Abstract
LGR5 marks resident adult epithelial stem cells at the gland base in the mouse pyloric stomach1, but the identity of the equivalent human stem cell population remains unknown owing to a lack of surface markers that facilitate its prospective isolation and validation. In mouse models of intestinal cancer, LGR5+ intestinal stem cells are major sources of cancer following hyperactivation of the WNT pathway2. However, the contribution of pyloric LGR5+ stem cells to gastric cancer following dysregulation of the WNT pathway—a frequent event in gastric cancer in humans3—is unknown. Here we use comparative profiling of LGR5+ stem cell populations along the mouse gastrointestinal tract to identify, and then functionally validate, the membrane protein AQP5 as a marker that enriches for mouse and human adult pyloric stem cells. We show that stem cells within the AQP5+ compartment are a source of WNT-driven, invasive gastric cancer in vivo, using newly generated Aqp5-creERT2 mouse models. Additionally, tumour-resident AQP5+ cells can selectively initiate organoid growth in vitro, which indicates that this population contains potential cancer stem cells. In humans, AQP5 is frequently expressed in primary intestinal and diffuse subtypes of gastric cancer (and in metastases of these subtypes), and often displays altered cellular localization compared with healthy tissue. These newly identified markers and mouse models will be an invaluable resource for deciphering the early formation of gastric cancer, and for isolating and characterizing human-stomach stem cells as a prerequisite for harnessing the regenerative-medicine potential of these cells in the clinic.
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Data availability
Microarray data that support the findings of this study have been deposited in the Gene Expression Omnibus (GEO) under accession code GSE121803. RNA-seq data of AQP5+ and AQP5− human samples have also been deposited in the GEO, under accession code GSE133036. Source Data for Figs. 1–4 and Extended Data Figs. 1, 2, 4–6, 9 are provided with the paper. Any other relevant data supporting the findings of this study are available from the corresponding author on reasonable request.
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Acknowledgements
The authors thank staff at the IMB-IMU and the SBIC-Nikon Imaging Centre for imaging assistance; the research coordination team and Department of Pathology at NUH for assistance with human samples; S. Sagiraju for assistance with animal experiments; A. Lin and A. Ng for empirical candidate validation; K. Saito for assistance with RNA-seq preparation; M. Taniguchi and K. Kita for assistance with FACS; D. H. Alpers for providing the GIF antibody; A. van Oudenaarden and A. Lyubimova for assistance with CEL-seq and RaceID; and F. de Sauvage for providing the Lgr5-DTR-eGFP mice. N.B. is supported by the Agency for Science, Technology and Research (A*Star), Singapore Gastric Cancer Consortium (SGCC) and Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Number 17H01399. This research is supported by Singapore Ministry of Health’s National Medical Research Council under its Open Fund-Young Individual Research Grant (NMRC/OFYIRG/0007/2016) and the National Research Foundation Singapore (Investigatorship Program award no. NRF-NRF12017-03).
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S.H.T and Y.S. contributed to all aspects of the study: they designed, performed all empirical experiments, collected and analysed data, and wrote the manuscript. S.T. designed and performed experiments, and collected and analysed data for profiling and validation studies for candidate-marker identification. J.G. performed immunostaining, CEL-seq experiments and mouse husbandry. R.S. provided advice and technical help with human and mouse cancer, analysed data and wrote the manuscript. K.M. performed FACS and immunostaining for human AQP5 FACS experiments. P.P. performed immunostaining and mouse husbandry. L.T.T. performed mouse husbandry. E.W. generated the trangsenic mouse lines. T.S. and S.W.T.H. analysed human cancer data in pathway analysis. S.L.I.J.D. analysed microarray, CEL-seq and RNA-seq data. S.M. performed FACS experiments. A.F. provided advice and technical help with human experiments and mouse cancer models. M.O., T.T., H.I.G., S.S., M.T., K.G.Y., J.S. and A.S. provided patient samples. H.I.G., S.S. and M.T. analysed and scored stained patient samples. P.T. designed and supervised cancer frequency analysis. N.B. supervised the project, analysed the data and wrote the manuscript. All authors discussed results and edited the manuscript.
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N.B. and S.H.T. are co-inventors on the provisional patent application 10201911742W titled ‘A method for functional classification and diagnosis of cancers’. This patent covers the analysis of human cancers using their signalling pathway statuses. All the other authors declare no competing interests.
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Extended data figures and tables
Extended Data Fig. 1 Comparative profiling of LGR5 populations in gastrointestinal tissues identifies new pyloric-specific markers.
a–c, FACS strategy sorting eGFPhigh and eGFPlow cells from Lgr5-eGFP-IRES-creERT2 pylorus (a), small intestine (b) and colon (c). d, Lgr5 expression (by qPCR) in sorted populations and unsorted tissues of the gastrointestinal tract. Data are represented as mean ± s.e.m. n = 4 biological replicates; one-way ANOVA. e, AQP5 protein expression in the mouse stomach through to the duodenum by immunostaining. n = 3 biological replicates. f–i, Aqp5 mRNA expression in the corpus (f), Brunner’s glands (g), small intestine (h) and colon (i) by ISH. n = 3 biological replicates. j–n, A4gnt (j), Gif (k), Muc6 (l), Slc9a3 (m) and Spp1 (n) expression in the corpus, Brunner’s glands, small intestine and colon by qPCR, ISH and co-ISH with LGR5. For histology experiments, n = 3; for qPCR, n = 4 biological replicates for Gif, Muc6 and Slc9a3 qPCRs, for which data are represented as mean ± s.e.m., n = 2 technical replicates from a pooled sample of 8 for A4gnt and Spp1 qPCRs. Scale bars, 500 μm (e), 20 μm (f–n).
Extended Data Fig. 2 AQP5 marks the major subpopulation of LGR5high pyloric stem cells.
a, Exon 1 knock-in gene strategy to generate EGFP–CreERT2 reporters of Aqp5, A4gnt, Slc9a3 and Spp1 expression. b, The 3′ UTR knock-in gene strategy to generate 2A–eGFP, 2A–CreERT2 or 2A–DTR reporters of Aqp5, Slc9a3 and Lgr5 expression. c–f, eGFP signal in the pylorus and small intestine of Aqp5-2A-eGFP (c, d) and Slc9a3-2A-eGFP mice (e, f). g, h, Quantification of the overlap between eGFP+ cells and AQP5+ cells in Slc9a3-2A-eGFP pylori (g) (n = 102 glands from 3 mice) and a representative image of the immunostaining (h). Results are presented as mean ± s.e.m. i, j, Quantification of overlap between LGR5–eGFP+ cells with AQP5+ cells (i) (n = 117 glands from 4 mice) and a representative image of the immunostaining (j). Results are presented as mean ± s.e.m. k–m, Colocalization of LGR5–eGFP in the pylorus with GIF (k), GAST (l) and CHGA (m). n = 3 biological replicates. n, t-distributed stochastic neighbour embedding (t-SNE) map of single LGR5–eGFPhigh cells from the pylorus. n = 285 cells from 3 mice. o–s, t-SNE maps showing enrichment of candidate markers in major (o–q) and minor (r, s) subpopulations of LGR5high pyloric cells. n = 285 cells from 3 mice. t, Frequency of 10 published proliferation markers (Bcl2, Ccnd1, Ckap2, Foxm1, Ki67, Mcm2, Mybl2, Plk1, Rrm2 and Top2a) in major versus minor subpopulations, compared by two-tailed Mann–Whitney test. n = 285 cells from 3 mice, 248 cells in major, 8 cells in minor-1 and 29 cells in minor-2 populations. u, v, Aqp5 (u) and Lgr5 (v) expression in cells sorted from Aqp5-eGFP-IRES-creERT2 pylori. Mean ± s.e.m., n = 4 biological replicates. w, x, Co-immunostaining for eGFP driven by Aqp5-eGFP-IRES-creERT2 and endogenous AQP5 (w) and KI67 (x). n = 3 mice. Scale bars, 50 μm (g, h), 25 μm (k, m, w, x).
Extended Data Fig. 3 AQP5 and other newly identified pyloric markers label pyloric stem cells, but not other gastrointestinal stem cells, in vivo.
a–p, Lineage tracing in A4gnt-, Aqp5-, Spp1- and Slc9a3-eGFP-IRES-creERT2 mice crossed with tdTomatoLSL reporter mice after a short trace (20–48 h) in the pylorus (a–d) and small intestine (i–l), and a long trace (>3 months) in the pylorus (e–h) and small intestine (m–p). n = 3 mice per genotype. q–x, Lineage tracing in pylorus (q–t) and small intestine (u–x) of the Aqp5-2A-creERT2 and Slc9a3-2A-creERT2 mice after a short trace (q–r, u, v) and a long trace (s, t, w, x). y, z, a′, b′, Whole-mount imaging of pylorus from induced Aqp5-eGFP-IRES-creERT2;tdTomatoLSL mice 20 h (y) and 6 months (z) after induction. Whole-mount imaging of pylorus from uninduced 8-week-old (a′) and 8-month-old (b′) Aqp5-eGFP-IRES-creERT2;tdTomatoLSL mice. n = 3 mice per condition. tdTomato (dTom) signal through the entire height of the pyloric epithelium is shown, and DAPI from the upper parts of pyloric glands is depicted for clarity. c′, d′, e′, tdTomato signal in clusters of glands in 1-year-traced pylorus (c′) and small intestine (d′, e′). f′, g′, h′, tdTomato expression in gastric corpus (f′), colon (g′) and Brunner’s glands (h′) 20 h and 6 months after induction. n = 3 biological replicates. Scale bars, 50 μm.
Extended Data Fig. 4 Detailed characterization of AQP5-expressing pyloric cells by transcriptomic profiling, in vivo ablation and ex vivo organoid culture.
a, AQP5+ gating strategy with cells from wild-type pylorus stained only with propidium iodide. b, Heat map of transcriptomes from AQP5+ and AQP5− cells. n = 4 biological replicates. c, Gene set enrichment analysis comparing the degree of overlap between transcriptomes of AQP5+ cells and LGR5+ cells from the pylorus using Kolmogorov–Smirnov statistic. n = 4 biological replicates each. d, e, Relative Aqp5 (d) and Lgr5 (e) expression (from microarray) in AQP5+ and AQP5− cells (n = 4 biological replicates), by one-way ANOVA in the Partek analysis software. f–h, Relative expression of various pyloric markers (f), other published pyloric stem cell markers (g) and lineage and proliferation markers (h) in AQP5+ population versus AQP5− population in microarray. n = 4 biological replicates. Data are represented as mean, as derived from Partek analysis software by one-way ANOVA. i, j, AQP5 staining in a whole-mount organoid (i) and AQP5 colocalization with KI67 (j) in an organoid section. Organoids were derived from single AQP5+ cells. n = 3 biological replicates. k–r, Pylori of diphtheria-toxin-treated wild-type (k–n) and Aqp5-2A-DTR (o–r) mice stained for H & E (k, o), E-cadherin (l, p), GIF (m, q) and GAST (n, r). n = 3 biological replicates. s–u, Outgrowth efficiency of AQP5+, AQP5−, LGR5–eGFP+, LGR5–eGFP− cells (s) n = 5 biological replicates for AQP5+ and AQP5− cells, n = 3 biological replicates for eGFP+ and eGFP− cells from Lgr5-2A-eGFP pylori. Representative images of organoids derived from eGFP+ (t) and eGFP− (u) cells from Lgr5-2A-eGFP pylori. Paired two-sided t-test. Scale bars, 25 μm (i, j), 50 μm (k–r), 500 μm (t, u).
Extended Data Fig. 5 AQP5 is expressed at human pyloric gland bases together with other pyloric markers, and facilitates the isolation of human pyloric stem cells.
a–f, a′, b′, c′, d′, e′, f′, MUC6 (a, b, a′, b′), A4GNT (c, d, c′, d′) and SLC9A3 (e, f, e′, f′) expression (co-ISH with LGR5 and immunostaining) in normal human pylorus. n = 3 biological replicates. g–j, Co-ISH to colocalize AQP5 with PEPC (g), MUC6 (h), GIF (i) and MUC5AC (j) pyloric lineage markers. n = 3 biological replicates. k, l, AQP5 labelling in whole-mount human organoids (k) and AQP5 colocalization with KI67 (l) in organoid sections. n = 3 biological replicates. m–o, Relative AXIN2 (m), TFF2 (n) and AQP5 (o) expression in AQP5+ cell-derived organoids three days after WNT3A, Noggin and FGF10 withdrawal, by qPCR. n = 3 biological replicates. Scale bars, 100 μm (a–j, l), 25 μm (a′ b′, c′, d′, e′, f′, k).
Extended Data Fig. 6 Profiling and validation of the transcriptome of the human pyloric AQP5-expressing population.
a–e, qPCR validation (green) (n = 5 biological replicates) and RNA-seq values (blue) (n = 8 biological replicates) of homologues of mouse stem cell markers (a), membrane components (b), chemokine signalling components (c), extracellular matrix components (d) and other genes (e). Two-sided Mann–Whitney test was used to determine statistical significance of qPCR result differences for all genes except AQP5, which was determined by two-tailed paired t-test. qPCR and RNA-seq results are presented as mean. f, f′, f′′, ISH of SMOC2 (brown) on normal human pylorus. f′ is a magnified inset of surface mucosa, and f′′ is a magnified inset of gland base. n = 4 biological replicates. Scale bars, 100 μm (f), 10 μm (f′, f′′). g, Top 10 Panther pathways enriched with the most candidate genes.
Extended Data Fig. 7 WNT, PI3K and KRAS pathways are commonly co-dysregulated in human distal gastric cancers.
a, b, Co-hyperactivation status of the WNT, PI3K and KRAS pathways in human distal gastric cancer samples from TCGA3 (a) (n = 155) and GSE1545916 (b) (n = 42) datasets. Heat maps show distribution of pathway hyperactivation status across samples. Graphs depict distribution of μ scores (degree of signalling activity) of normal and tumour samples for each of the pathways we examined.
Extended Data Fig. 8 Targeted conditional mutation of pyloric stem cells using our mouse models selectively drives tumour formation in the distal stomach.
a, Sample sizes, tumour and invasion incidences observed in various permutations of creERT2 drivers and oncogenic alleles. b–g, Whole-mount and H & E images of entire pyloric regions for each creERT2-oncogenic-allele combination. h–l, H & E images of pylori from multiple-pyloric-marker-creERT2;KrasLSL-G12D models (h, i), APK-only model (without creERT2 driver) (j), and small intestine (k) and colon (l) from Aqp5-IRES-creERT2 APK mouse model of gastric cancer. Scale bars, 1 cm (whole-mount insets in b–g), 200 μm (H & E images in b–l).
Extended Data Fig. 9 Phenotypic characterization of Aqp5-IRES-creERT2 APK and Slc9a3-2A-creERT2 AP distal stomach tumours.
a–g, Immunostaining of various markers in Aqp5-IRES-creERT2 APK pyloric tumour. h, h′, h′′, Co-ISH of AQP5 and LGR5 in tumour region; region in black box in h is magnified in h′. Dual ISH of AQP5 and LGR5 in an adjacent normal pyloric region from the same mouse (h′′). i, i′, Representative H & E stain of a salivary gland tumour from Aqp5-IRES-creERT2 APK mouse. j–o, Immunostaining of various markers in Slc9a3-2A-creERT2 AP pyloric tumour. p–w, Immunostaining of various markers in the APK-only (no creERT2) control pyloric stomach. x, x′, Colocalization of eGFP and endogenous AQP5 protein in pyloric tumour from an Aqp5-IRES-creERT2 APK mouse. y, z, Control FACS gating for eGFP+ cells using normal Aqp5-eGFP-IRES-creERT2 (y) and wild-type (z) pylori. n = 3 biological replicates. y, z, z′, z′′, Organoid assay for stemness of AQP5–eGFP+ tumour cells. n = 3 biological replicates. y, Experimental timeline. FACS gating strategy to isolate eGFP+ tumour cells from Aqp5-creERT2; APK pyloric tumour (z), eGFP+ cells from normal Aqp5-eGFP-IRES-creERT2 pylorus (z′), and control GFP gating with wild-type pylorus (z′′). Scale bars, 100 μm (a–g, i–x, h′, i′, x′), 20 μm (h′′).
Extended Data Fig. 10 AQP5 expression is commonly dysregulated in human distal gastric cancers.
a, Summary of AQP5 expression in a tumour microarray panel of 145 cores of human distal gastric cancer. AQP5 expression is scored as positive if observed in >5% of malignant cells. b–e, Examples of AQP5+ cores with intestinal (b, c) and diffuse (d, e) subtypes, often with cytoplasmic and/or membranous staining. f, Summary of AQP5 expression from 54 full sections of distal human gastric cancer. *Mixed refers to AQP5 localization in cytoplasm and nucleus, or cytoplasm and membrane. g–n, AQP5 expression in intestinal (g, h, k, l) and diffuse (i, j, m, n) subtypes. Yellow arrowheads indicate cells co-expressing AQP5 and KI67. o, Summary of other observations of AQP5 expression in full gastric tumour sections. p–s, AQP5 expression in the invasive edge of the tumour (p), intestinal metaplasia (IM) (q) (dotted lines denote intestinal metaplasia region that is negative for AQP5), Signet ring cells (r) (black arrows denote cells with weak AQP5 expression) and tumour cells in lymph node metastasis (s). Scale bars, 20 μm (g–n, q, r), 50 μm (b–e, p, s).
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Tan, S.H., Swathi, Y., Tan, S. et al. AQP5 enriches for stem cells and cancer origins in the distal stomach. Nature 578, 437–443 (2020). https://doi.org/10.1038/s41586-020-1973-x
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DOI: https://doi.org/10.1038/s41586-020-1973-x
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