Combined High—Throughput Proteomics and Random Forest Machine-Learning Approach Differentiates and Classifies Metabolic, Immune, Signaling and ECM Intra-Tumor Heterogeneity of Colorectal Cancer
Abstract
:1. Introduction
2. Materials and Methods
- Reagents and Instruments
- Study subjects
- Sample Preparation
- HPLC–HR–MS/MS analysis
- Statistical analysis
- Pathway/process enrichment analysis
- Protein–Protein interaction network and topological analysis
3. Results
3.1. Statistical Analysis of LFQ Abundances Measured in S, D, and H Samples
Differential Statistical Analysis
- 30 in the S vs. H comparison (MW test), with 19 less-abundant and 11 more-abundant proteins in the S tumor region;
- 31 in the D vs. H comparison (MW test), with 16 less-abundant and 15 more-abundant proteins in the D tumor region.
- 20 in both S vs. H and D vs. H comparisons (MW test), with 18 less-abundant and 2 more-abundant proteins in both tumor regions;
- 2 in both S vs. D and D vs. H comparisons (MW test).
3.2. RF Classification Analysis
3.3. Enrichment Analysis of Biological Processes and Pathways
3.3.1. Proteoglycans and Extracellular Matrix Dynamics
3.3.2. Metabolic Processes
3.3.3. Leukocyte Migration and Aggregation
3.4. PPI Network and Topological Analysis
3.5. Correlation between Proteomic and Clinical Data
4. Discussion
4.1. Quantitative Differences in Protein Profiles in Tumor and Healthy Tissues and the Implication of Biological Processes/Pathways
4.1.1. Proteins Implicated in Processes Related to Proteoglycans and ECM
4.1.2. Proteins Implicated in Leukocyte Migration and Aggregation
4.1.3. Proteins Implicated in Metabolic Processes
4.1.4. Other Interesting Proteins Potentially Hallmarks of CRC
Hallmarks Implicated in Nucleic Acid Processing
Hallmarks Implicated in Protein Trafficking
Hallmarks Implicated in Regulation of Intra-/Extracellular Signaling Paths
4.2. Identification of Highly Sensitive and Specific Classifying Proteins
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Patients | Gender and Age | Dukes Stage | Budding |
---|---|---|---|
#4 | F, 79 yr | B | 3 |
#5 | M, 78 yr | B | 3 |
#6 | F, 55 yr | B | 2 |
#7 | M, 83 yr | B | 1 |
#8 | M, 70 yr | B | 2 |
#9 | F, 81 yr | B | 0 |
#11 | M, 75 yr | B | 1 |
#12 | M, 66 yr | B | 3 |
#13 | F, 52 yr | C | 1 |
#14 | M, 52 yr | C | 3 |
#15 | M, 64 yr | C | 3 |
#17 | M, 76 yr | A | 1 |
#19 | M, 76 yr | C | 1 |
#22 | M, 80 yr | B | 0 |
#23 | F, 66 yr | B | 2 |
#24 | F, 80 yr | B | 1 |
UniProt KB Code (Gene) | Protein | ND | MW S vs. D p Change FC | MW S vs. H p Change FC | MW D vs. H p Change FC | KW p | GDA Score | Ref. for CRC and Used Technique | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Proteins changing in the comparison S–D and D–H | ||||||||||||||
Q4V328 (GRIPAP1) | GRASP-1 | ND in S | 0.00001 | S<D | >100 | 0.0001 | D>H | >100 | 0.00001 | |||||
Q96RF0 (SNX18) | Sorting nexin-18 | ND in D | 0.00001 | S>D | >100 | 0.0003 | D<H | >100 | 0.0001 | LC–MS/MS [24] | ||||
Proteins changing in the comparison S–H with S↓ | ||||||||||||||
P15090 (FABP4) | A-FABP | ND in S | 0.0007 | S<H | >100 | 0.0009 | 0.02 | qPCR a, IF b [4] | ||||||
P02511 (CRYAB) | AlphaB-crystallin | 0.0009 | S<H | >100 | 0.0016 | 0.04 | qPCR, IHC c, WB d [25,26] | |||||||
P50995 (ANXA11) | Annexin A11 | 0.0011 | S<H | 2.8 | 0.01 | MALDI–TOF MS e, IHC [27] | ||||||||
P00403 (MT–CO2) | Cytochrome c oxidase subunit 2 | ND in S | 0.0007 | S<H | >100 | 0.5 | Gene expression, WB, IHC [28] | |||||||
P08294 (SOD3) | EC–SOD | 0.0001 | S<H | 4.1 | ||||||||||
Q13642 (FHL1) | FHL-1 | 0.0002 | S<H | 10.1 | 0.0003 | mRNA expression [29] | ||||||||
P21695 (GPD1) | GPDH-C | ND in S | 0.0001 | S<H | >100 | 0.0004 | MALDI–TOF [30] | |||||||
P10915 (HAPLN1) | HPLPN1 | ND in S | 0.0003 | S<H | >100 | 0.0004 | 0.5 | Gene expression, qMSP f [31] | ||||||
P51884 (LUM) | Lumican | 0.0001 | S<H | 7.2 | 0.0004 | 0.01 | WB, IHC, PCR [32] | |||||||
P20774 (OGN) | Mimecan (osteoglycin) | 0.0004 | S<H | 11.7 | 0.0004 | 0.03 | IHC, WB, IF [33] | |||||||
Q02218 (OGDH) | OGDH-E1 | 0.0008 | S<H | >100 | 0.0002 | 0.01 | LC–MS/MS, WB [5] | |||||||
Q9UIQ6 (LNPEP) | OTase | ND in S | 0.0000 | S<H | >100 | 0.00001 | ||||||||
P11177 (PDHB) | PDHE1-B | 0.0002 | S<H | >100 | 0.0005 | |||||||||
P36871 (PGM1) | PGM-1 | 0.0009 | S<H | 3.2 | 0.3 | qPCR, WB IHC [34] | ||||||||
Q5T013 (HYI) | Putative Hyi | ND in S | 0.0007 | S<H | >100 | |||||||||
Q9HD15 (SRA1) | SRA1 | ND in S | 0.0007 | S<H | >100 | WGCNA g [35] | ||||||||
Q9C0C2 (TNKS1BP1) | TAB182 | 0.0009 | S<H | 1.6 | ||||||||||
P09936 (UCHL1) | UCH-L1 | 0.0002 | S<H | >100 | 0.0004 | 0.04 | WB, gene expression, qMSP [36] | |||||||
P51452 (DUSP3) | VHR | ND in S | 0.0007 | S<H | >100 | |||||||||
Proteins changing in the comparison S–H with S↑ | ||||||||||||||
P13674 (P4HA1) | 4-PH alpha-1 | ND in H | 0.0003 | S>H | >100 | 0.0006 | LC–MS/MS [37] | |||||||
P55957 (BID) | BH3-interacting domain death agonist | 0.0012 | S>H | >100 | 0.01 | qPCR [38] | ||||||||
P02788 (LTF) | Lactotransferrin | 0.0001 | S>H | 6.0 | 0.0004 | qPCR, IHC, WB [39] | ||||||||
P49321 (NASP) | NASP | 0.0012 | S>H | 4.3 | ||||||||||
P48681 (NES) | Nestin | ND in H | 0.0007 | S>H | >100 | 0.01 | IHC [40] | |||||||
P02775 (PPBP) | PBP | 0.0004 | S>H | 2.2 | 0.03 | mRNA analysis, WB, IF [41] | ||||||||
O15212 (PFDN6) | Prefoldin subunit 6 | 0.0006 | S>H | 2.8 | ||||||||||
Q9Y2Z0 (SUGT1) | Protein SGT1 homolog | ND in H | 0.0003 | S>H | >100 | 0.0008 | ||||||||
P05109 (S100A8) | S100-A8 | 0.0006 | S>H | 7.7 | qPCR, WB, IHC [42] | |||||||||
P06702 (S100A9) | S100-A9 | 0.0000 | S>H | 8.1 | 0.0001 | 0.08 | qPCR, WB, IHC [42] | |||||||
P61964 (WDR5) | WDR5 | ND in H | 0.0003 | S>H | >100 | 0.0008 | 0.01 | qPCR, WB [43] | ||||||
Proteins changing in the comparison D–H with D↓ | ||||||||||||||
P15121 (AKR1B1) | Aldo-keto reductase 1B1 | 0.0008 | D<H | 3.7 | 0.05 | gene expression, qMSP [44] | ||||||||
P17050 (NAGA) | Alpha-N-acetylgalactosaminidase | 0.0009 | D<H | 5.1 | ||||||||||
P35613 (BSG) | Basigin | 0.0002 | D<H | 4.8 | 0.0011 | 0.06 | WB [45] | |||||||
P17174 (GOT1) | cAspAT | 0.0002 | D<H | 2.4 | 0.01 | qPCR [46] | ||||||||
Q9Y5K6 (CD2AP) | CD2-associated protein | 0.0012 | D<H | 3.7 | 0.02 | LC–MS/MS, IHC [47] | ||||||||
P10606 (COX5B) | Cytochrome c oxidase sub. 5B | 0.0012 | D<H | 4.5 | ||||||||||
Q13011 (ECH1) | DI (mitochondrial) | 0.0007 | D<H | 3.3 | ||||||||||
P36957 (DLST) | DLST | 0.0008 | D<H | 3.4 | 0.0011 | |||||||||
O95571 (ETHE1) | ETHE1 | 0.0000 | D<H | 4.0 | 0.0002 | 0.02 | IHC, WB, LC–MS/MS [48] | |||||||
Q05315 (CLC) | Gal-10 | 0.0011 | D<H | 4.9 | 0.03 | RNA analysis [49] | ||||||||
P00390 (GSR) | GRase | 0.0002 | D<H | 4.6 | 0.0012 | 0.01 | Enzymatic assay [50] | |||||||
P06870 (KLK1) | Kallikrein-1 | 0.0006 | D<H | >100 | 0.0003 | |||||||||
O00401 (WASL) | N-WASP | 0.0009 | D<H | >100 | 0.01 | qPCR [51] | ||||||||
Q8IV08 (PLD3) | PLD3 | 0.0005 | D<H | >100 | 0.0012 | |||||||||
O95716 (RAB3D) | Rab-3D | 0.0010 | D<H | >100 | IHC, WB, qPCR [52] | |||||||||
O43760 (SYNGR2) | Synaptogyrin-2 | ND in D | 0.0007 | D<H | >100 | 0.0015 | GSEA h [53] | |||||||
Proteins changing in the comparison D–H with D↑ | ||||||||||||||
Q15121 (PEA15) | 15 kDa phosphoprotein enriched in astrocytes | 0.0009 | D>H | >100 | 0.0011 | 0.02 | WB, cell assays [54] | |||||||
O94875 (SORBS2) | ArgBP2 | 0.0007 | D>H | >100 | ||||||||||
P53618 (COPB1) | Beta-COP | 0.0002 | D>H | 5.7 | 0.0001 | 0.01 | WB, IHC, LC–TOF MS [55] | |||||||
P08572 (COL4A2) | Collagen alpha-2(IV) chain | 0.0003 | D>H | >100 | 0.0005 | 0.1 | LC–MS/MS [37] | |||||||
P02751 (FN1) | FN | 0.0002 | D>H | 2.9 | 0.0004 | 0.4 | RNA analysis, WB, IHC, GSEA [56] | |||||||
P29279 (CCN2) | CTGF | ND in H | 0.0003 | D>H | >100 | 0.0012 | 0.08 | WB, qPCR [57] | ||||||
P13639 (EEF2) | EF-2 | 0.0002 | D>H | 10.7 | 0.01 | MALDI–TOF, IHC, WB, ELISA [58] | ||||||||
P84243 (H3–3A) | Histone H3.3 | 0.0012 | D>H | >100 | 0.01 | RNA analysis [49] | ||||||||
O14979 (HNRNPDL) | hnRNP D-like | 0.0001 | D>H | 2.0 | 0.0009 | 0.03 | LC–MS/MS [59] | |||||||
P14174 (MIF) | MIF | 0.0007 | D>H | 2.4 | 0.03 | IHC, WB, qPCR [60] | ||||||||
P14543 (NID1) | NID-1 | 0.0002 | D>H | >100 | 0.000001 | 0.3 | qPCR [61] | |||||||
P42696 (RBM34) | RNA-binding protein 34 | 0.0009 | D>H | >100 | 0.0013 | qPCR, WB, IHC [62] | ||||||||
P50454 (SERPINH1) | Serpin H1 | 0.0004 | D>H | 3.4 | 0.01 | DEGs i, WGCNA [63] | ||||||||
Q8WUH6 (TMEM263) | Transmembrane protein 263 | ND in S/H | 0.0003 | D>H | >100 | 0.000001 | 0.02 | DEGs, ML j [64] | ||||||
P18887 (XRCC1) | XRCC1 | ND in H | 0.0001 | D>H | >100 | 0.00001 | 0.4 | Gene expression, IHC [65] | ||||||
Proteins changing in the comparison D–H and S–H with D↓ and S↓ | ||||||||||||||
P27348 (YWHAQ) | 14-3-3 protein theta | 0.0001 | S<H | 8.2 | 0.0003 | D<H | 8.3 | 0.0001 | ||||||
P00325 (ADH1B) | ADH1B | 0.0010 | S<H | 9.5 | 0.0013 | D<H | 8.3 | 0.0006 | 0.4 | Gene expression [66] | ||||
P00326 (ADH1C) | ADH1C | 0.00001 | S<H | 22.3 | 0.00001 | D<H | 26.3 | 0.00001 | 0.06 | DEGs, ML, IHC, WB, qPCR [67] | ||||
P48047 (ATP5PO) | ATP synthase subunit O | 0.0008 | S<H | 16.5 | 0.0013 | D<H | 3.5 | 0.0004 | LC–MS/MS, qPCR, WB [68] | |||||
O75363 (BCAS1) | Breast carcinoma-amplified sequence 1 | 0.0011 | S<H | 3.5 | 0.00001 | D<H | 7.4 | 0.0001 | qPCR [69] | |||||
A8H7I4 (CLCA1) | CaCC-1 | 0.00001 | S<H | 9.2 | 0.00001 | D<H | 22.1 | 0.00001 | 0.06 | ELISA, IHC, WB [70] | ||||
P00918 (CA2) | CA-II | 0.00001 | S<H | 5.7 | 0.00001 | D<H | 8.0 | 0.00001 | 0.02 | IHC [71] | ||||
O00748 (SULT2) | CE-2 | 0.0006 | S<H | 9.2 | 0.0004 | D<H | 10.9 | 0.0004 | 0.03 | WB [72] | ||||
P34913 (EPHX2) | CEH | 0.0002 | S<H | 4.8 | 0.00001 | D<H | >100 | 0.00001 | IHC, qPCR, WB [73] | |||||
P10645 (CHGA) | CgA, pro-protein | 0.0001 | S<H | 8.7 | 0.00001 | D<H | 18.2 | 0.00001 | 0.03 | ML of gene data, qPCR [74] | ||||
P07585 (DCN) | Decorin | 0.0002 | S<H | 9.7 | 0.0008 | D<H | 5.7 | 0.0001 | 0.08 | IF [75] | ||||
P16422 (EPCAM) | Ep-CAM | 0.0001 | S<H | >100 | 0.0001 | D<H | >100 | 0.00001 | 0.1 | IHC [76] | ||||
Q9UHB6 (LIMA1) | EPLIN | 0.0010 | S<H | 4.0 | 0.0000 | D<H | 5.6 | 0.0001 | 0.1 | LC–MS/MS [59] | ||||
P17931 (LGALS3) | Gal-3 | 0.0008 | S<H | 2.2 | 0.0007 | D<H | 2.5 | 0.0008 | 0.1 | IHC [77] | ||||
Q9Y6R7 (FCGBP) | IgGFc-binding protein | 0.00001 | S<H | 9.8 | 0.00001 | D<H | 35.7 | 0.00001 | DEGs and ML [78] | |||||
P10082 (PYY) | PYY | ND in D | 0.0010 | S<H | >100 | 0.0000 | D<H | >100 | 0.000001 | 0.01 | LC–MS/MS, qPCR, IHC [79] | |||
Q15661 (TPSAB1) | Tryptase-1 | 0.0003 | S<H | 10.1 | 0.0002 | D<H | 6.5 | 0.0003 | ||||||
O60701 (UGDH) | UDP-GlcDH | 0.0001 | S<H | 3.4 | 0.0000 | D<H | 5.0 | 0.0001 | qPCR, WB [80] | |||||
Proteins changing in the comparison D–H and S–H with D↑ and S↑ | ||||||||||||||
Q15582 (TGFBI) | Beta ig-h3 | 0.0008 | S>H | 3.1 | 0.0000 | D>H | 2.7 | 0.0001 | 0.02 | LC–MSMS, GSEA [81] | ||||
P04899 (GNAI2) | Galphai2 | 0.00001 | S>H | 6.3 | 0.0003 | D>H | 5.4 | 0.00001 | IF, WB, qPCR [82] | |||||
Proteins changing in KW comparisons among all three groups but not in MW pairwise comparisons | ||||||||||||||
Q9NZK5 (ADA2) | Adenosine deaminase 2 | N.D in D | 0.0006 | |||||||||||
P35611 (ADD1) | Alpha-adducin | 0.0012 | 0.01 | Gene expression [83] | ||||||||||
P0C0L5 (C4B) | Complement C4-B | ND in S/H | 0.0013 | |||||||||||
Q96S86 (HAPLN3) | HPLPN3 | ND in D | 0.0009 | |||||||||||
C9JLW8 (MCRIP1) | MCRIP1 | ND in S | 0.0001 | |||||||||||
P49821 (NDUFV1) | NDUFV1 | ND in S/D | 0.0003 | WB, enzyme assay [84] | ||||||||||
Q96IQ7 (VSIG2) | VSIG2 | 0.0015 | WGCNA [85] | |||||||||||
O75312 (ZPR1) | Zinc finger protein ZPR1 (ZPR1) | ND in S | 0.0005 |
Biological Processes/ Pathways | GO/Reactome Entry (FDR) | Proteins |
---|---|---|
Degradation of the ECM | REAC:R-HSA-3560782 (0.02) | Decorin; lumican; mimecan; basigin; collagen alpha-2(IV) chain; FN; NID-1, tryptase-1 |
ECM proteoglycans | REAC:R-HSA-3000178 (0.01) | Decorin; lumican; HPLPN1; collagen alpha-2(IV) chain; FN |
ECM organization | REAC:R-HSA-1474244 (0.003) | Decorin; lumican; HPLPN1; basigin; collagen alpha-2(IV) chain; FN; tryptase-1; 4-PH alpha-1; NID-1; serpin H1 |
Aerobic respiration/ Cellular respiration | GO:0009060/GO:0045333 (0.02) | PDHE1-B; OGDH-E1; ATP synthase subunit O; cytochrome c oxidase subunit 2; cytochrome c oxidase sub. 5B; DLST; NDUFV1 |
Generation of precursor metabolites and energy | GO:0006091 (0.02) | PDHE1-B; OGDH-E1; DLST; ATP synthase subunit O; cytochrome c oxidase subunit 2; cytochrome c oxidase sub. 5B; NDUFV1; PGM-1; ADH1C; ADH1B |
Citric acid cycle and respiratory electron transport | REAC:R-HSA-1428517 (0.003) | PDHE1-B; OGDH-E1; DLST; ATP synthase subunit O; cytochrome c oxidase subunit 2; cytochrome c oxidase sub. 5B; NDUFV1; basigin |
2-oxoglutarate metabolic process | GO:0006103 (0.02) | OGDH-E1; DLST; cAspAT |
Histone succinylation/ Protein succinylation | GO:0106077/GO:0018335 (0.03)/(0.04) | OGDH-E1; DLST |
Metabolism | REAC:R-HSA-1430728 (0.01) | PDHE1-B; OGDH-E1; DLST; cAspAT; ATP synthase subunit O; cytochrome c oxidase subunit 2; cytochrome c oxidase sub. 5B; NDUFV1; PGM-1; GPDH-C; ETHE1; ADH1C; ADH1B; CEH; CE-2; A-FABP; aldo-keto reductase 1B1; UDP-GlcDH; decorin; lumican; mimecan; CA-II; basigin; Galphai2; PLD3; N-WASP |
Neutrophil chemotaxis | GO:0030593 (0.03) | S100A8; S100A9; Gal-3; PBP; basigin |
Leukocyte chemotaxis/ Myeloid leukocyte migration | GO:0030595/GO:0097529 (0.02) | S100A8; S100A9; Gal-3; PBP; basigin; CgA; MIF |
Leuckocyte migration | GO:0050900 (0.04) | S100A8; S100A9; Gal-3; PBP; basigin; CgA; MIF; N-WASP |
Neutrophil aggregation | GO:0070488 (0.02) | S100A8; S100A9 |
Metal sequestration by antimicrobial proteins | REAC:R-HSA-6799990 (0.002) | Lactotransferrin; S100A8; S100A9 |
Sequestering of zinc ion | GO:0032119 (0.02) | S100A8; S100A9 |
Gene | Closeness Centrality | Degree | Betweenness Centrality | Protein |
---|---|---|---|---|
COPB2 * | 0.36 | 6 | 0.002 | Beta-COP |
DPP4 * | 0.37 | 5 | 0.0001 | ADABP |
EEF2 | 0.52 | 44 | 0.022 | EF-2 |
FN1 | 0.51 | 37 | 0.025 | FN |
GOT1 * | 0.32 | 5 | 0.0002 | cAspAT |
IGHV3–43D * | 0.31 | 2 | 0.0001 | Immunoglobulin heavy variable 3–43D |
LGALS3 * | 0.43 | 12 | 0.004 | Gal-3 |
LTF * | 0.38 | 10 | 0.003 | Lactotransferrin |
PDHB * | 0.41 | 9 | 0.0003 | PDHE1-B |
WASL * | 0.41 | 14 | 0.003 | N-WASP |
WDR5 * | 0.41 | 9 | 0.002 | WD repeat-containing protein 5 |
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Contini, C.; Manconi, B.; Olianas, A.; Guadalupi, G.; Schirru, A.; Zorcolo, L.; Castagnola, M.; Messana, I.; Faa, G.; Diaz, G.; et al. Combined High—Throughput Proteomics and Random Forest Machine-Learning Approach Differentiates and Classifies Metabolic, Immune, Signaling and ECM Intra-Tumor Heterogeneity of Colorectal Cancer. Cells 2024, 13, 1311. https://doi.org/10.3390/cells13161311
Contini C, Manconi B, Olianas A, Guadalupi G, Schirru A, Zorcolo L, Castagnola M, Messana I, Faa G, Diaz G, et al. Combined High—Throughput Proteomics and Random Forest Machine-Learning Approach Differentiates and Classifies Metabolic, Immune, Signaling and ECM Intra-Tumor Heterogeneity of Colorectal Cancer. Cells. 2024; 13(16):1311. https://doi.org/10.3390/cells13161311
Chicago/Turabian StyleContini, Cristina, Barbara Manconi, Alessandra Olianas, Giulia Guadalupi, Alessandra Schirru, Luigi Zorcolo, Massimo Castagnola, Irene Messana, Gavino Faa, Giacomo Diaz, and et al. 2024. "Combined High—Throughput Proteomics and Random Forest Machine-Learning Approach Differentiates and Classifies Metabolic, Immune, Signaling and ECM Intra-Tumor Heterogeneity of Colorectal Cancer" Cells 13, no. 16: 1311. https://doi.org/10.3390/cells13161311