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

Human conjunctiva organoids to study ocular surface homeostasis and disease

Bannier-Hélaouët M, Korving J, Ma Z, Begthel H, [...] Wu W, Clevers H

Cell Stem Cell 1;31(2):227-243


Human fetal brain self-organizes into long-term expanding organoids

Hendriks D, Pagliaro A, Andreatta F, Ma Z [...] Clevers H, Artegiani B

Cell 1;187(3):712-732


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


Science 382:451-458


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


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


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


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


SARS-CoV-2 productively Infects Human Gut Enterocytes

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

Science 369:50-54


Snake Venom Gland Organoids

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

Cell 180:233-247


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


Nat Cell Biol. 22:321-331


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


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


Nature Medicine 25:838-849


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


Cell 176:1158-1173


Cell 175:1591-1606


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

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

Nature 556:457-462


Cell 172(1-2):373-386


Other publications



COVID-19 organoids go viral


Nature Reviews


Current Protocols in Immunology


Science 358(6360):234-238


Cell 165:1586-1597


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


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


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


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


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


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


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


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


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


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


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


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


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


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


Nature 476:293-297


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


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


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


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


Cell Stem Cell 6:25-36


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


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


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


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


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


Cell 127:469-480


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


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


Nature 434:843-850


Science 307:1904-1909


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


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


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


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


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


Linking colorectal cancer to Wnt signaling

Bienz, M., and Clevers, H.

Cell 103:311-320


Nature 406:527-532


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


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


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


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


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


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


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


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


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


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.

Scientific training and positions


Prize juries

Honorary Professorships

Elected Memberships

Advisory Boards


Group members

Hans Clevers


Johan van Es


Stieneke van den Brink


Laura Zeinstra


Harry Begthel


Jeroen Korving


Veerle Geurts


Benaissa El Haddouti


Lissanne van Rooijen


Wim de Lau


Marie Bannier


Jochem Bernink


Amanda Andersson-Rolf


Lin Lin


Delilah Hendriks


Sangho Lim


Elena Reckzeh


Daniel Krueger


Daisong Wang


Antonella Dost


Theodore Grenier


Sarina Shabso


Xuan Zheng


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


Show all group members