Clevers: Adult stem cell-based organoids

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Hans Clevers is Head of pharma Research and Early Development (pRED) of Roche, Basel Switzerland, since March 2022. He was group leader at the Hubrecht Institute from 2002 until March 2022 and currently he is advisor/guest researcher at the Hubrecht Institute.

The Organoid group, previously Clevers group, studies the molecular mechanisms of tissue development and cancer of various organs using organoids made from adult Lgr5 stem cells.

Tcf as Wnt effector
In 1991, we reported the cloning of a T cell specific transcription factor that we termed TCF1 (1). Related genes exist in genomes throughout the animal kingdom. We have shown in frogs (4), flies (7) and worms (11) that the TCF proteins constitute the effectors of the canonical Wnt pathway. Upon Wnt signaling, ß-catenin binds and activates nuclear TCFs by providing a trans-activation domain. For these studies, we designed the widely used pTOPFLASH Wnt reporters. In the absence of Wnt signaling, we found that Tcf factors associate with proteins of the Groucho family of transcriptional repressors to repress target gene transcription (9).

Wnt signaling in cancer
The tumor suppressor protein APC forms the core of a cytoplasmic complex which binds ß-catenin and targets it for degradation in the proteasome. In APC-deficient colon carcinoma cells, we demonstrated that ß-catenin accumulates and is constitutively complexed with the TCF family member TCF4, providing a molecular explanation for the initiation of colon cancer (5).

Latest publicationsView all publications

Cancer Cell 11;41(12):2083-2099

Download|2023

Science 382:451-458

Download|2023

Engineered human hepatocyte organoids enable CRISPR-based target discovery and drug screening for steatosis.

Hendriks D, Brouwers JF, Hamer K, Geurts MH, […] Artegiani B, Clevers H

Nat Biotechnol 41:1567-1581

Download|2023

Optimized human intestinal organoid model reveals interleukin-22-dependency of paneth cell formation.

He GW, Lin L, DeMartino J, Zheng X, Staliarova N, [...] Holstege F, Clevers H.

Cell Stem Cell 1;29(9):1333-1345

Download|2022

Patient-derived organoids model cervical tissue dynamics and viral oncogenesis in cervical cancer

Lohmussaar K, Oka R, Espejo Valle-Inclan J, Veersema S, [...] van Boxtel R, Clevers H

Cell Stem Cell 28:1-17

Download|2021

Exploring the human lacrimal gland using organoids and single-cell sequencing

Bannier-Hélaouët M, Post Y, Korving J [...] Imhoff S, Clevers H

Cell Stem Cell 28:1-12

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SARS-CoV-2 productively Infects Human Gut Enterocytes

Lamers MM, Beumer J, van der Vaart J [...] Haagmans, BL, Clevers H

Science 369:50-54

Download|2020

Snake Venom Gland Organoids

Post Y, Puschhof J, Beumer B [...] Casewell NR, Clevers H

Cell 180:233-247

Download|2020

High Resolution mRNA and Secretome Atlas of Human Enteroendocrine Cells

Beumer J, Puschhof J, Bauzá-Martinez [...] Wu, W and Clevers H

Cell 181:1291-1306

Download|2020

Nat Cell Biol. 22:321-331

Download|2020

CRISPR-Based Adenine Editors Correct Nonsense Mutations in a Cystic Fibrosis Organoid Biobank

Geurts, MH de Poel E, Amatngalim, GD [...}, Beekman, JM and Clevers, H

Cell Stem Cell 26:503-510

Download|2020

Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli

Pleguezuelos-Manzano C, Puschhof J, Rosendahl A [...] van Boxtel R, Clevers H

Nature 580:269-273

Download|2020

Nature Medicine 25:838-849

Download|2019

Tubuloids derived from human adult kidney and urine for personalized disease modeling

Schutgens F, Rookmaaker MB [...] Verhaar MC, Clevers H

Nature Biotechnology 37:303–313

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Cell 176:1158-1173

Download|2019

Cell 175:1591-1606

Download|2018

Intra-tumour diversification in colorectal cancer at the single-cell level

Roerink SF, Sasaki N [...] Stratton MR, Clevers H

Nature 556:457-462

Download|2018

Cell 172(1-2):373-386

Download|2018

Other publications

Nature

Download|2020

COVID-19 organoids go viral

EU-Organoid-67013

Nature Reviews

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Current Protocols in Immunology

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Science 358(6360):234-238

Download|20171013

Cell 165:1586-1597

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Sequential cancer mutations in cultured human intestinal stem cells

Drost, J, van Jaarsveld, R.H., Ponsioen, B., Zimberlin, C., van Boxtel, R., Buijs, A.,Sachs, N., Overmeer, R.M., Offerhaus, G.J., Begthel, H. Korving, J., van de Wetering, M., Schwank, G. Logtenberg, M., Cuppen, E., Snippert, H.J., Medema, J.P., Kops, G. J. P. L., Clevers, H.

Nature 521:43-47

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Visualization of the short-range Wnt gradient in the intestinal stem cell niche

Farin, H.F., Jordens, I., Mosa, M.H., Basak, O., Korving, J., Tauriello, D.V.F., de Punder, K., Angers, S., Peters, P.J. Maurice, M.M. and Clevers, H.

Nature 530:340-343

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Prospective derivation of a ‘Living Organoid Biobank’ of colorectal cancer patients

van de Wetering, M., Francies, H.E., Francis, J.M., Bounova, G., Iorio, F., Pronk, A., ... Garnett, M.J., Clevers, H.

Cell 161:933-945

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Organoid models of human and mouse ductal pancreatic cancer

Boj, S.F., Hwang, C.I., Baker, L.A., Chio, I.I., Engle, D.D., ..., Clevers, H, Tuveson, D.A.

Cell 160:324-338

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Long-term culture of genome-stable bipotent stem cells from adult human liver

Huch, M., Gehart, H., van Boxtel, R., Hamer, K., Blokzijl, F., Verstegen, M.A., Ellis, E., van Wenum, M., Fuchs, S., de Ligt, S., van de Wetering, M., Sasaki, N., Boers, S.J., Kemperman, H., de Jonge, J., Ijzermans, J.N.M., Niewenhuis, E.E.S., Hoekstra, R., Strom, S., Vries, R.G.J., van der Laan, L.J.W., Cuppen, E., Clevers, H.

Cell 160:299-312

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Identification of multipotent luminal progenitor cells in human prostate organoid cultures

Karthaus, W.R., Iaquinta, P.J., Drost, J., Gracanin, A.., van Boxtel, R., Wongvipat, J., Dowling, C.M., Gao, D., Begthel, H., Sachs, N., Vries, R.G., Cuppen, E., Chen, Y., Sawyers, C.L., Clevers, H.

Cell 159:163-75

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Intestinal crypt homeostasis revealed at single-stem-cell level by in vivo imaging

Ritsma, L., Ellenbroek, S.I., Zomer, A., Snippert, H.J., de Sauvage, F.J., Simons, B.D., Clevers, H., van Rheenen, J.

Nature 507:362-5

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Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients

Schwank, G., Koo, B.K., Sasselli, V., Dekkers, J.F., Heo, I., Demircan, T., Sasaki, N., Boymans, S., Cuppen, E., van der Ent, C.K., Nieuwenhuis, E.E., Beekman, J.M. and Clevers, H.

Cell Stem Cell 13:653-658

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Differentiated Troy+ chief cells act as ‘reserve’ stem cells to generate all lineages of stomach epithelium

Stange, D.E., Koo, B.K., Huch, M., Sibbel, G., Basak, O., Lyubimova, A.,Kujalla, P., Bartfeld, S., Koster, J., Geahlen, J.H., Peters, P.J., van Es, J., van de Wetering, M., Mills, J.C., Clevers, H.

Cell 155:357-368

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In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration

Huch M., Dorell, C., Boj, S.F., van Es, J.H., van de Wetering, M., Li, V.S.W., Hamer, K., Sasaki, N., Finegold, M.J., Haft, A., Grompe, M., Clevers, H.

Nature 494: 247-250

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Diabetes risk gene and Wnt effector Tcf7l2/TCF4 controls hepatic response to perinatal and adult metabolic demand

Boj, S,F., van Es, J.H.,Huch. M., Li, V.S., Jose, A., Hatzis, P., Mokry, M., Haegebarth, A., van den Born, M., Chambon, P., Voshol, P., Dor, Y., Cuppenm E., Fillat, C., Clevers, H.

Cell 151:1595-1607

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DII (+) secretory progenitor cells revert to stem cells upon crypt damage

van Es, J.H., Sato, T., van de Wetering, M., Lyubimova, A., Yee Nee, A.N., Gregorieff, A., Sasaki, N., Zeinstra, L., van de Born, M., Korving, J., Martens, A.C., Barker, N., van Oudenaarden, A., Clevers, H.

Nat Cell Biol 14:1099-1104

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Lineage Tracing Reveals Lgr5+ Stem Cell Activity in Mouse Intestinal Adenomas

Schepers, A.G., Snippert, H.J., Stange, D.E., van den Born, M., van Es, J.H., van de Wetering, M., Clevers, H.

Science 337:730-735

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Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors

Koo, B-K., Spit, M. Jordens, I., Low, T.Y., Stange, D.E., van de Wetering, M., van Es, J.H., Mohammed, S., Heck, A.J.R., Maurice, M.M. and Clevers, H.

Nature 488:665-669

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Nature 476:293-297

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Wnt signaling inhibits proteasomal β-catenin degradation within a compositionally intact Axin1 complex

Li, V.S., Ng, S.S., Boersema, P.J., Low, T.Y., Karthaus, W.R., Gerlach, J.P., Mohammed, S., Heck, A.J., Maurice, M.M., Mahmoudi, T. and Clevers, H.

Cell 149:1245-1256

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Intestinal Crypt Homeostasis results from Neutral Competition between Symmetrically Dividing Lgr5 Stem Cells

Snippert, .J., van der Flier, L.G., Sato, T., van Es, J.H., van den Born, M., Kroon-Veenboer, C., Barker, N.,Klein, A.M., van Rheenen, J. Benjamin D. Simons, B.D. and Clevers, H.

Cell 143:134-144

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Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts

Sato, T., van Es, J.H., Snippert, H.J., Stange, D.E., Vries, R.G., van den Born, M., Barker, N., Shroyer, N.F., van de Wetering, M., Clevers, H.

Nature 469:415-418

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Lgr6 marks stem cells in the hair follicle that generate all cell lineages of the skin

Snippert, H.J., Haegebarth, A., Kasper, M., Jaks, V., van Es, J.H., Barker, N., van de Wetering, M., van den Born, M., Begthel, H., Vries, R.G., Stange, D.E., Toftgård, R., Clevers, H.

Science 327:1385-1389

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Cell Stem Cell 6:25-36

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Single Lgr5 gut stem cells build crypt-villus structures in vitro without a mesenchymal niche

Sato, T., Vries, R., Snippert, H., van de Wetering, M., Barker, N., Stange, D., van Es, J., Abo, A., Kujala, P., Peters, P., and Clevers, H.

Nature 459:262-5

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Transcription factor Achaete scute-like 2 (Ascl2) controls intestinal stem cell fate

van der Flier, L.G., van Gijn, M.E., .., and Clevers, H.

Cell 136:903-12

Download|20090501

Crypt Stem Cells as the Cells-of-Origin of Intestinal Cancer

Barker N., Ridgway R.A., van Es J.H.,van de Wetering M., Begthel H., van den Born M., Danenberg E., Clarke A.R., Sansom O.J., Clevers, H.

Nature 457:608-611

Download|20090501

Lgr5 marks cycling, yet long-lived, hair follicle stem cells

Jaks V., Barker N., Kasper M., van Es J.H., Snippert H.J., Clevers H., Toftgård, R.

Nat Genet. 40:1291-1299

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Identification of Stem Cells in Small Intestine and Colon by a Marker Gene LGR5

Barker, N, van Es, J.H., Kuipers, J., Kujala P., van den Born, M., Cozijnsen, M., Korving, J., Begthel, H., Peters, P.C., and Clevers, H.

Nature 449:1003-1007

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Cell 127:469-480

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EphB activity suppresses colorectal cancer progression

Batlle E., Bacani J., Begthel H., Jonkheer S., Gregorieff A., Van de Born M., Malats N., Sancho E., Boon E., Pawson T., Gallinger S., Pals S., Clevers, H.

Nature 435:1126-1130

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Notch pathway/gamma-secretase inhibition turns proliferative cells in intestinal crypts and neoplasia into Goblet cells

Van Es J.H., Van Gijn M.E., Riccio O., Van den Born M., Vooijs M., Begthel H., Cozijnsen M., Robine S., Winton D.J., Radtke F., Clevers, H.

Nature 435:959-963

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Nature 434:843-850

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Science 307:1904-1909

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De novo crypt formation and Juvenile Polyposis upon BMP inhibition

Haramis A.P., Begthel H., van den Born M., van Es J., Jonkheer S., Offerhaus G.J., Clevers H.

Science 303:1684-6

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Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD

Baas A.F., Kuipers J., van der Wel N.N., Batlle E., Koerten H.K., Peters P.J., Clevers H.C.

Cell 116:457-66

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The Wnt/beta-catenin pathway regulates cardiac valve formation

Hurlstone A.F., Haramis A.P., Wienholds E., Begthel H., Korving J., Van Eeden F., Cuppen E., Zivkovic D., Plasterk R.H., Clevers H.

Nature 425:633-7

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Beta- catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB

Battle, E., Henderson, J.T., Beghtel, H., van den Born, M., Sancho, E., Huls, G., Meeldijk, J., Robertson, J., van de Wetering, M., Pawson, T., Clevers, H.

Cell 111:251-263

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The beta-catenin/TCF4 complex imposes a crypt progenitor phenotype on colorectal cancer cells

Van de Wetering, M., Sancho, E., Verweij, C., de Lau, W., Oving, I., Hurlstone, A., Van der Horn, K., Batlle, E., Coudreuse, D., Haramis, A-P., Tjon-Pon-Fong, M., Moerer, P., Van den Born, M., Soete, G., Pals, S., Eilers, M., Medema, R., Clevers, H.

Cell 111:241-250

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Linking colorectal cancer to Wnt signaling

Bienz, M., and Clevers, H.

Cell 103:311-320

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Nature 406:527-532

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Synergy between tumor suppressor APC and the beta-catenin/Tcf4 target gene Tcf1

Roose, J., Huls, G., van Beest, M., Moerer, P., van der Horn, K., Goldschmeding, R., Logtenberg, T., and Clevers, H.

Science 285:1923-1926

Download|19990501

The Xenopus Wnt effector XTcf-3 interacts with Groucho-related transcriptional repressors

Roose, J., Molenaar, M., Peterson, J., Hurenkamp, J., Brantjes, H., Moerer, P., van de Wetering, M., Destree, O., and Clevers, H.

Nature 395(6702): 608-612

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Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4

Korinek, V., Barker, N., Moerer, P., van Donselaar, E., Huls, G., Peters, P.J. and Clevers, H.

Nat Genet 19(4):379-383

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Armadillo co-activates transcription driven by the product of the Drosophila segment polarity gene dTCF

Van de Wetering, M., Cavallo, R., Dooijes, D., Van Beest, M., Van Es, J., Loureiro, J., Ypma, A., Hursh, D., Jones, T., Bejsovec, A., Peifer, M., Mortin, M., and Clevers, H.

Cell 88:789-799

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Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC

Morin, P.J., Sparks, A., Korinek, V., Barker, N., Clevers, H., Vogelstein, B., and Kinzler, K.

Science 275:1787-1790

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Constitutive Transcriptional Activation by a beta-catenin-Tcf complex in APC -/- Colon Carcinoma

Korinek, V, Barker, N., Morin, P.J., van Wichen, D., de Weger, R., Kinzler, K.W., Vogelstein, B., and Clevers, H.

Science 275:1784-1787

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Xtcf-3 Transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos

Molenaar, M., Van de Wetering, M., Oosterwegel, M., Peterson-Maduro, J., Godsave, S., Korinek, V., Roose, J., Destrée, O. And Clevers, H.

Cell 86:391-399

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Defects in cardiac outflow tract formation and pro-B-lymphocyte expansion in mice lacking Sox-4

Schilham, M., Oosterwegel, M., Moerer, P., Jing Ya, de Boer, P., van de Wetering, M., Verbeek, S., S., Lamers, W., Kruisbeek, A., Cumano, A., and Clevers, H .

Nature 380:711-714

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An HMG box containing T-cell factor required for thymocyte differentiation

Verbeek, J.S., Ison, D., Hofhuis, F., Robanus-Maandag, E., te Riele, H., van de Wetering, M., Oosterwegel, M., Wilson, A., MacDonald, H.R. and Clevers, H.C.

Nature 374:70-74

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EMBO J ., 10:123-132

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Advisor/Guest researcher

Hans Clevers

The Organoid group, previously Clevers group, studies the biology of Wnt signaling in tissue turnover and in cancer. The discovery of Lgr5 as a generic marker of Wnt-dependent stem cells within multiple adult tissues has led to the development of technology to grow these stem cells into ever-expanding epithelial organoids. These organoids recapitulate many aspects of their tissue of origin and allow the study of a multitude of physiological and pathological processes. Patient-derived organoids hold promise to predict drug response in a personalized fashion and open up new avenues for regenerative medicine and, in combination with genome editing technology, for gene therapy.

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Group members

Hans Clevers

advisorguestresearcher

Johan van Es

actinggroupleader

Stieneke van den Brink

Technician

Laura Zeinstra

Technician

Harry Begthel

Technician

Jeroen Korving

Technician

Veerle Geurts

Technician

Benaissa El Haddouti

Technician

Lissanne van Rooijen

Technician

Wim de Lau

Postdoc

Marie Bannier

Postdoc

Jochem Bernink

Postdoc

Amanda Andersson-Rolf

Postdoc

Lin Lin

Postdoc

Delilah Hendriks

Postdoc

Sangho Lim

Postdoc

Elena Reckzeh

Postdoc

Daniel Krueger

Postdoc

Daisong Wang

Postdoc

Antonella Dost

Postdoc

Theodore Grenier

Postdoc

Sarina Shabso

Postdoc

Xuan Zheng

Postdoc

Cayetano Pleguezuelos

PhD Student

Fjodor Yousef Yengej

PhD Student

Carla Pou Casellas

PhD Student

Adriana Maritinez

PhD Student

Lulu Huang

PhD Student

Martina Celotti

PhD Student

Sam Willemsen

PhD Student

Katarina Balazova

PhD Student

Joost Wijnakker

PhD Student

Carola Ammerlaan

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