Background
Methods
PDAC samples and xenografts
Xenograft no. | Sex | Age (y) | pG | pT | pN | pM | pR | PNI | VI | LVI | Preop RCT | Postop RCT/CT | OS (m) | DFS (m) | SP% |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
101* | F | 45.5 | 2 | 4 | 1 | 0 | 1 | 1 | 0 | 0 | 0 | RCT | 35.4 | 18.5 | 1.5 |
110* | M | 77.8 | 2 | 3 | 0 | 0 | 1 | 1 | 1 | 1 | 0 | 0 | 1.1 | 1.1 | 6.0 |
112* | F | 77.8 | 2 | 3 | 1 | 0 | 0 | 1 | 1 | 1 | 0 | CT | 10.1 | 3.6 | 6.8 |
127 | M | 52.9 | 2 | 2 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | CT | 37.7 | 34.8 | 6.4 |
128* | M | 53.6 | 2 | 3 | 1 | 0 | 1 | 1 | 0 | 0 | 0 | CT | 11.2 | 10.2 | 6.8 |
136* | M | 78.4 | 2 | 3 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 37.8 | 24.5 | 6.1 |
151° | M | 45.9 | 2 | 3 | 1 | 0 | 0 | 1 | 1 | 1 | 0 | CT | 13.5 | 10.3 | 17.6 |
169 | F | 80.5 | 2 | 3 | 1 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 10.2 | 2.4 | 4.3 |
174**,° | M | 66.9 | 2 | 3 | 0 | 0 | 0 | 1 | 1 | 1 | 0 | CT | 43.3 | 19.8 | 2.7 |
178** | F | 53.2 | 3 | 4 | 1 | 0 | 0 | 1 | 0 | 1 | 0 | CT | 27.2 | 27.2 | 12.0 |
199 | M | 52.2 | 3 | 3 | 0 | 0 | 1 | 1 | 1 | 1 | 0 | CT | 23.5 | 4.9 | 5.0 |
207**,° | F | 67.0 | 2 | 3 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | CT | 7.2 | 5.5 | 10.0 |
218 | F | 62.6 | 3 | 3 | 1 | 0 | 0 | 1 | 1 | 1 | 0 | 0 | 0.3 | 0.3 | 1.4 |
223**,° | F | 57.3 | 2 | 2 | 1 | 0 | 0 | 1 | 1 | 1 | 0 | 0 | 24.5 | 7.4 | 2.0 |
229** | F | 73.2 | 3 | 3 | 1 | 0 | 0 | 1 | 1 | 1 | 0 | 0 | 4.5 | 4.0 | 5.4 |
235**,° | F | 57.4 | 1 | 3 | 1 | 0 | 1 | 1 | 0 | 0 | 0 | CT | 19.6 | 7.7 | 2.1 |
241**,° | F | 74.6 | 2 | 3 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 6.9 | 2.9 | 2.7 |
SP analysis
Treatment of mice bearing xenograft tumours with gemcitabine
Whole-genome expression profiling
Tumourigenic (CSC) activity as analyzed by in vitrosphere formation
Statistical analysis
Results
Presence of a SP in human PDAC xenografts
The SP is resistant to gemcitabine as assessed in vivo
Whole-genome expression analysis of the PDAC xenograft SP reveals upregulation of genes related to therapy resistance
Gene Symbol | Genbank Accession no. | Gene Name | Fold SP/MP | p-value |
---|---|---|---|---|
ZAP70 | NM_001079 | zeta-chain (TCR) associated protein kinase 70 kDa | 24.25 | 0.00002 |
PRKCQ | NM_006257 | protein kinase C, theta | 21.56 | 0.00008 |
FASLG | NM_000639 | Fas ligand (TNF superfamily, member 6) | 19.56 | 0.00003 |
LEF1 | NM_000639 | lymphoid enhancer-binding factor 1 | 16.45 | 0.00009 |
PACSIN1 | NM_020804 | protein kinase C and casein kinase substrate in neurons 1 | 12.47 | 0.00015 |
MEOX2 | NM_005924 | mesenchyme homeobox 2 | 8.22 | 0.00060 |
STAT4 | NM_003151 | signal transducer and activator of transcription 4 | 7.46 | 0.00050 |
EMX2 | NM_003151 | empty spiracles homeobox 2 | 6.87 | 0.00006 |
SOX11 | NM_003108 | SRY (sex determining region Y)-box 11 | 6.19 | 0.00029 |
FGF7 | NM_002009 | fibroblast growth factor 7 (keratinocyte growth factor) | 5.74 | 0.00072 |
FOXG1B | NM_005249 | forkhead box G1B | 5.62 | 0.00019 |
PKNOX2 | NM_022062 | PBX/knotted 1 homeobox 2 | 5.58 | 0.00017 |
ITGB3 | NM_000212 | integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61) | 5.35 | 0.00062 |
KLF12 | NM_007249 | Kruppel-like factor 12 | 5.03 | 0.00048 |
SNAI2 | NM_003068 | snail homolog 2 (Drosophila) | 4.99 | 0.00079 |
TIE1 | NM_005424 | tyrosine kinase with immunoglobulin-like and EGF-like domains 1 | 4.76 | 0.00019 |
IRX2 | AY335940 | iroquois homeobox protein 2 | 4.53 | 0.00010 |
EFNB2 | NM_004093 | ephrin-B2 | 4.23 | 0.00016 |
ETS1 | NM_005238 | v-ets erythroblastosis virus E26 oncogene homolog 1 (avian) | 3.95 | 0.00095 |
BCL2L11 | NM_138621 | BCL2-like 11 | 3.68 | 0.00019 |
GRB10 | NM_001001555 | growth factor receptor-bound protein 10 | 3.68 | 0.00034 |
NFIB | NM_005596 | nuclear factor I/B | 3.46 | 0.00010 |
INHBB | NM_002193 | inhibin, beta B (activin AB beta polypeptide) | 3.32 | 0.00059 |
TCF7L1 | NM_031283 | transcription factor 7-like 1 (T-cell specific, HMG-box) | 3.14 | 0.00073 |
EPC2 | NM_053001 | enhancer of polycomb homolog 2 (Drosophila) | 2.95 | 0.00090 |
GATA1 | NM_002049 | GATA binding protein 1 (globin transcription factor 1) | 2.57 | 0.00082 |
KITLG | NM_000899 | KIT ligand | 2.50 | 0.00052 |
ERRFI1 | NM_018948 | ERBB receptor feedback inhibitor 1 | 2.45 | 0.00074 |
CADM1 | NM_014333 | cell adhesion molecule 1 | −22.84 | 0.00077 |
TREM2 | NM_018965 | triggering receptor expressed on myeloid cells 2 | −9.90 | 0.00017 |
ALOX5AP | NM_001629 | arachidonate 5-lipoxygenase-activating protein | −9.32 | 0.00017 |
PLA2G7 | NM_005084 | phospholipase A2, group VII (platelet-activating factor acetylhydrolase, plasma) | −7.66 | 0.00007 |
CD74 | NM_004355 | CD74 molecule, major histocompatibility complex, class II invariant chain | −7.28 | 0.00006 |
MADCAM1 | NM_130760 | mucosal vascular addressin cell adhesion molecule 1 | −6.53 | 0.00004 |
CD14 | NM_130760 | CD14 molecule | −5.94 | 0.00038 |
CTSA | NM_000308 | cathepsin A | −3.29 | 0.00068 |
CTSC | NM_001814 | cathepsin C | −2.97 | 0.00085 |
A. ENRICHED GENE CLUSTERS | ||
---|---|---|
Gene group 1: Transcription Factors Enrichment Score: 1.78 | ||
1 | TCF7L1 | transcription factor 7-like 1 (T-cell specific, HMG-box) |
2 | SNAI2 | snail homolog 2 (Drosophila) |
3 | CNOT4 | CCR4-NOT transcription complex, subunit 4 |
4 | ZBTB10 | zinc finger and BTB domain containing 10 |
5 | KLF12 | Kruppel-like factor 12 |
6 | ZFPM2 | zinc finger protein, multitype 2 |
7 | STAT4 | signal transducer and activator of transcription 4 |
8 | OSR2 | odd-skipped related 2 (Drosophila) |
9 | IKZF2 | IKAROS family zinc finger 2 (Helios) |
10 | PHF6 | PHD finger protein 6 |
11 | ZFHX4 | zinc finger homeobox 4 |
12 | SOX11 | SRY (sex determining region Y)-box 11 |
13 | CITED4 | Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 4 |
14 | ARNTL | aryl hydrocarbon receptor nuclear translocator-like |
15 | NFIB | nuclear factor I/B |
16 | GATA1 | GATA binding protein 1 (globin transcription factor 1) |
17 | ETS | v-ets erythroblastosis virus E26 oncogene homolog 1 (avian) |
18 | LEF1 | lymphoid enhancer-binding factor 1 |
Gene group 2: Adhesion Molecules Enrichment Score: 1.71 | ||
1 | HLA-DPB1 | major histocompatibility complex, class II, DP beta 1 |
2 | MADCAM1 | mucosal vascular addressin cell adhesion molecule 1 |
3 | TREM2 | triggering receptor expressed on myeloid cells 2 |
4 | EFNB2 | ephrin-B2 |
5 | IGSF6 | immunoglobulin superfamily, member 6 |
6 | LRFN5 | leucine rich repeat and fibronectin type III domain containing 5 |
7 | DSCAM | Down syndrome cell adhesion molecule |
8 | JAM2 | junctional adhesion molecule 2 |
9 | MDGA1 | MAM domain containing glycosylphosphatidylinositol anchor 1 |
Gene group 3: Homeobox Genes Enrichment Score: 1.51 | ||
1 | PKNOX2 | PBX/knotted 1 homeobox 2 |
2 | MEOX2 | mesenchyme homeobox 2 |
3 | SPIC | Spi-C transcription factor (Spi-1/PU.1 related) |
4 | IRX2 | iroquois homeobox 2 |
5 | EMX2 | empty spiracles homeobox 2 |
B. KEGG PATHWAYS
| ||
Upregulated in SP
| ||
Number of genes | genes | |
Arrhythmogenic rightventricular cardiomyopathy | 4 | GJA1, ITGB3, LEF1, TCFL1 |
Pathways in cancer | 6 | TCF7L1, KITL, FASL, LEF1, FGF7, ETS1 |
Adherens junction | 3 | LEF1, SNAI2, TCF7L1 |
Downregulated in SP
| ||
Number of genes | genes | |
Lysosome | 3 | CTSA, CTSC, SLC11A1 |
Cell adhesion molecules (CAMs) | 3 | CADM1, HLA-DPB1, MADCAM1 |