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Visualization and targeting of LGR5+ human colon cancer stem cells

Nature volume 545, pages 187–192 (2017)Cite this article

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Abstract

The cancer stem cell (CSC) theory highlights a self-renewing subpopulation of cancer cells that fuels tumour growth. The existence of human CSCs is mainly supported by xenotransplantation of prospectively isolated cells, but their clonal dynamics and plasticity remain unclear. Here, we show that human LGR5+ colorectal cancer cells serve as CSCs in growing cancer tissues. Lineage-tracing experiments with a tamoxifen-inducible Cre knock-in allele of LGR5 reveal the self-renewal and differentiation capacity of LGR5+ tumour cells. Selective ablation of LGR5+ CSCs in LGR5-iCaspase9 knock-in organoids leads to tumour regression, followed by tumour regrowth driven by re-emerging LGR5+ CSCs. KRT20 knock-in reporter marks differentiated cancer cells that constantly diminish in tumour tissues, while reverting to LGR5+ CSCs and contributing to tumour regrowth after LGR5+ CSC ablation. We also show that combined chemotherapy potentiates targeting of LGR5+ CSCs. These data provide insights into the plasticity of CSCs and their potential as a therapeutic target in human colorectal cancer.

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Figure 1: Recapitulation of stem cell hierarchy using colon cancer organoids.
Figure 2: Lineage tracing of human LGR5+ CSCs.
Figure 3: Ablation of LGR5+ CSCs.
Figure 4: Lineage tracing of human KRT20+ CRC cells.

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Acknowledgements

This work was supported by the Project for Cancer Research And Therapeutic Evolution (P-CREATE) from the Japan Agency for Medical Research and Development (AMED), by a Grant-in-Aid for Scientific Research on Innovative Areas ‘Stem Cell Ageing and Disease’, and by Grants-in-Aid for Scientific Research funded by the Ministry of Education, Culture, Sports, Science and Technology of Japan. Y.O., M.F. and S.S. were supported by the Japan Society for the Promotion of Science Research Fellowships for Young Scientists. We also thank the Collaborative Research Resources, School of Medicine, Keio University for the technical assistance provided.

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Author notes

  1. Mariko Shimokawa and Yuki Ohta: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Gastroenterology, Keio University School of Medicine, Tokyo, Japan

    Mariko Shimokawa, Yuki Ohta, Shingo Nishikori, Mami Matano, Ai Takano, Masayuki Fujii, Shoichi Date, Shinya Sugimoto, Takanori Kanai & Toshiro Sato

  2. Fujii Memorial Research Institute, Otsuka Pharmaceutical Company, Limited, Shiga, Japan

    Shingo Nishikori & Shoichi Date

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  1. Mariko Shimokawa
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Contributions

M.S. performed genetic construction and genetic data analyses. Y.O. performed imaging analyses. S.N., A.T., S.D. and S.S. performed and analysed animal experiments. M.M. engineered organoids. M.F. established CRC organoids. T.K. provided clinical materials. T.S. conceived the project and designed experiments. M.S., Y.O., M.F. and T.S. wrote the manuscript.

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Correspondence to Toshiro Sato.

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S.N. and S.D. are employees of Otsuka Pharmaceutical Co., Ltd.

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Reviewer Information Nature thanks C. Blanpain, A. Ventura and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Figure 1 Generation of LGR5–GFP organoids.

a, Targeting strategy for the generation of LGR5–GFP organoids. The locations of PCR primers, restriction sites and loxP sites in the targeted and wild-type alleles are indicated. b, Gel electrophoresis of the PCR products from knocked-in organoids using the primers shown in a. Primer pairs a/b and c/e detected knock-in of the 5′ and 3′ arms, respectively. Primer pair d/e detected Cre-recombined alleles in the organoids treated with adenoviral-Cre. M, size marker; C, control organoids; KI, knock-in organoids. c, Left, Southern blot analyses with a 5′ external probe of NdeI/SacI-digested DNA with 4.6 kb size in control CCO. In the LGR5–GFP organoids, 2.0-kb bands appeared. Right, Southern blot with an internal probe against SacI-digested DNA from LGR5–GFP organoids authenticated locus-specific knock-in. d, Confocal images of LGR5–GFP organoids. Each organoid clone was derived from a different patient-derived clone as summarized in Supplementary Table 2. Scale bars, 25 μm.

Extended Data Figure 2 Generation of KRT20–GFP organoids.

a, Targeting strategy for the generation of KRT20–GFP organoids. The locations of PCR primers and loxP sites in the targeted and wild-type alleles are indicated. b, Gel electrophoresis of the PCR products from knocked-in organoids using the primers shown in a. Primer pairs a/b and c/e detected knock-in of the 5′ and 3′ arms, respectively. Primer pair d/e detected Cre-recombined alleles in the organoids treated with adenoviral-Cre. M, size marker; C, control organoids; KI, knock-in organoids. c, Confocal images of KRT20–GFP CCOs. Each organoid clone was derived from different patient-derived clones as summarized in Supplementary Table 2. Confocal image of LGR5–GFP/KRT20–tdTomato CCO7 (c, bottom right) GFP (green) and tdTomato (red) are visualized. Scale bars, 25 μm.

Extended Data Figure 3 Gene expression and histological expression pattern of LGR5+ CRCs.

a, b, Gene-set enrichment analysis (GSEA). Genes are ranked according to their differential expression between sorted LGR5–GFP+ and LGR5–GFP− CCO cells. GSEA confirmed significant enrichment of two independent intestinal stem cell signature gene sets17,38 in LGR5–GFP+ CCO cells (top). GSEA for KRT20–GFP+ and KRT20–GFP− cells show inverse correlation with the intestinal stem cell signature genes (bottom). FDR, false discovery rate; NES, normalized enrichment score. c, Immunostaining for the LGR5 reporter (green) and α-smooth muscle actin (αSMA, red) in xenografted (xeno) LGR5-reporter CCOs (top). LGR5 ISH (green) and immunostaining of αSMA (red) in the corresponding parental tissue samples (bottom). αSMA+ cells (red) are found adjacent to LGR5-reporter+ cells (top) or LGR5 mRNA (bottom) in the xenograft and the original patient samples, respectively. Nuclear counterstaining (Hoechst33342) is shown in white. Scale bars, 100 μm.

Extended Data Figure 4 Generation of LGR5-CreER organoids.

a, Targeting strategy for the generation of LGR5-CreER organoids. The locations of PCR primers and loxP sites in the targeted and wild-type alleles are indicated. b, Gel electrophoresis of PCR products from knocked-in organoids using the primers shown in a. Primer pair a/b detected knock-in of the 5′ arm. Primer pair c/e detected the Cre-recombined 3′ arm in the organoids treated with adenoviral-Cre. c, d, In vitro tracing of LGR5+ cells using LGR5-CreER/rainbow CCO12 (c) and CCO7 (d). Time (hours) after the tamoxifen treatment is indicated. Recombined clones are detected by dual (c) and quad (d) colour fluorescence reporters: nGFP (green), YFP (yellow), RFP (red) and mCFP (cyan). Scale bars, 20 μm.

Extended Data Figure 5 Lineage tracing of LGR5-CreER organoids.

a–c, Lineage tracing of LGR5-CreER/rainbow CCO7 (a), CCO20 (b) and CCO12 (c). Number of days after tamoxifen treatment is indicated. Descendants of LGR5-CreER+ cells are traced by the RFP reporter (LGR5-tr, red) Non-traced cells are indicated by nuclear GFP (nGFP, green) and no reporter leakage by unintended recombination was observed in the absence of tamoxifen (a–c, far left). For some images, differentiated cells are visualized with KRT20 staining (green) as indicated. Persistent expansion of the RFP reporter in a secondary xenografted tumour (a, far right). Nuclear counterstaining (Hoechst33342, white). Scale bars, 100 μm.

Extended Data Figure 6 Generation of LGR5-iCT organoids.

a, Targeting strategy for the generation of LGR5-iCT organoids. The locations of PCR primers and loxP sites in the targeted and wild-type alleles are indicated. b, Gel electrophoresis of PCR products from knocked-in organoids using the primers shown in a and Supplementary Table 1. Primer pairs a/b and c/e detected knock-in of 5′ and 3′ arms. c, d, LGR5-iCT CCO7 was cultured with (c) or without (d) dimerizer. LGR5+ cells (red) and dead cells (blue) are depicted by tdTomato reporter and DAPI staining, respectively. e–g, After 1 nM dimerizer treatment, residual LGR5− cancer cells regrew at the same time as re-expression of LGR5–tdTomato (LGR5-r, red). Bright field (top) and epifluorescence (bottom) images. Time (days) after dimerizer treatment is indicated. Scale bars, 100 μm.

Extended Data Figure 7 Validation of LGR5+ cell ablation.

a, Ablation of LGR5+ cells in LGR5-iCT CCO7 in vivo. Five days after dimerizer treatment, LGR5 mRNA (red) expression was lost, whereas KRT20+ (green) cells were preserved. b, Immunostaining of cleaved caspase-3. After dimerizer treatment, apoptotic cells appeared along the tumour edge (red arrowheads). c–f, Ablation of LGR5+ cells in vivo using a mixture of LGR5-iCT and CMV-GFP-Luc CCO7 cells. c–f, Time course (c) of LGR5+ cells ablation experiments (d–f). d, Relative total flux value of the vehicle-treated (n = 8) and dimerizer-treated (n = 8) tumours to their original value. e, f, LGR5-iCT (red) and CMV-GFP-Luc (green) organoids intermingled in the tumour after vehicle treatment (e), whereas LGR5–tdTomato expression (red) was lost after dimerizer treatment (f) without reduction in the tumour size (d). Number of tumours for vehicle, n = 8; dimerizer, n = 8. g–i, Double-labelling nucleotide pulse-chase assay in LGR5-iCT CCO7. g, Schematic of the experiment. h, Percentage of cells positive for BrdU, EdU and BrdU/EdU staining in control (grey) and on day 15 (dark blue) and day 56 (light blue). i, Confocal imaging of LGR5–tdTomato (purple), BrdU (red) and EdU (green) on day 15 after vehicle (left) or dimerizer treatment (middle), and day 56 after dimerizer treatment (right). EdU-labelled short-term cycling cells exist over time. EdU/BrdU-double-labelled long-term cycling cells decreased on day 15 and recovered on day 56 after dimerizer treatment. LGR5-recovering regions on day 15 after dimerizer treatment are indicated (dotted circle). Scale bars, 100 μm. Data are mean ± s.e.m. (d, h); *P = 0.004, one-way ANOVA (h).

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Extended Data Figure 8 Generation of KRT20-CreER organoids.

a, Targeting strategy for the generation of KRT20-CreER organoids. The locations of PCR primers and loxP sites in the targeted and wild-type alleles are indicated. b, Gel electrophoresis of PCR products from knocked-in organoids using the primers shown in a. Primer pair a/b detected knock-in of the 5′ arm. Primer pair c/e detected the Cre-recombined 3′ arm in the organoids treated with adenoviral-Cre. c, d, Lineage tracing of KRT20-CreER/rainbow organoids derived from CCO12 (c) and CCO7 (d). Number of days after tamoxifen treatment is indicated. c, Lineage tracing of KRT20-CreER/rainbow organoids derived from CCO12. No reporter leakage by unintended recombination was observed in the absence of tamoxifen (left). KRT20-CreER RFP reporter+ cells (KRT20-tr, red) were devoid of Ki67 expression (green) at day 6 (middle), whereas rare reporter+ clonal ribbons appeared at day 28 and co-expressed Ki67 (right). d, Diminishment of KRT20-CreER YFP-tracing reporter+ cells (KRT20-tr, red) was also observed in organoids derived from CCO7. e, Rare clonal ribbons at day 28 detected by four-colour fluorescence; nGFP (green), YFP (yellow), RFP (red) and mCFP (cyan). Scale bars, 100 μm.

Extended Data Figure 9 In vitro colony formation from sorted CRC organoid cells.

a, b, In vitro colony-formation assay using LGR5–GFP (a) or KRT20–GFP (b) cells from indicated lines of CCO. Both GFP+ (top) and GFP− cells (bottom) formed colonies. c, LGR5–GFP− cells gave rise to organoids containing de novo LGR5–GFP+ cells. d, e, The number of colonies was counted for LGR5–GFP+ and LGR5–GFP− cells (d) or KRT20–GFP+ and KRT20–GFP− cells (e). Scale bars, 25 μm. *P = 0.018 (d), P = 0.0002 (e, left), P < 0.0001 (e, right), two-tailed Student’s t-test. Colony numbers for four to six wells were counted for each analysis.

Source data

Extended Data Figure 10 Combined effect of chemotherapeutics and CSC targeting.

a–c, LGR5 mRNA expression in CCO7 (b) and CCO25 (c) xenografts treated with vehicle, cetuximab (CTX) or oxaliplatin (OX) (a). Relative LGR5 expression to ACTB is shown. d–h, Combination therapy by anti-cancer agents and CSC ablation. Time course of chemotherapeutic and/or dimerizer treatments of mice with for LGR5-iCT CCO xenografts (d). Effects of vehicle (V), chemotherapeutics (CTX) or chemotherapeutics + dimerizer (CTX + D) on CCO7 (e) and CCO25 (f) xenografts. CCOs were xenografted subcutaneously and monitored by bioluminescence or caliper measurements. Relative tumour size based on day 0 volume is plotted (e, f). g, h, Relative tumour size 3 weeks after treatment with the indicated therapeutics (V, vehicle; CTX, cetuximab; D, dimerizer; CTX + D, cetuximab + dimerizer) for CCO7 (g) and CCO25 (h). Values from the CTX and CTX + D groups (e, f) were compared to those from the V and D groups aggregated from four (g) or three (h) individual experiments. Each grey plot represents the size of each tumour and tumours with extensive regression (>95% tumour reduction) are highlighted in red. Note that >95% tumour reduction was only achieved by CTX + D treatment. When a tumour was not detectable, the size was set to 0.01 to avoid arithmetic error during log transformation. For each treatment group, number of the analysed tumours is indicated.

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Shimokawa, M., Ohta, Y., Nishikori, S. et al. Visualization and targeting of LGR5+ human colon cancer stem cells. Nature 545, 187–192 (2017). https://doi.org/10.1038/nature22081

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