China
8. Surgery Department, Affiliated Fuzhou First Hospital of Fujian Medical University, Fuzhou 350009, China
9. National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen 361102, China
10. Department of Hepatobiliary Surgery, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, China
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Abstract

Retroperitoneal liposarcoma (RLPS) is the main subtype of retroperitoneal soft sarcoma (RSTS) and has a poor prognosis and few treatment options, except for surgery. The proteomic and metabolic profiles of RLPS have remained unclear. The aim of our study was to reveal the metabolic profile of RLPS. Here, we performed proteomic analysis (n = 10), metabolomic analysis (n = 51), and lipidomic analysis (n = 50) of retroperitoneal dedifferentiated liposarcoma (RDDLPS) and retroperitoneal well-differentiated liposarcoma (RWDLPS) tissue and paired adjacent adipose tissue obtained during surgery. Data analysis mainly revealed that glycolysis, purine metabolism, pyrimidine metabolism and phospholipid formation were upregulated in both RDDLPS and RWDLPS tissue compared with the adjacent adipose tissue, whereas the tricarboxylic acid (TCA) cycle, lipid absorption and synthesis, fatty acid degradation and biosynthesis, as well as glycine, serine, and threonine metabolism were downregulated. Of particular importance, the glycolytic inhibitor 2-deoxy-D-glucose and pentose phosphate pathway (PPP) inhibitor RRX-001 significantly promoted the antitumor effects of the MDM2 inhibitor RG7112 and CDK4 inhibitor abemaciclib. Our study not only describes the metabolic profiles of RDDLPS and RWDLPS, but also offers potential therapeutic targets and strategies for RLPS.
Keywords RLPS      proteomics      metabolomics      lipidomics      metabolism     
Corresponding Author(s): Ting Wu,Chenghua Luo,Shu-Hai Lin,Wengang Li   
Just Accepted Date: 15 November 2023   Online First Date: 25 December 2023    Issue Date: 27 May 2024
 Cite this article:   
Fu’an Xie,Yujia Niu,Lanlan Lian, et al. Multi-omics joint analysis revealed the metabolic profile of retroperitoneal liposarcoma[J]. Front. Med., 2024, 18(2): 375-393.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-023-1020-z
https://academic.hep.com.cn/fmd/EN/Y2024/V18/I2/375
Fig.1  Flowchart of this study. RDDLPS, retroperitoneal de-differentiated liposarcoma; RWDLPS, retroperitoneal well-differentiated liposarcoma.
Variable DDLPS WDLPS
Amount 35 16
Age, mean ± SD 55.14 ± 1.912 56.8 ± 2.328
Age, range 39–73 29–74
Male, n 21 9
Female, n 14 7
Recurrence, n (%) 27 (77.1%) 6 (37.5%)
Location Retroperitoneal Retroperitoneal
Tumor size ± SD (cm) 19.98 ± 1.167 18.54 ± 2.063
< 10 cm, n (%) 1, 2.86% 3, 18.75%
10–20 cm, n (%) 19, 54.29% 7, 43.75%
> 20 cm, n (%) 15, 42.86% 6, 37.5%
Tab.1  Characteristics of the clinical samples used in this study
Fig.2  Proteomic analysis of sarcoma tissue and adjacent adipose tissue from RDDLPS and RWDLPS patients. (A) Principal component analysis of proteomic data in sarcoma tissue and adjacent adipose tissue. (B) Volcano plot showing the relative abundance of proteins. Differentially regulated proteins are labeled in red (upregulated) and blue (downregulated), n = 10 per group. (C, D) KEGG functional enrichment analysis of the differential proteins in sarcoma tissue and adjacent adipose tissue; n = 10 per group. (E–G) The heat map of the enrichment test results of biological process, molecular function, and KEGG pathways based on gene ontology and KEGG pathway analysis. N, normal adjacent adipose tissue; S, liposarcoma tissue; var., variance.
Fig.3  Targeted metabolic analysis of sarcoma tissue and adjacent adipose tissue from RDDLPS and RWDLPS patients. (A) Principal component analysis of metabolomic data of sarcoma tissue and adjacent adipose tissue from RDDLPS and RWDLPS patients; n = 51 per group. (B) Volcano plot shows the relative abundance of changed metabolites in sarcoma tissue and adjacent adipose tissue from RDDLPS and RWDLPS patients. Enriched metabolite features are labeled in red (upregulated) and blue (downregulated); n = 51 per group. (C, D) KEGG functional enrichment analysis of the differential metabolites in sarcoma tissue and adjacent adipose tissue from RDDLPS and RWDLPS patients; n = 51 per group. N, normal adjacent adipose tissue; S, liposarcoma tissue.
Fig.4  Lipidomic analysis of sarcoma tissue and adjacent adipose tissue from RDDLPS and RWDLPS patients. (A) Principal component analysis of lipid data of liposarcoma tissue and adjacent adipose tissue from RDDLPS and RWDLPS patients; n = 50 per group. (B) Volcano plot shows the relative abundance of changed lipids in liposarcoma tissue and adjacent adipose tissue from RDDLPS and RWDLPS patients. Enriched lipid features are labeled in red (upregulated) and blue (downregulated); n = 50 per group. (C, D) Chemical structure analysis of the identified lipids; n = 50 per group. (E, F) KEGG functional enrichment analysis of the differential lipids in sarcoma tissue and adjacent adipose tissue from RDDLPS and RWDLPS patients; n = 50 per group. N, normal adjacent adipose tissue; S, liposarcoma tissue.
KEGG pathway Upregulated proteins Downregulated proteins Upregulated metabolites and lipids Downregulated metabolites and lipids
Alanine, aspartate and glutamate metabolism GFPT2 GLUL, ALDH4A1, ASS1 N-acetyl-L-aspartic acid, l-aspartic acid, carbamoyl phosphate Gamma-aminobutyric acid, citric acid, fumaric acid, citrulline, glycine
Alcoholism CAMKK2, H2AFY2, HDAC2 GNAS, MAOB, GNAI1, MAOA
Amino sugar and nucleotide sugar metabolism NPL, UGDH, GFPT2,GMPPA GPI, CYB5R3, UGP2 N-acetyl-D-glucosamine, N-acetyl-glucosamine 1-phosphate, N-acetylneuraminic acid, fructose 6-phosphate, glucose 6-phosphate
Aminoacyl-tRNA biosynthesis YARS2 L-histidine, L-aspartic acid Glycine, L-methionine, L-threonine, L-tyrosine
Arachidonic acid metabolism GPX8, PTGES3 GGT5, PLA2G2A 11H-14, 15-EETA, 20-carboxy-leukotriene B4, arachidonic acid PC(14:0/20:4(5Z,8Z,11Z,14Z)), 5-KETE
Arginine and proline metabolism P4HA1, LAP3, P4HA2, SRM ALDH3A2, ALDH4A1, MAOA, CKMT2, ARG1, MAOB Adenosine monophosphate, L-aspartic acid, carbamoyl phosphate Creatine, gamma-aminobutyric acid, ornithine, glycine, fumaric acid, citrulline
Arginine biosynthesis GLUL, ARG1, ASS1 L-aspartic acid, carbamoyl phosphate Citrulline, ornithine, N-acetylglutamic acid, fumaric acid
beta-Alanine metabolism ALDH1A3 ACADS, ALDH3A2, ECHS1, AOC3, ALDH2 L-aspartic acid, carnosine, uracil, L-histidine
Biosynthesis of unsaturated fatty acids HACD2, ACOT1 PUFAs, MUFAs, SFAs, carnitines
Butanoate metabolism ACADS, ACAT1, ECHS1, HADH Gamma-aminobutyric acid
Cholesterol metabolism APOC1, APOA2,PLTP,SOAT1 Bile acids, cholesterol esters, cholesterol
Citrate cycle (TCA cycle) ACO1, SUCLA2, CS, MDH1, PCK1, PC, OGDH, SDHA, IDH1 Citric acid, fumaric acid, L-malic acid, coenzyme Q10
Cysteine and methionine metabolism PSAT1, MTR, SRM GCLC, TST, MDH1, LDHB Glycine, L-methionine
Dopaminergic synapse CAMK2D GNAS,MAOB,GNAI1,MAOA
Ether lipid metabolism PLA2G2A Glycerophosphocholine
Fat digestion and absorption AGPAT2, PLA2G2A, CD36, FABP5 Triglycerides, diglycerides
Fatty acid biosynthesis ACACA, ACACB, FASN, ACSL1 Palmitic acid, myristic acid Triglycerides, diglycerides
Fatty acid degradation ACADS, ACADVL, ALDH3A2, ACAT1, ACADL, ACADM, ECHS1, HADH, ACSL1, ADH1B, ALDH2 Palmitic acid, L-palmitoylcarnitine Triglycerides, diglycerides
Fatty acid elongation HACD2, ECHS1, ACOT1, HADH Cholesterol, palmitic acid Triglycerides, diglycerides
Fructose and mannose metabolism ALDOC Fructose 6-phosphate, dihydroxyacetone phosphate
Galactose metabolism GLB1 UGP2 Galactitol
Glutathione metabolism LAP3, GPX8, SRM, TXNDC12 GCLC, GGT5, GPX4, MGST1 Glycine, ornithine
Glycerolipid metabolism GPAM, ALDH3A2, AGPAT2, MGLL, ALDH2 Palmitic acid, DG(16:0/16:0/0:0), dihydroxyacetone phosphate Glycerol 3-phosphate, triglycerides, diglycerides
Glycerophospholipid metabolism GPAM, PCYT2, AGPAT2, PLA2G2A, GPD1 Dihydroxyacetone phosphate, citicoline, phosphorylcholine, acetylcholine, O-phosphoethanolamine Glycerol 3-phosphate
Glycine, serine and threonine metabolism SHMT2, PSAT1, MTR, SRM SHMT1, BPGM, MAOB, AOC3, MAOA Glycine, L-threonine, serine, creatine, ornithine, L-methionine
Glycolysis/Gluconeogenesis ALDH1A3, ADPGK GPI, ALDOC, ALDH3A2, LDHB, PCK1, ACSS2, BPGM, ADH1B, ALDH2 Fructose 6-phosphate, L-Lactic acid, glucose 6-phosphate, dihydroxyacetone phosphate
Glyoxylate and dicarboxylate metabolism SHMT2 PCCB, ACO1,SHMT1, ACAT1, GLUL, CS, MDH1, ACSS2, HYI, CAT Citric acid, glycine
Histidine metabolism ALDH1A3 ALDH3A2, MAOB, MAOA L-histidine, carnosine, histamine, L-aspartic acid, adenosine
Inositol phosphate metabolism PIP4K2C Glucose 6-phosphate, dihydroxyacetone phosphate
Lysine degradation PLOD2, PLOD1, COLGALT1, PLOD3 ALDH3A2, ACAT1, ECHS1, HADH, ALDH2 Aminoadipic acid
Metabolism of xenobiotics by cytochrome P450 ALDH1A3 AKR1C1, MGST1, EPHX1, ADH1B
Nicotinate and nicotinamide metabolism ENPP1,BST1 L-aspartic acid Nicotinamide
Nitrogen metabolism GLUL, CA4, CA3, CA1, CA2 Carbamoyl phosphate Serine
One carbon pool by folate SHMT2, MTR SHMT1, ALDH1L1
Other types of O-glycan biosynthesis COLGALT1, GALNT2, PLOD3
Pantothenate and CoA biosynthesis ENPP1 Adenosine monophosphate, uracil, L-aspartic acid
Pentose and glucuronate interconversions UGDH UGP2
Phenylalanine metabolism ALDH1A3 MAOB, GLYAT, AOC3, MAOA
Phospholipid biosynthesis Phosphatidylserines, phosphatidylinositol, phosphatidylglycerol, phosphatidylethanolamines
Pentose phosphate pathway GPI, ALDOC, TKT Adenosine monophosphate; fructose 6-phosphate, glucose 6-phosphate
Phosphonate and phosphinate metabolism PCYT2 Phosphorylcholine
Porphyrin and chlorophyll metabolism CP BLVRB, ALAD Glycine
Primary bile acid biosynthesis AKR1D1 Cholesterol, palmitic acid, taurochenodesoxycholic acid, glycocholic acid, taurocholic acid Glycine
Propanoate metabolism ACACA, PCCB, ACADS, SUCLA2, ACAT, 1LDHB, ECHS1, ACSS2, ECHDC1, ACACB
Purine metabolism PAPSS1 ENPP1 Xanthine, adenosine monophosphate, guanosine monophosphate, guanosine, uric acid, L-aspartic acid Hypoxanthine, allantoic acid, adenine, allantoin, glycine, fumaric acid
Pyrimidine metabolism ENPP1 Carbamoyl phosphate, uridine, cytidine monophosphate, cytidine, deoxycytidine, uracil
Pyruvate metabolism ACACA, ALDH3A2, ACAT1, HAGH, MDH1, LDHB, PCK1, ACSS2, LDHD, ACACB, PC, ALDH2 L-lactic acid Fumaric acid
Regulation of lipolysis in adipocytes GNAS, LIPE, GNAI1, FABP4, PLIN1, PNPLA2, PDE3B, NPR1, MGLL, ABHD5
Retinol metabolism RETSAT, ADH1B Phosphatidylcholines
Sphingolipid metabolism GLB1 O-phosphoethanolamine, sphinganine; SM(d18:1/18:0), ceramide (d18:1/18:0)
Starch and sucrose metabolism GBE1, ENPP1, GPI, UGP2, PYGL Glucose 6-phosphate, fructose 6-phosphate, O-phosphoethanolamines, sphingomyelins Serine
Steroid biosynthesis SOAT1 LSS Cholesterol, palmitic acid, CE(18:0)
Steroid hormone biosynthesis AKR1C1, AKR1D1, AKR1C2 Cholesterol
Taurine and hypotaurine metabolism GGT5 Taurocholic acid
Thiamine metabolism ALPL Adenosine monophosphate
Phenylalanine metabolism ALDH1A MAOB, AOC3, MAOA L-tyrosine
Tryptophane metabolism ALDH3A2, ACAT1, ECHS1, HADH, MAOB, CAT, MAOA L-tyrosine
Tyrosine metabolism ALDH1A3 MAOB, FAH, AOC3, ADH1B, MAOA L-tyrosine, fumaric acid, dehydroascorbic acid
Ubiquinone and other terpenoid-quinone biosynthesis VKORC1L1, NQO1 L-tyrosine
Valine, leucine and isoleucine degradation PCCB, ACADS, ALDH3A2, ACAT1, ACADM, ECHS1, HADH, ALDH2 L-threonine
Tab.2  Statistical tables of proteins, metabolites, and lipids associated with metabolic pathways
Fig.5  Mapping of the joint analysis of proteomics, metabolomics, and lipdomics of RDDLPS and RWDLPS and adjacent adipose tissue. Left: targeted metabolomics and proteomics in key metabolic pathways. Right: lipdomics and proteomics in key lipid metabolic pathways. Red: upregulated, bule: downregulated, purple: unidentified or unchanged.
Fig.6  Proteomic analysis and lipidomic analysis between RWDLPS and RDDLPS. (A) The heat map of the enrichment test results of metabolic pathway based on GSVA; n = 5. (B) Relative abundance of significantly changed representative proteins. (C, D) Chemical structures analysis of the identified lipids. (E) Relative abundance of significantly changed representative lipids. Data are mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001.
Fig.7  Validation of key proteins in key pathways. (A–C) IHC staining of RLPS tissue and adipose tissue microarray with the indicated antibodies. CD36 (fat digestion and absorption marker), MDM2 (DDLPS and WDLPS markers), G6PD (key enzyme of the PPP), and LDHA (lactate metabolism marker). Positive cell % = number of positive cells/total number of cells; Histochemistry SCORE = ∑ (pi × i) = (percentage of weak intensity × 1) + (percentage of moderate intensity × 2) + (percentage of strong intensity × 3); IRS = SI (positive intensity) × PP (positive cell ratio). Adipose tissue: n = 60; RWDLPS: n = 20; RDDLPS: n = 30. Data are mean ± SD. *P < 0.05; **P < 0.01; ***P < 0.001, ns: not significant. (D, E) Cell viability was analyzed in dedifferentiated liposarcoma cells SW872 and LPS510 after treatment with 2-deoxy-D-glucose (150 μM), RRX-001 (2 μM), cisplatin (0.5 μM), doxorubicin (0.5 μmol/L), gemcitabine (0.5 μmol/L), RG7112 (1 μmol/L), and abemaciclib (0.5 μmol/L) alone or jointly. n = 3. Data are mean ± SD. *P < 0.05; **P < 0.01; ***P < 0.001, ns: not significant.
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