Endometrial disorders represent a major gynaecological burden. Current research models fail to recapitulate the nature and heterogeneity of these diseases, thereby hampering scientific and clinical progress. Here we developed long-term expandable organoids from a broad spectrum of endometrial pathologies. Organoids from endometriosis show disease-associated traits and cancer-linked mutations. Endometrial cancer-derived organoids accurately capture cancer subtypes, replicate the mutational landscape of the tumours and display patient-specific drug responses. Organoids were also established from precancerous pathologies encompassing endometrial hyperplasia and Lynch syndrome, and inherited gene mutations were maintained. Endometrial disease organoids reproduced the original lesion when transplanted in vivo. In summary, we developed multiple organoid models that capture endometrial disease diversity and will provide powerful research models and drug screening and discovery tools.
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RNA-seq data were deposited in the Gene Expression Omnibus with accession number GSE118928. Raw sequencing reads of shallow-seq and WES have been deposited in the ArrayExpress database at EMBL−EBI (www.ebi.ac.uk/arrayexpress) under accession numbers E-MTAB-7687 and E-MTAB-7688, respectively. Source data for Fig. 1b–d,g, Fig. 3b–d, Fig. 4b, Fig. 5a,c, Fig. 6a–d, Supplementary Fig. 1d,g-i, Supplementary Fig. 2b, Supplementary Fig. 3c,d, Supplementary Fig. 5d,e,g and Supplementary Fig. 6d−g reported in this study are provided as supplementary source data tables in Supplementary Table 12. All other data supporting the findings of this study are available from the corresponding authors on reasonable request. Unique biological materials can be made available to third parties depending on their research goals (that is, an absence of a conflict of interest), mutual ethical permissions and a Material Transfer Agreement.
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We thank our other colleagues (H.V. group: Y. Van Goethem; Stem Cell Institute: A. Santo Ramalho Venâncio; D. Costamagna; P. Peetermans) for their valuable input and technical help. We are also grateful to J. Laureys (Department of Clinical and Experimental Medicine, KU Leuven) and K. Eggermont for their expert help in mouse transplantation experiments, and to the patients, staff and nurses at UZ Leuven for providing the clinical samples. We thank the VIB Nucleomics Core and KU Leuven Genomics Core (particularly Á. Calabuig) for their expert assistance in RNA-seq and aCGH analysis. We are also grateful to InfraMouse (VIB−KU Leuven, Hercules type 3 project ZW09-03) for the use of histological instruments and microscopes. Finally, we acknowledge the use of the Electron Microscopy Platform of the Centre for Human Genetics (VIB−KU Leuven). This work was supported by grants from the KU Leuven Research Fund and from the FWO−Flanders (Belgium). A.H., I.V.Z. and B.C. are supported by a PhD Fellowship from the FWO. M.B. is a PhD Fellow supported by a GOA grant from the Research Fund of the KU Leuven. D.T. is a Senior Clinical Investigator of the FWO.
The authors declare no competing interests.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Integrated supplementary information
Supplementary Figure 1 Long-term expandable organoids can be established from endometriosis at all stages.
(a) Flowchart depicting organoid establishment from the indicated spectrum of endometrial diseases, downstream analyses and biobanking. (b) Brightfield pictures of development of EM-O and matched ECT-O and EUT-O after seeding (P0). Representative pictures of 3 independent experiments (that is 3 independent donors per condition) are shown. Scale bar, 200 µm. (c) Representative brightfield pictures showing clonal ECT-O formation. Arrow indicates a single cell monitored for 20 days (n=3 biologically independent experiments). Boxed area is magnified. Scale bars, 50 µm. (d) Passaging time of EM-O (3 independent donors) and of matched EUT-O/ECT-O (3 other independent donors), as monitored for 6 passages. Box plot depicts mean, minimum and maximum per individual organoid line. (e) Brightfield and H&E images of organoids derived from rASRM stage I to IV endometriosis. Representative pictures of 3 independent donors per rASRM stage are shown. Scale bars, 200 µm for brightfield and 50 µm for H&E. (f) aCGH plots of short-term (1–2 months; low passage) and long-term (4–6 months; high passage) cultured EM-O and EUT-O. Representative plots of 3 independent experiments are shown. (g) Gene expression analysis of endometrial markers in ECT-O and EM-O after short- and long-term culture, presented as ΔCt (Ct of gene – Ct of GAPDH) (mean ± s.e.m. of n=3 biologically independent experiments). (h) Rescue of IWP2-induced organoid growth inhibition represented as percentage of organoids formed after 10 days with the indicated treatment as compared to SOM (left graphs), and gene expression analysis of canonical (middle) and non-canonical (right) WNT target genes in ECT-O (top) (mean ± s.e.m of n=5 biologically independent experiments) and EM-O (bottom) (mean ± s.e.m of n=4 biologically independent experiments). *P<0.05, **P<0.01, P***<0.001; non-parametric Kruskal-Wallis test for multiple comparison with Dunn’s post-test (95% confidence intervals). (i) WNT ligand gene expression in ECT-O as determined by RT-qPCR and represented as ∆Ct (Ct of gene – Ct of GAPDH) (mean ± s.e.m of 8 independent donors) (left) and as extracted from the RNA-seq dataset and presented as heatmap of transcript per million values (right) in which colors range from white (low) to red (high).
(a) H&E analysis of matched EUT-O and ECT-O. Representative pictures of 5 independent experiments (that is 5 independent donors per condition) are shown. Scale bar, 50 µm. (b) Immunohistochemical analysis of MMP2 and MMP7 in primary peritoneal endometriotic lesions and ECT-O. Representative pictures of 4 independent experiments (that is 4 independent donors per condition) are shown. Scale bar, 50 µm. Gene expression of MMP2 and MMP7, as normalized to GAPDH and expressed as fold change relative to EM-O (mean ± s.e.m. of n=4 biologically independent experiments). *P=0.0286 as compared to EM-O; two-tailed non-parametric T-test (95% confidence intervals). (c) E-cadherin immunofluorescence staining of ECT-O showing the epithelial nature and correct positioning of tight junctions which supports the cells’ polarization. Representative pictures of 5 independent experiments (that is 5 independent donors) are shown. Scale bar, 10 µm. (d) TEM pictures of matched EUT-O and ECT-O from an individual patient. The EUT-O are composed of a single-cell layer bordering a lumen, containing microvilli (magnified box) and ciliated cells (as revealed by acetylated (Ac) α-tubulin immunofluorescence), whereas a stratified, double-cell layer (*) is present in the ECT-O with extensive microvilli (magnified box) and ciliated cells. Representative pictures of 3 independent experiments (that is 3 independent donors per condition) are shown. Scale bars, 10 µm. (e) ECT-O, subrenally transplanted according to the schedule, give rise to lesions with endometriotic features. H&E images and immunohistochemical analysis for ERα and PR of the kidney capsule and ECT-O grafts are presented. Lower panels display H&E staining of the non-grafted kidney, lacking any lesion. Representative pictures of 6 biologically independent experiments with 4 independent donors are shown. Scale bar, 200 µm.
Supplementary Figure 3 Transcriptomic analysis of endometriotic organoids reveals disease-specific pathways and genes.
(a) PCA plot showing the distribution of EM-O, EUT-O and ECT-O, based on the RNA-seq data (n=4 independent donors for EM-O and EUT-O, n=7 independent donors for ECT-O). (b) Diagram of the differentially expressed genes in EM-O, EUT-O and ECT-O as identified by RNA-seq analysis. Of the 277 differentially expressed genes between EM-O/EUT-O and ECT-O, 34 are specifically expressed in EM-O/EUT-O and 243 in ECT-O. Of the 35 differentially expressed genes between EM-O and EUT-O, 15 are specifically expressed in EM-O and 20 in ECT-O (see Supplementary Tables 3–5). Relevant genes are indicated. (c) Expression of WNT ligand and Hippo pathway target genes in stage I to IV ECT-O as normalized to GAPDH and expressed as fold change relative to EM-O (mean ± s.e.m. of n=3 biologically independent experiments for stage I and IV ECT-O, n=5 for stage II ECT-O and n=4 for stage III ECT-O). *P<0.05; non-parametric Kruskal-Wallis test for multiple comparison with Dunn’s post-test (95% confidence intervals). (d) Expression of invasion and inflammatory marker genes in stage I to IV ECT-O as normalized to GAPDH and expressed as fold change relative to EM-O (mean ± s.e.m. of n=3 biologically independent experiments for stage I and IV ECT-O, n=5 for stage II ECT-O and n=4 for stage III ECT-O). *P<0.05; non-parametric Kruskal-Wallis test for multiple comparison with Dunn’s post-test (95% confidence intervals). (e) PCA plot showing the distribution of matched EUT-O and ECT-O, based on the RNA-seq data (n=4 independent donors for the EUT-O and matched ECT-O). (f) Heatmap of 75 differentially expressed genes (log2 normalized counts) as identified by RNA-seq analysis of 4 matched ECT-O and EUT-O organoid lines as indicated. Colors range from blue (low expression) to red (high expression). LGR6 is among the top upregulated genes in the ECT-O.
Supplementary Figure 4 Organoids from endometrial pre-cancer lesions display disease-associated phenotype.
(a) Organoid development from hyperplastic endometrium (HYP-O) after seeding (P0). Representative brightfield pictures of 6 independent experiments (that is 6 independent donors) are shown. Overview (left; scale bar, 200 µm) and magnified organoid pictures (right; scale bar, 50 µm) are presented. (b) H&E analysis, immunohistochemical examination of ERα, PR and P53, and mucin detection (PAS) in primary biopsies and corresponding HYP-O of different types of endometrial hyperplasia as indicated. H&E staining reveals glandular-like morphology with a well-defined lumen in the organoids of simple benign and complex atypical hyperplasia and a poorly-defined lumen in hyperplastic polyp. P53 expression, being present in simple benign hyperplasia and endometrial polyp but absent in complex atypical hyperplasia, is reproduced in the matching organoids. Mucus production is only detected in the lumen of the endometrial polyp and derived organoids (*). Representative brightfield pictures of 2 independent donors for hyperplastic polyp and 3 independent donors for the other hyperplasia types are shown. Scale bars, 50 µm. (c) TEM analysis reveals some stratified epithelium (*). Microvilli are present while cilia are not observed (magnified box). Representative pictures of 3 independent experiments (that is 3 independent donors) are shown. Scale bars, 10 µm. (d) aCGH plots indicate the absence of SCNA in both primary hyperplastic tissue and corresponding HYP-O. Representative plots of 3 independent experiments (that is 3 independent donors) are shown.
(a) EC-O development. Representative pictures of 6 independent experiments (donors). Scale bars, 50 µm. (b) EC-O cultures (P0). Representative pictures of 3 independent donors. Scale bars, 200 µm. (c) aCGH plot of tumor and corresponding organoids, and culture image (n=3 independent donors). (d) Medium optimization. Representative pictures (top) and bar graph (bottom) displaying organoid numbers formed in absence (“-“) of indicated compounds (line and dashed line: SOM for EC-O and HYP-O, respectively) (mean ± s.e.m. of n=3 independent experiments). *P<0.05 among HYP-O as compared to SOM; non-parametric Kruskal-Wallis test with Dunn’s post-test (95% confidence intervals). (e) Organoid passageability (left) (mean ± s.e.m of n=4 independent experiments) and passaging time as monitored for 6 passages (right) (3 independent donors per condition). Box plot depicts mean, minimum and maximum. (f) Representative pictures showing long-term EC-O passaging (n=3 independent donors; magnified organoid in inset). Scale bars, 200 µm (brightfield) and 50 µm (H&E). (g) Clonogenicity (mean organoid numbers for 3 independent donors per group). (h) Different EC-O morphologies (representative pictures of 10 independent cultures). (i) TEM of EC-O showing nuclear abnormalities. Representative pictures of 2 independent experiments. Scale bars, 5 µm. (j) Immunohistochemistry of EC markers and mucin detection (PAS) in primary tumors and corresponding EC-O (each performed in triplicate for 10 independent donors). Scale bars, 50 µm. (k) Flowchart of genomic screen performed on EC-O and primary tumors. (l) aCGH (left) and shallow-seq plot (right), representative of n=8 and n=5 independent donors, respectively. (m) Matrix of SCNA in primary tumor and corresponding organoids. EC-O_12 and EC-O_17 were overtaken by healthy cells (“EC → EM-O”). (n) Genetic aberrations in primary tumors and EC-O. (o) Immunofluorescence of β-catenin in EC-O (n=3 independent donors). Scale bars, 50 µm. Representative pictures of EC-O lines harboring CTNNB1 mutations (EC-O_3), or not (EC-O_6, EC-O_7), cultured in SOM ± XAV939 (n=3 independent donors). Scale bars, 200 µm. (p) Distance matrix based on gene expression data (Supplementary Table 9), from white (identical) to red (divergent). (q) PCA plot based on gene expression analysis (n=4 independent donors for EM-O and HYP-O, n=8 for EC-O, n=4 for primary tumors).
Supplementary Figure 6 EC-derived organoids are amenable to in vivo growth, drug screening, ion channel exploration and biobanking.
(a) Histological analysis of endometrial (cancer) markers in primary EC samples and EC-O-derived xenografts. Representative pictures of n=5 independent donors. Scale bars, 50 µm. (b) Macroscopic pictures of the uterine horns after orthotopic transplantation of samples as indicated (* indicates the non-affected part of the uterine horn). Representative pictures of experiments with 5 independent donors. (c) Immunohistochemical examination of the uterine grafts for the markers indicated. Representative pictures of experiments with 5 independent donors. Scale bars, 50 µm. (d) IC50 of indicated drugs determined from the dose-response curves (Fig. 6a). (e) Gene expression of ion channels in EUT-O and ECT-O subdivided into different rASRM stages, as normalized to the geometric mean of housekeeping genes HPRT1 and PGK1 and expressed as fold change relative to EM-O (mean (± s.e.m. if n≥3) of n=5 EM-O, n=2 EUT-O stage I-II, n=3 EUT-O stage III-IV, n=5 ECT-O stage I-II and n=5 ECT-O stage III-IV independent donors). **P<0.01 compared to EM-O; two-way ANOVA and Dunn’s multiple comparison test. (f) Percentage of responding cells in EM-O, EUT-O and ECT-O to specific ion channel activators. The data represent the following n independent experiments encompassing the indicated total number of cells: GSK in EM-O: n=6, 339 cells; GSK in EUT-O: n=5, 905 cells; GSK in ECT-O: n=4, 458 cells; OAG in EM-O: n=6, 726 cells; OAG in EUT-O: n=4, 772 cells; OAG in ECT-O: n=5, 535 cells; THC in EM-O: n=6, 706 cells; THC in EUT-O: n=4, 959 cells; THC in ECT-O: n=4, 541 cells. (g) Gene expression of ion channels in HYP-O and EC-O, the latter subdivided into non-invasive (N-IN) and invasive (IN) phenotypes, as normalized to HPRT1 and PGK1 and expressed as fold change relative to EM-O (mean ± s.e.m. of n=5 EM-O, n=4 HYP-O, n=3 EC-O N-IN and n=4 EC-O IN independent donors). *P<0.05, **P<0.01, ***P<0.001 compared to EM-O; two-way ANOVA and Dunn’s multiple comparison test. (h) EC-O biobanking with representative organoid line ID card.
Supplementary Figs. 1–6, Supplementary table titles/legends and Supplementary video titles/legends.
Endometrial organoid biobank.
SOM for healthy, eutopic, ectopic and hyperplastic endometrium.
List of genes differentially expressed between EM-O and ECT-O.
List of genes differentially expressed between EUT-O and ECT-O.
List of genes differentially expressed between EM-O and EUT-O.
Top divergent pathways between ECT-O and EM-O as identified by KEGG PATHWAY analysis using the 277 differentially expressed genes.
Top divergent biological terms between ECT-O and EM-O as identified by DAVID Gene Ontology enrichment using the 277 differentially expressed genes.
Optimized culture medium for EC-O formation and expansion.
RT−qPCR gene expression analysis of organoid lines derived from multiple endometrial conditions.
List of antibodies for immunostaining.
List of primers for qPCR.
Statistics source data.
z-stacks (up to 350 µm) from the bottom to the top of nuclear Hoechst-stained EM-O acquired using two-photon microscopy displaying a single-cell layer surrounding a central lumen.
z-stacks (up to 350 µm) from the bottom to the top of nuclear Hoechst-stained ECT-O acquired using two-photon microscopy displaying a stratified cell layer surrounding a central lumen.
z-stacks (up to 350 µm) from the bottom to the top of nuclear Hoechst- and membrane DiI-stained low-grade EC-O acquired using two-photon microscopy displaying a stratified cell layer and the presence of a lumen.
z-stacks (up to 350 µm) from the bottom to the top of nuclear Hoechst-stained high-grade EC-O combined with brightfield displaying a stratified cell layer and an absence of a lumen.
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Science Translational Medicine (2019)