Clevers: Adult stem cell-based organoids

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The 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

Cell 172(1-2):373-386.

Download|2018

Science 358(6360):234-238.

Download|2017

Cell 165(7):1586-1597.

Download|2016

Nature 530(7590):340-3.

Download|2016

Sequential cancer mutations in cultured human intestinal stem cells.

Drost J, van Jaarsveld RH [...] Kops GJ, Clevers H

Nature 521(7550):43-7.

Download|2016

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

van de Wetering M, Francies HE [...] Garnett MJ, Clevers H

Cell 161(4):933-45.

Download|2015

Other publications

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

Roerink, S.F., Sasaki, N., ..., Stratton, MR, and Clevers H.

Nature 556, 437-462

Download|2018

A living biobank of breast cancer organoids captures disease heterogeneity

Sachs, N., de Ligt, J., Kopper, O., Gogola, E., Bounova, G., Weeber, F., Balgobind, A.V., Wind, K., Gracanin, A., Begthel, H., Korving, J., van Boxtel, R., ... Cuppen, E., Clevers, H.

Cell 172:373-386

Download|2017

Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer

Drost, J., van Boxtel, R., Blokzijl, F., Mizutani, T., Sasaki, N., Sasselli, V., de Ligt, J., Behjati, S., Grolleman, J.E., van Wezel, T., Nik-Zainal, S., Kuiper, R.P., Cuppen, E., and Clevers, H.

Science 358:234-238

Download|2017

Cell 165:1586-1597

Download|2016

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

Download|2015

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

Download|2016

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

Download|2015

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 DA.

Cell 160: 324-338

Download|2015

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

Download|2015

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.C.

Cell 159: 163-75

Download|2014

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

Download|2014

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

Download|2013

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

Download|2013

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

Download|2013

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

Download|2012

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

Download|2012

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

Download|2012

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 Hans Clevers.

Nature 488: 665-669

Download|2012

Nature 476: 293-297

Download|2011

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

Download|2012

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 143:134-44

Download|2010

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

Download|2010

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

Download|2010

Cell Stem Cell, 6: 25-36

Download|2010

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

Download|2009

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|2009

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|2009

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

Download|2008

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

Download|2007

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

Download|2005

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

Download|2005

Nature 434:843-850

Download|2005

Science. 307:1904-1909

Download|2005

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

Download|2004

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

Download|2004

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

Download|2003

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

Download|2002

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

Download|2002

Linking colorectal cancer to Wnt signaling

Bienz, M., and Clevers, H.

Cell 103: 311-320

Download|2000

Nature 406: 527-532

Download|2000

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|1999

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

Download|1998

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

Download|1998

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

Download|1997

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

Download|1997

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

Download|1997

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

Download|1996

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

Download|1996

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

Download|1995

EMBO J ., 10:123-132

Download|1991

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Group leader

Hans Clevers

Hans Clevers is group leader at the Hubrecht Institute for Developmental Biology and Stem Cell Research and professor of Molecular Genetics at the University Medical Center Utrecht and Utrecht University. He is also Director Research of the Princess Máxima Center for Pediatric Oncology and Oncode Investigator.

The 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 other positions

Prizes and awards

Prize juries

Honorary Professorships

Elected Memberships

Advisory Boards


Group members

Hans Clevers

Principal Investigator

Stieneke van den Brink

Technician

Laura Zeinstra

Technician

Harry Begthel

Technician

Maaike van den Born

Technician

Karien Hamer

Technician

Anjali Balgobind

Technician

Jeroen Korving

Technician

Priyanca Asra

Technician

Sigrid Kolders

Technician

Veerle Geurts

Technician

Evelien de Jongh

Technician

Lisanne den Hartigh

Technician

Johan van Es

Senior Researcher

Benedetta Artegiani

Postdoc

Helmut Gehart

Postdoc

Kai Kretzschmar

Postdoc

Oded Kopper

Postdoc

Devanjali Dutta

Postdoc

Angelos Papaspyropoulos

Postdoc

Jasper Mullenders

Postdoc

Lena Böttinger

Postdoc

Huili Hu

Postdoc

Tomohiro Mizutani

Postdoc

Yoshiyuki Tsukamoto

Postdoc

Yotam Bar-Ephraim

Postdoc

Jochem Bernink

Postdoc

Georg Busslinger

Postdoc

Talya Dayton

Postdoc

Florijn Dekkers

Postdoc

Marrit Putker

Postdoc

Amanda Andersson-Rolf

Postdoc

Else Driehuis

PhD Student

Yorick Post

PhD Student

Kim Boonekamp

PhD Student

Joep Beumer

PhD Student

Kadi Lõhmussaar

PhD Student

Marie Bannier

PhD Student

Jens Puschhof

PhD Student

Maarten Geurts

PhD Student

Cayetano Pleguezuelos

PhD Student

Jelte van der Vaart

PhD Student

Roksan Franko

Student

Jan Blom

Student

Pablo Tapia

Student

Sonia Aristin Revilla

Student

Esmée van Vliet

Student

Fàtima de la Jara Ortiz

Student

Xingyi Cheng

Student

Eric Moyer

Student

Wim de Lau

Guest

Carola Ammerlaan

Guest

Dymph Klay

Guest

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