Table 3 Gastrointestinal cancer subclassifications with CSC traits

Liver cancer

Zhu et al. [30]

Notch-high

Notch and TGF-β signaling, KRT19, DCLK1, SOX9 (+)

higher tumor stage, worse survival outcome

Liu et al. [31]

ES⁺, LP⁺

ES⁺: pluripotency and stem cell self-renewal signaling pathways (+), Gli, Notch and Wnt pathways (+);

LP⁺: TGF-β, Notch and Wnt pathways (+)

ES⁺: HLM6474 (+);

LP⁺: SIS3 (+)

Lee et al. [32]

HB, HC

HB: KRT7, KRT19, VIM, AP-1 complex (+)

HB: tumor-invasive, worse survival, poorer prognosis

Yamashita et al. [33]

HpSC-HCC (EpCAM⁺AFP⁺), MH-HCC (EpCAM⁻AFP⁻)

HpSC-HCC: KRT19, c-Myc, Wnt/β-catenin (+); MH-HCC: HepPar1 (+)

HpSC-HCC: tumor-invasive, poor prognosis

MH-HCC: good prognosis

HpSC-HCC: β-catenin inhibitor (+);

EpCAM⁺ HCC cells: GSK-3β inhibitor BIO, 5-FU (−);

EpCAM⁻ HCC cells: 5-FU (+)

Hoshida et al. [34]

S1, S2, S3

S1: Wnt, TGF-β, EMT (+);

S2: Myc, AKT, EpCAM, AFP (+);

S3: hepatocyte differentiation (+)

S1: earlier recurrence, tumor-invasive, poor survival; S2: poor survival;

S3: good survival

Boyault et al. [35]

G1, G2, G3, G4, G5, G6

G1: AXINI mutations, fetal liver expressing genes, AFP (+);

G2: AKT (+);

G3: cell cycle genes (+);

G5: Wnt (+);

G6: Wnt, LEF1 (+), CDH1 (−)

G4-G6: better survival VS

G1-G3

Colorectal cancer

Marisa et al. [36]

C1, C2, C3, C4, C5, C6

C1: EMT (−); C2: Wnt (−); C3: EMT (−); C4: EMT (+); C5: Wnt (+); C6: EMT (+)

C4 plus C6: worse prognosis VS all other subtypes

Colorectal cancer

Sadanandam et al. [37]

Enterocyte, goblet-like, inflammatory, transit-amplifying (CS-TA, CR-TA), stem-like

Goblet-like and enterocyte: differentiation markers (+), stem cell and Wnt markers (−);

Transit-amplifying: stem and progenitor markers (+), Wnt-target genes (−);

Stem-like: Wnt, stem cell, myoepithelial and mesenchymal markers (+), differentiation markers (−)

Goblet-like and transit-amplifying: good prognosis;

Enterocyte and inflammatory: intermediate DFS; Stem-like tumors: shortest DFS

Goblet-like: cetuximab (+);

Inflammatory: FOLFIRI (+);

Stem-like: cetuximab, FOLFIRI (+);

CS-TA: cetuximab (+);

CR-TA: cMET inhibitors (+), cetuximab (−)

De Sousa et al. [38]

CCS1, CCS2, CCS3

CCS1: Wnt (+); CCS3: EMT, matrix remodeling and TGF-β (+)

CCS3: poor prognosis

CCS3: cetuximab (−)

Budinska et al. [39]

Surface crypt-like, lower crypt-like, CIMP-H-like, mesenchymal, mixed

Surface crypt-like: EMT (−),Wnt (−), β-catenin (−);

Lower crypt-like: EMT (−), Wnt (+);

CIMP-H-like: β-catenin (−);

Mesenchymal: EphB2, EMT (+), Wnt (−), β-catenin (−);

Mixed: EphB2, EMT, Wnt (+)

Surface crypt-like and lower crypt-like: better prognosis VS mesenchymal;

CIMP-H-like: poor OS and SAR; Mesenchymal: recurrence risk, poor OS; Mixed: poorer

SAR VS lower crypt-like

Roepman et al. [40]

Type A, Type B, Type C

Type A: EMT (−);

Type B: EMT (−);

Type C: EMT (+)

Type A: good prognosis;

Type B: poor prognosis;

Type C: poor prognosis

Type A: 5-FU (+);

Type B: 5-FU (+);

Type C: 5-FU (-)

Guinney et al. [41]

CMS1, CMS2, CMS3, CMS4

CMS1 and CMS3: RTK and MAPK pathways (+);

CMS2: HNF4A, Myc and Wnt (+); CMS4: EMT, TGF-β, angiogenesis, matrix remodeling pathways (+)

CMS1: worse SAR;

CMS4: worse RFS and OS

CMS1: HSP90 inhibitors (+);

CMS2: HSP90 inhibitors, EGFR inhibitors, HER2 inhibitors (+);

CMS4: combination treatment of 5-FU and luminespib (+)

Pancreatic cancer

Collisson et al. [43]

Classical, QM-PDA, exocrine-like

Classical: GATA6 (+);

QM-PDA: mesenchyme associated genes (+)

Classical: good prognosis;

Exocrine-like: intermediate prognosis;

QM-PDA: worst prognosis

Classical: erlotinib (+), docetaxel (−);

QM-PDA: oxaliplatine, 5-FU, BET inhibitor (+);

Exocrine-like: SN-38 (−)

Moffitt et al. [44]

Normal stromal, activated stroma, basal-like, classical

Activated stroma: SPARC, WNT2, WNT5A, MMP9, MMP11 (+);

Classical: GATA6 (+);

Activated stroma: worse survival VS normal stroma;

Basal-like: worse survival VS classical

Normal stroma: Hedgehog pathway inhibitor (+);

Basal-like: oxaliplatine, 5-FU, BET inhibitor (+);

Classical: docetaxel, SN-38 (−)

Bailey et al. [45, 81]

Pancreatic progenitor (PP), squamous, immunogenic and aberrantly differentiated endocrine exocrine (ADEX)

Squamous: pancreatic endodermal cell-fate determination genes, Hedgehog/Wnt pathway (−); TGF-β and Myc pathway (+);

PP: developmental transcription factors (+), Notch pathway (+)

ADEX: pancreatic developmental and differentiational genes (+), Notch pathway (+)

PP: good survival outcomes;

Immunogenic and ADEX: intermediate survival outcomes;

Squamous: worst survival outcomes

Squamous: oxaliplatine, 5-FU, BET inhibitor, GSK3β inhibitor (+);

Squamous and PP subtypes: docetaxel (−);

PP: SN-38 (−)

Biederstädt et al. [80]

Squamous/basal- like

SUMO pathway and Myc (+)

Worse prognosis

SUMOylation inhibitor (+)

Mueller et al. [46]

Cluster 1, Cluster 2, Cluster 3, Cluster 4,

Cluster 5

Cluster 1: squamous differentiation;

Cluster 2: epithelial differentiation;

Cluster 3: embryonic development, EMT, MAPK pathway;

Cluster 5: embryonic development

Pancreatic cancer

Puleo et al. [47]

Pure classical, immune classical, pure basal-like, stroma activated, desmoplastic

Stroma activated and pure basal-like: MET, Hedgehog pathway (+)

Pure classical and immune classical: good prognosis;

Stroma activated and desmoplastic: poor prognosis; Pure basal-like: worst prognosis

Sivakumar et al. [48]

Notch, repressed Hedgehog/Wnt,

cell cycle

Notch: best prognosis;

Repressed Hedgehog/Wnt: worst prognosis

Seino et al. [49]

W⁺,

W⁻,

WRi

W⁺: exogenous Wnt (−), R-spondin (+); W⁻: exogenous Wnt (+), R-spondin (+); WRi: Wnt signaling (−)

W⁺: poor survival and metastatic progression

Gastric cancer

Lei et al. [53]

Proliferative, metabolic, mesenchymal

Proliferative: E2F, Myc, RAS (+);

Mesenchymal: EMT, CSC pathway (+)

No significant differences among the 3 subtypes

Metabolic: 5-FU (+);

Mesenchymal: PI3K-AKT-mTOR inhibitors (+)

Cristescu et al. [54]

MSI, MSS/EMT, MSS/p53⁺ and MSS/p53⁻

MSS/EMT: EMT (+)

MSS/EMT: worst prognosis, recurrence, stage III/IV, earlier age;

MSI: stage I/II, best prognosis

Cheul Oh et al. [55]

EP, MP

EP: Wnt (+), EMT (−);

MP: EMT, IGF pathway, Hedgehog pathway (+)

EP: better survival;

MP: poor survival

EP: adjuvant chemotherapy (+);

MP: adjuvant chemotherapy (−), IGF1/IGF1R pathway inhibitor (+)

Cheong et al. [56]

Epithelial, immune, stem-like

Epithelial: CDX1 (+);

Stem-like: SFRP4 (+)

Low-risk (immune-high), intermediate-risk (immune-low and stem-like-low), or high risk (immune-low and stem-like-high)

No-benefit (immune-high or immune-low and epithelial-low) or chemotherapy-benefit

(immune-low and epithelial-high)

Oesophageal cancer

Walker et al. [57]

ESCC1, ESCC2, ESCC3

ESCC1: SOX2, TP63 (+);

ESCC2: ZNF750 and Notch1 mutation, CDK6 amplification (+), KDM6A and KDM2D (−), PIK3R1 and PTEN (−)

ESCC3: mutations associated with RTK/RAS/PI3K pathway (+)

Wang et al. [58]

Subtype I,

Subtype II

Subtype II: epithelium development genes (+)

No significant differences between the 2 subtypes

Jammula et al. [59]

Subtype 1,

Subtype 2,

Subtype 3,

Subtype 4

Subtype 1: DNA repair and cell cycle driver genes (+);

Subtype 2: differentiational and developmental transcription factors (+);

Subtype 4: high level of copy

number alterations (+)

Subtype 1: CDK4/6 inhibitors, docetaxel (+);

Subtype 2: CDK4/6 inhibitors (+);

Subtype 3: CDK4/6 inhibitors (+);

Subtype 4: CDK4/6 inhibitors (+), CDK2 inhibitors (+);