Intestinal Stem Cells And Organoids

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1 Intestinal Stem Cells And Organoids Marc van de Wetering NVMO 2015

2 Disclosure belangen spreker (potentiële) belangenverstrengeling Voor bijeenkomst mogelijk relevante relaties met bedrijven Sponsoring of onderzoeksgeld Honorarium of andere (financiële) vergoeding Aandeelhouder Andere relatie, namelijk Geen Bedrijfsnamen

3

4

5 All Tcf4 Target Genes are Cancer Genes. Most are physiologically expressed either in Paneth cells or in Transit Amplifying Cells Wnt drives maturation of Paneth Cells (van Es 2005) Wnt is a mitogen for transit amplifying cells

6 Identifying Stem Cells Lineage tracing

7 Nick Barker Generation of Lgr5-GFP-ires-CreERT2 Knock-in Mouse SP 18x Leucine Repeats Cys TM Domain C-Term Exon UTR egfp IRES Cre-ERT2 Neo Intron I

8

9 Lgr5 Cells are the Multipotent Stem Cells of the Small Intestine 1 Day 5 Days 60 Days 6 months Goblet Cells Paneth Cells Enteroendocrine Cells

10 20 months later..

11 Crypt Base Columnar cells are Intestinal Stem Cells After (Leblond, Bjerknes and Cheng)

12 Lgr5 marks cycling stem cell populations in the small intestine.

13 Lgr5-Driven GFP in Crypt Base Columnar Cells

14 Rosa-Confetti Multicolor lineage tracing based on Brainbow (J.Lichtman)

15

16 Neutral drift towards crypt monoclonality

17 Neutral competition vs. Asymmetrical Stem Cell Division

18 Lgr5 marks cycling stem cell populations in the small intestine, colon and stomach. Lgr5 intestinal stem cells can generate self-organizing intestinal organoids in-vitro. Paneth cells are niche cells for intestinal stem cells. Lgr5 intestinal stem cells divide symmetrically. Lgr5 stem cells compete for restricted niche space

19 Defining the Cell-of-Origin of Intestinal Cancer i) Loss of APC in Stem Cells IP Tamoxifen LGR5KI het /APCflox hom ii) Loss of APC in Non-Stem Cells Oral ß-NF AhCre/APCflox hom

20 Loss of APC in Non-Stem Cell Populations Fails to Initiate Adenoma Formation

21 Transformation of Stem Cells Rapidly Initiates Intestinal Adenoma Formation Lgr5

22 Restricted Expression of LGR5 Stem Cell Marker in Adenomas Lgr5 Lgr5

23 Lgr5 marks cycling stem cell populations in the small intestine, colon and stomach. Lgr5 intestinal stem cells can generate self-organizing intestinal organoids in-vitro in the absence of a non-epithelial niche. Paneth cells constitute the intestinal niche. Lgr5 intestinal stem cells divide symmetrically. Lgr5 stem cells compete for restricted niche space Lgr5 stem cells are the cell-of-origin of intestinal cancer.

24 Rosa-Confetti Multicolor lineage tracing based on Brainbow (J.Lichtman) Hugo Snippert Laurens van der Flier Ben Simons (Cambridge)

25 Deleting floxed APC in stem cells by Lgr5-CreER. Confetti reporter crossed in (ArnoutSchepers).

26 A single Lgr5 cell in a red adenoma is turned blue: Does it behave like a stem cell?

27 Lgr5 cells in adenomas behave like stem cells

28 Lgr5 marks cycling stem cell populations in the small intestine, colon and stomach. Lgr5 intestinal stem cells can generate self-organizing intestinal organoids in-vitro in the absence of a non-epithelial niche. Paneth cells constitute the intestinal niche. Lgr5 intestinal stem cells divide symmetrically. Lgr5 stem cells compete for restricted niche space Dll1 + early secretory precursors can revert to stem cells upon tissue damage Intestinal label retaining cells are Lgr5+ Lgr5 marks adenoma stem cells

29 Organoids

30 20 months later..

31 Lgr5-GFP In-Vitro Intestinal Organoids Resemble In-Vivo Crypt-Villus Units Enterocytes Goblet Cells Paneth Cells Enteroendocrine cells Lgr5+ CBC cells Toshiro Sato

32 Lgr5-GFP In-Vitro Intestinal Organoids Resemble In-Vivo Crypt-Villus Units o Organoids can be generated from human intestine, colon, stomach, oesophagus, liver, pancreas, lung, ovary, prostate and breast (from normal/healthy and tumor samples).

33 Question 1 Can we use organoid technology for disease modeling? Cystic fibrosis Colon cancer

34 Question Cystic fibrosis: 1 CFTR, a chloride channel, is defective (with Florijn Dekkers and Jeff Beekman ) Inactive + Forskolin Active

35 Wt human CFTR opened with forskolin mutant CFTR Does not open

36 Experimental compounds (correctors/potentiators) can be profiled on CFTR-mutant mini-guts VRT-325 Corr-4a VX-809 VX-770 CFTR -/- CFTR -/- CFTR -/-

37 Question 1 Can we use organoid technology for disease modeling? Cystic fibrosis (colon) cancer

38 Establishment of Pancreas Tumor Organoids Sylvia Boj

39 Can we make an organoid Biobank to determine genotype phenotype interactions? Criteria: Easy to make Resemble the tumor Cover the spectrum of mutations found in tumors Useable in high-troughput screens

40 Tumor organoid Primary tumor Outline of the study P19a P19b P31 P19a P19b P31

41 Organoids reflect tumors Josh Francis Matthew Meyerson Broad Institute Cambridge MA USA

42 Genetic diversity found in CRC is maintained in organoids Josh Francis Matthew Meyerson Broad Institute Cambridge MA USA

43 RNA analysis subtypes Enterocyte: None Goblet.like: P7T, P11T, P16T Inflammatory: P19Ta, P19Tb, P23T Stem.like: P5T, P27T TA: P6T, P8T, P10T, P17T, P18T, P20T, P24Ta, P24Tb, P25T, P26T, P9T, P14T, P28T, P31T Gergana Bounova Lodewyk Wessels NKI, Amsterdam The Netherlands

44 Heatmap of IC50 s Hayley Francies Francesco Iorio Mathew Garnett Ultan McDermott Sanger Institute, Hinxton, UK

45 Autocrine/paracrine WNT signaling drives P19b proliferation Hayley Francies Mathew Garnett Ultan McDermott Sanger Institute, Hinxton, UK

46 F r a c t io n V ia b ilit y o f C o n t r o l F r a c t io n V ia b ilit y o f C o n t r o l Gene-drug associations F lu o r o u r a c il A D F lu o r o u r a c il 1. 5 P 1 0 T P 1 1 T P 1 4 T B C F r a c t io n V ia b ilit y o f C o n t r o l P1 17 0T P 1 8 T P P 1 9 T a PP 1 19 T4 b 0. 0 P2 10 T P 2 3 T P F lu o r o u r a c il ( M ) M K A K T 1 /2 P 2 4 T a P 1 8 P 2 5 T PP 2 61 T9 a 1. 5 P 1P TT9 b PP1 31 1T T P PP1 64 T P 2 3 PP1 76 T 5 - F lu o r o u r a c il ( M ) P 1P 87 T2 4 a 0. 5 PP1 98 T P 2 5 P 1 9 T a P 2 6 P 1 9 T b P P 2 0 T A Z D E R B B 1, E R B B 2, E R R B 3 P 2P 33T 1 M K ( M ) P 2P 46T a 2. 0 P 2 5 T P 7 PP 216 0T T PP P TT 1. 5 PP 3P 1 49 TT PP 6T 1 6 T 1. 0 PP 7T 1 7 T P P 8T 1 8 T 0. 5 P P 9T 1 9 T a P 1 9 T b 0. 0 P 2 0 T P 2 3 T A Z D ( M ) P 2 4 T a Hayley Francies P 2 5 T FrancescoP 2 6Iorio T P 2 8 T Mathew Garnett P 3 1 T F r a c t io n V ia b ilit y o f C o n t r o l P 1 6 T Ultan McDermott P 6T Sanger Institute, P 7T Hinxton, UK

47 Pospective derivation of a Living Organoid Biobank of colorectal cancer patients - The succes rate of organoid derivation > 90% - Organoids closely resemble the original tumor - The spectrum of mutations within the living biobank agrees well with large-scale mutational analysis of CRC - Gene expression analysis indicates that the major CRC subtypes are represented - Tumor organoids are amenable to robotized high-troughput drug screens

48 Hubrecht Institute/ HUB: Collaborators: Toshiro Sato Nick Barker Hugo Snippert Laurens van der Flier Arnout Schepers Sylvia Boj Joyce Blokker Sridevi Jaksani Johan van Es Jarno Drost Norman Sachs Robert Vries Hans Clevers Lennart Kester, Alexander van Oudenaarden: Hubrecht Institute, The Netherlands Apollo Pronk, Joost van Gorp, Winan van Houdt: Diakonessen Hospital, The Netherlands Hayley Francies, Mathew Garnett, Mike Stratton: Sanger Institute, UK Josh Francis, Matthew Meyerson, Broad Institute: USA J Offerhaus, I Borel Rinkes, Q Molenaar, O Kranenburg: UMC Utrecht, The Netherlands Hans Bos, Hugo Snippert: UMC Utrecht, The Netherlands Florijn Dekkers, Jeffrey Beekman, Kors van der Ent: UMC Utrecht, The Netherlands Fleur Weeber, Krijn Dijkstra, Emile Voest: AVL, The Netherlands

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