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3. Uncovering the mode of action of engineered T cells in patient cancer organoids

Author

Dekkers, Johanna F., Alieva, Maria, Cleven, Astrid, Keramati, Farid, Wezenaar, Amber K. L., van Vliet, Esmée J., Puschhof, Jens, Brazda, Peter, Johanna, Inez, Meringa, Angelo D., Rebel, Heggert G., Buchholz, Maj-Britt, Barrera Román, Mario, Zeeman, Amber L., de Blank, Sam, Fasci, Domenico, Geurts, Maarten H., Cornel, Annelisa M., Driehuis, Else, Millen, Rosemary, Straetemans, Trudy, Nicolasen, Mara J. T., Aarts-Riemens, Tineke, Ariese, Hendrikus C. R., Johnson, Hannah R., van Ineveld, Ravian L., Karaiskaki, Froso, Kopper, Oded, Bar-Ephraim, Yotam E., Kretzschmar, Kai, Eggermont, Alexander M. M., Nierkens, Stefan, Wehrens, Ellen J., Stunnenberg, Henk G., Clevers, Hans, Kuball, Jürgen, Sebestyen, Zsolt, and Rios, Anne C.

Published
2023
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5. Next-Generation Surrogate Wnts Support Organoid Growth and Deconvolute Frizzled Pleiotropy In Vivo

Author

Miao, Yi, Ha, Andrew, de Lau, Wim, Yuki, Kanako, Santos, António JM, You, Changjiang, Geurts, Maarten H, Puschhof, Jens, Pleguezuelos-Manzano, Cayetano, Peng, Weng Chuan, Senlice, Ramazan, Piani, Carol, Buikema, Jan W, Gbenedio, Oghenekevwe M, Vallon, Mario, Yuan, Jenny, de Haan, Sanne, Hemrika, Wieger, Rösch, Kathrin, Dang, Luke T, Baker, David, Ott, Melanie, Depeille, Philippe, Wu, Sean M, Drost, Jarno, Nusse, Roeland, Roose, Jeroen P, Piehler, Jacob, Boj, Sylvia F, Janda, Claudia Y, Clevers, Hans, Kuo, Calvin J, and Garcia, K Christopher

Subjects
Biotechnology, Digestive Diseases, Regenerative Medicine, Frizzled Receptors, Hepatocytes, Organoids, Stem Cells, Wnt Signaling Pathway, DARPin, Frizzled, Wnt, canonical Wnt signaling, organoids, protein engineering, regenerative medicine, stem cell, surrogate Wnt, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Modulation of Wnt signaling has untapped potential in regenerative medicine due to its essential functions in stem cell homeostasis. However, Wnt lipidation and Wnt-Frizzled (Fzd) cross-reactivity have hindered translational Wnt applications. Here, we designed and engineered water-soluble, Fzd subtype-specific "next-generation surrogate" (NGS) Wnts that hetero-dimerize Fzd and Lrp6. NGS Wnt supports long-term expansion of multiple different types of organoids, including kidney, colon, hepatocyte, ovarian, and breast. NGS Wnts are superior to Wnt3a conditioned media in organoid expansion and single-cell organoid outgrowth. Administration of Fzd subtype-specific NGS Wnt in vivo reveals that adult intestinal crypt proliferation can be promoted by agonism of Fzd5 and/or Fzd8 receptors, while a broad spectrum of Fzd receptors can induce liver zonation. Thus, NGS Wnts offer a unified organoid expansion protocol and a laboratory "tool kit" for dissecting the functions of Fzd subtypes in stem cell biology.

Published
2020

6. Patient-derived head and neck cancer organoids allow treatment stratification and serve as a tool for biomarker validation and identification

Author

Millen, Rosemary, De Kort, Willem W.B., Koomen, Mandy, van Son, Gijs J.F., Gobits, Roán, Penning de Vries, Bas, Begthel, Harry, Zandvliet, Maurice, Doornaert, Patricia, Raaijmakers, Cornelis P.J., Geurts, Maarten H., Elias, Sjoerd G., van Es, Robert J.J., de Bree, Remco, Devriese, Lot A., Willems, Stefan M., Kranenburg, Onno, Driehuis, Else, and Clevers, Hans

Published
2023
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7. Nanoblades allow high-level genome editing in murine and human organoids

Author

Tiroille, Victor, Krug, Adrien, Bokobza, Emma, Kahi, Michel, Bulcaen, Mattijs, Ensinck, Marjolein M., Geurts, Maarten H., Hendriks, Delilah, Vermeulen, François, Larbret, Frédéric, Gutierrez-Guerrero, Alejandra, Chen, Yu, Van Zundert, Indra, Rocha, Susana, Rios, Anne C., Medaer, Louise, Gijsbers, Rik, Mangeot, Philippe E., Clevers, Hans, Carlon, Marianne S., Bost, Frédéric, and Verhoeyen, Els

Published
2023
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8. Tuft cells act as regenerative stem cells in the human intestine

Author

Huang, Lulu, primary, Bernink, Jochem H., additional, Giladi, Amir, additional, Krueger, Daniel, additional, van Son, Gijs J.F., additional, Geurts, Maarten H., additional, Busslinger, Georg, additional, Lin, Lin, additional, Zandvliet, Maurice, additional, Peters, Peter J., additional, Lopez-Iglesias, Carmen, additional, Buskens, Christianne J., additional, Bemelman, Willem A., additional, Begthel, Harry, additional, and Clevers, Hans, additional

Published
2024
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9. Epidermal growth factor receptor (EGFR) is a target of the tumor-suppressor E3 ligase FBXW7

Author

Boretto, Matteo, primary, Geurts, Maarten H., additional, Gandhi, Shashank, additional, Ma, Ziliang, additional, Staliarova, Nadzeya, additional, Celotti, Martina, additional, Lim, Sangho, additional, He, Gui-Wei, additional, Millen, Rosemary, additional, Driehuis, Else, additional, Begthel, Harry, additional, Smabers, Lidwien, additional, Roodhart, Jeanine, additional, van Es, Johan, additional, Wu, Wei, additional, and Clevers, Hans, additional

Published
2024
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10. Epidermal growth factor receptor (EGFR) is a target of the tumor-suppressor E3 ligase FBXW7

Author

Onderzoek Medische Oncologie, Cancer, MS Medische Oncologie, CMM, Hubrecht Institute with UMC, Boretto, Matteo, Geurts, Maarten H, Gandhi, Shashank, Ma, Ziliang, Staliarova, Nadzeya, Celotti, Martina, Lim, Sangho, He, Gui-Wei, Millen, Rosemary, Driehuis, Else, Begthel, Harry, Smabers, Lidwien, Roodhart, Jeanine, van Es, Johan, Wu, Wei, Clevers, Hans, Onderzoek Medische Oncologie, Cancer, MS Medische Oncologie, CMM, Hubrecht Institute with UMC, Boretto, Matteo, Geurts, Maarten H, Gandhi, Shashank, Ma, Ziliang, Staliarova, Nadzeya, Celotti, Martina, Lim, Sangho, He, Gui-Wei, Millen, Rosemary, Driehuis, Else, Begthel, Harry, Smabers, Lidwien, Roodhart, Jeanine, van Es, Johan, Wu, Wei, and Clevers, Hans

Published
2024

11. Epidermal growth factor receptor (EGFR) is a target of the tumor-suppressor E3 ligase FBXW7

Author

Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Boretto, Matteo, Geurts, Maarten H., Gandhi, Shashank, Ma, Ziliang, Staliarova, Nadzeya, Celotti, Martina, Lim, Sangho, He, Gui Wei, Millen, Rosemary, Driehuis, Else, Begthel, Harry, Smabers, Lidwien, Roodhart, Jeanine, van Es, Johan, Wu, Wei, Clevers, Hans, Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Boretto, Matteo, Geurts, Maarten H., Gandhi, Shashank, Ma, Ziliang, Staliarova, Nadzeya, Celotti, Martina, Lim, Sangho, He, Gui Wei, Millen, Rosemary, Driehuis, Else, Begthel, Harry, Smabers, Lidwien, Roodhart, Jeanine, van Es, Johan, Wu, Wei, and Clevers, Hans

Published
2024

13. SARS-CoV-2 Omicron entry is type II transmembrane serine protease-mediated in human airway and intestinal organoid models

Author

Mykytyn, Anna Z., primary, Breugem, Tim I., additional, Geurts, Maarten H., additional, Beumer, Joep, additional, Schipper, Debby, additional, van Acker, Romy, additional, van den Doel, Petra B., additional, van Royen, Martin E., additional, Zhang, Jingshu, additional, Clevers, Hans, additional, Haagmans, Bart L., additional, and Lamers, Mart M., additional

Published
2023
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14. Evolved Cas9 variants with broad PAM compatibility and high DNA specificity

Author

Hu, Johnny H., Miller, Shannon M., Geurts, Maarten H., Tang, Weixin, Chen, Liwei, Sun, Ning, Zeina, Christina M., Gao, Xue, Rees, Holly A., Lin, Zhi, and Liu, David R.

Subjects
DNA sequencing -- Methods, Genetic variation -- Observations, Streptococcus pyogenes -- Genetic aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

A key limitation of the use of the CRISPRCas9 system for genome editing and other applications is the requirement that a protospacer adjacent motif (PAM) be present at the target site. For the most commonly used Cas9 from Streptococcus pyogenes (SpCas9), the required PAM sequence is NGG. No natural or engineered Cas9 variants that have been shown to function efficiently in mammalian cells offer a PAM less restrictive than NGG. Here we use phage-assisted continuous evolution to evolve an expanded PAM SpCas9 variant (xCas9) that can recognize a broad range of PAM sequences including NG, GAA and GAT. The PAM compatibility of xCas9 is the broadest reported, to our knowledge, among Cas9 proteins that are active in mammalian cells, and supports applications in human cells including targeted transcriptional activation, nuclease-mediated gene disruption, and cytidine and adenine base editing. Notably, despite its broadened PAM compatibility, xCas9 has much greater DNA specificity than SpCas9, with substantially lower genome-wide off-target activity at all NGG target sites tested, as well as minimal off-target activity when targeting genomic sites with non-NGG PAMs. These findings expand the DNA targeting scope of CRISPR systems and establish that there is no necessary trade-off between Cas9 editing efficiency, PAM compatibility and DNA specificity., Author(s): Johnny H. Hu [1, 2, 3]; Shannon M. Miller [1, 2, 3]; Maarten H. Geurts [1, 2, 3]; Weixin Tang [1, 2, 3]; Liwei Chen [1, 2, 3]; Ning [...]

Published
2018
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16. Patient-derived head and neck cancer organoids allow treatment stratification and serve as a tool for biomarker validation and identification

Author

Interne geneeskunde GD, CS_Cancer, Millen, Rosemary, De Kort, Willem W B, Koomen, Mandy, van Son, Gijs J F, Gobits, Roán, Penning de Vries, Bas, Begthel, Harry, Zandvliet, Maurice, Doornaert, Patricia, Raaijmakers, Cornelis P J, Geurts, Maarten H, Elias, Sjoerd G, van Es, Robert J J, de Bree, Remco, Devriese, Lot A, Willems, Stefan M, Kranenburg, Onno, Driehuis, Else, Clevers, Hans, Interne geneeskunde GD, CS_Cancer, Millen, Rosemary, De Kort, Willem W B, Koomen, Mandy, van Son, Gijs J F, Gobits, Roán, Penning de Vries, Bas, Begthel, Harry, Zandvliet, Maurice, Doornaert, Patricia, Raaijmakers, Cornelis P J, Geurts, Maarten H, Elias, Sjoerd G, van Es, Robert J J, de Bree, Remco, Devriese, Lot A, Willems, Stefan M, Kranenburg, Onno, Driehuis, Else, and Clevers, Hans

Published
2023

17. Uncovering the mode of action of engineered T cells in patient cancer organoids

Author

Dekkers, Johanna F, Alieva, Maria, Cleven, Astrid, Keramati, Farid, Wezenaar, Amber K L, van Vliet, Esmée J, Puschhof, Jens, Brazda, Peter, Johanna, Inez, Meringa, Angelo D, Rebel, Heggert G, Buchholz, Maj-Britt, Barrera Román, Mario, Zeeman, Amber L, de Blank, Sam, Fasci, Domenico, Geurts, Maarten H, Cornel, Annelisa M, Driehuis, Else, Millen, Rosemary, Straetemans, Trudy, Nicolasen, Mara J T, Aarts-Riemens, Tineke, Ariese, Hendrikus C R, Johnson, Hannah R, van Ineveld, Ravian L, Karaiskaki, Froso, Kopper, Oded, Bar-Ephraim, Yotam E, Kretzschmar, Kai, Eggermont, Alexander M M, Nierkens, Stefan, Wehrens, Ellen J, Stunnenberg, Henk G, Clevers, Hans, Kuball, Jürgen, Sebestyen, Zsolt, Rios, Anne C, Dekkers, Johanna F, Alieva, Maria, Cleven, Astrid, Keramati, Farid, Wezenaar, Amber K L, van Vliet, Esmée J, Puschhof, Jens, Brazda, Peter, Johanna, Inez, Meringa, Angelo D, Rebel, Heggert G, Buchholz, Maj-Britt, Barrera Román, Mario, Zeeman, Amber L, de Blank, Sam, Fasci, Domenico, Geurts, Maarten H, Cornel, Annelisa M, Driehuis, Else, Millen, Rosemary, Straetemans, Trudy, Nicolasen, Mara J T, Aarts-Riemens, Tineke, Ariese, Hendrikus C R, Johnson, Hannah R, van Ineveld, Ravian L, Karaiskaki, Froso, Kopper, Oded, Bar-Ephraim, Yotam E, Kretzschmar, Kai, Eggermont, Alexander M M, Nierkens, Stefan, Wehrens, Ellen J, Stunnenberg, Henk G, Clevers, Hans, Kuball, Jürgen, Sebestyen, Zsolt, and Rios, Anne C

Abstract

Extending the success of cellular immunotherapies against blood cancers to the realm of solid tumors will require improved in vitro models that reveal therapeutic modes of action at the molecular level. Here we describe a system, called BEHAV3D, developed to study the dynamic interactions of immune cells and patient cancer organoids by means of imaging and transcriptomics. We apply BEHAV3D to live-track >150,000 engineered T cells cultured with patient-derived, solid-tumor organoids, identifying a 'super engager' behavioral cluster comprising T cells with potent serial killing capacity. Among other T cell concepts we also study cancer metabolome-sensing engineered T cells (TEGs) and detect behavior-specific gene signatures that include a group of 27 genes with no previously described T cell function that are expressed by super engager killer TEGs. We further show that type I interferon can prime resistant organoids for TEG-mediated killing. BEHAV3D is a promising tool for the characterization of behavioral-phenotypic heterogeneity of cellular immunotherapies and may support the optimization of personalized solid-tumor-targeting cell therapies.

Published
2023

18. One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids

Author

Geurts, Maarten H, Gandhi, Shashank, Boretto, Matteo G, Akkerman, Ninouk, Derks, Lucca L M, van Son, Gijs, Celotti, Martina, Harshuk-Shabso, Sarina, Peci, Flavia, Begthel, Harry, Hendriks, Delilah, Schürmann, Paul, Andersson-Rolf, Amanda, Chuva de Sousa Lopes, Susana M, van Es, Johan H, van Boxtel, Ruben, Clevers, Hans, Geurts, Maarten H, Gandhi, Shashank, Boretto, Matteo G, Akkerman, Ninouk, Derks, Lucca L M, van Son, Gijs, Celotti, Martina, Harshuk-Shabso, Sarina, Peci, Flavia, Begthel, Harry, Hendriks, Delilah, Schürmann, Paul, Andersson-Rolf, Amanda, Chuva de Sousa Lopes, Susana M, van Es, Johan H, van Boxtel, Ruben, and Clevers, Hans

Abstract

Optimization of CRISPR/Cas9-mediated genome engineering has resulted in base editors that hold promise for mutation repair and disease modeling. Here, we demonstrate the application of base editors for the generation of complex tumor models in human ASC-derived organoids. First we show efficacy of cytosine and adenine base editors in modeling CTNNB1 hot-spot mutations in hepatocyte organoids. Next, we use C > T base editors to insert nonsense mutations in PTEN in endometrial organoids and demonstrate tumorigenicity even in the heterozygous state. Moreover, drug sensitivity assays on organoids harboring either PTEN or PTEN and PIK3CA mutations reveal the mechanism underlying the initial stages of endometrial tumorigenesis. To further increase the scope of base editing we combine SpCas9 and SaCas9 for simultaneous C > T and A > G editing at individual target sites. Finally, we show that base editor multiplexing allow modeling of colorectal tumorigenesis in a single step by simultaneously transfecting sgRNAs targeting five cancer genes.

Published
2023

19. Establishment, Maintenance, Differentiation, Genetic Manipulation, and Transplantation of Mouse and Human Lacrimal Gland Organoids

Author

Bannier-Hélaouët, Marie, Geurts, Maarten H, Korving, Jeroen, Begthel, Harry, Clevers, Hans, Bannier-Hélaouët, Marie, Geurts, Maarten H, Korving, Jeroen, Begthel, Harry, and Clevers, Hans

Abstract

The lacrimal gland is an essential organ for ocular surface homeostasis. By producing the aqueous part of the tear film, it protects the eye from desiccation stress and external insults. Little is known about lacrimal gland (patho)physiology because of the lack of adequate in vitro models. Organoid technology has proven itself as a useful experimental platform for multiple organs. Here, we share a protocol to establish and maintain mouse and human lacrimal gland organoids starting from lacrimal gland biopsies. By modifying the culture conditions, we enhance lacrimal gland organoid functionality. Organoid functionality can be probed through a "crying" assay, which involves exposing the lacrimal gland organoids to selected neurotransmitters to trigger tear release in their lumen. We explain how to image and quantify this phenomenon. To investigate the role of genes of interest in lacrimal gland homeostasis, these can be genetically modified. We thoroughly describe how to genetically modify lacrimal gland organoids using base editors-from guide RNA design to organoid clone genotyping. Lastly, we show how to probe the regenerative potential of human lacrimal gland organoids by orthotopic implantation in the mouse. Together, this comprehensive toolset provides resources to use mouse and human lacrimal gland organoids to study lacrimal gland (patho)physiology.

Published
2023

20. SARS-CoV-2 Omicron entry is type II transmembrane serine protease-mediated in human airway and intestinal organoid models

Author

Mykytyn, Anna Z, Breugem, Tim I, Geurts, Maarten H, Beumer, Joep, Schipper, Debby, van Acker, Romy, van den Doel, Petra B, van Royen, Martin E, Zhang, Jingshu, Clevers, Hans, Haagmans, Bart L, Lamers, Mart M, Mykytyn, Anna Z, Breugem, Tim I, Geurts, Maarten H, Beumer, Joep, Schipper, Debby, van Acker, Romy, van den Doel, Petra B, van Royen, Martin E, Zhang, Jingshu, Clevers, Hans, Haagmans, Bart L, and Lamers, Mart M

Abstract

SARS-CoV-2 can enter cells after its spike protein is cleaved by either type II transmembrane serine proteases (TTSPs), like TMPRSS2, or cathepsins. It is now widely accepted that the Omicron variant uses TMPRSS2 less efficiently and instead enters cells via cathepsins, but these findings have yet to be verified in more relevant cell models. Although we could confirm efficient cathepsin-mediated entry for Omicron in a monkey kidney cell line, experiments with protease inhibitors showed that Omicron (BA.1 and XBB1.5) did not use cathepsins for entry into human airway organoids and instead utilized TTSPs. Likewise, CRISPR-edited intestinal organoids showed that entry of Omicron BA.1 relied on the expression of the serine protease TMPRSS2 but not cathepsin L or B. Together, these data force us to rethink the concept that Omicron has adapted to cathepsin-mediated entry and indicate that TTSP inhibitors should not be dismissed as prophylactic or therapeutic antiviral strategy against SARS-CoV-2. IMPORTANCE Coronavirus entry relies on host proteases that activate the viral fusion protein, spike. These proteases determine the viral entry route, tropism, host range, and can be attractive drug targets. Whereas earlier studies using cell lines suggested that the Omicron variant of SARS-CoV-2 has changed its protease usage, from cell surface type II transmembrane serine proteases (TTSPs) to endosomal cathepsins, we report that this is not the case in human airway and intestinal organoid models, suggesting that host TTSP inhibition is still a viable prophylactic or therapeutic antiviral strategy against current SARS-CoV-2 variants and highlighting the importance of relevant human in vitro cell models.

Published
2023

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

Author

CMM Sectie Molecular Cancer Research, CMM Groep Burgering, CMM Groep Rodriguez Colman, Cancer, CMM, Hubrecht Institute with UMC, Hendriks, Delilah, Brouwers, Jos F., Hamer, Karien, Geurts, Maarten H., Luciana, Léa, Massalini, Simone, López-Iglesias, Carmen, Peters, Peter J., Rodríguez-Colman, Maria J., Chuva de Sousa Lopes, Susana, Artegiani, Benedetta, Clevers, Hans, CMM Sectie Molecular Cancer Research, CMM Groep Burgering, CMM Groep Rodriguez Colman, Cancer, CMM, Hubrecht Institute with UMC, Hendriks, Delilah, Brouwers, Jos F., Hamer, Karien, Geurts, Maarten H., Luciana, Léa, Massalini, Simone, López-Iglesias, Carmen, Peters, Peter J., Rodríguez-Colman, Maria J., Chuva de Sousa Lopes, Susana, Artegiani, Benedetta, and Clevers, Hans

Published
2023

22. Nanoblades allow high-level genome editing in murine and human organoids

Author

CMM, Cancer, Hubrecht Institute with UMC, Tiroille, Victor, Krug, Adrien, Bokobza, Emma, Kahi, Michel, Bulcaen, Mattijs, Ensinck, Marjolein M., Geurts, Maarten H., Hendriks, Delilah, Vermeulen, François, Larbret, Frédéric, Gutierrez-Guerrero, Alejandra, Chen, Yu, Van Zundert, Indra, Rocha, Susana, Rios, Anne C., Medaer, Louise, Gijsbers, Rik, Mangeot, Philippe E., Clevers, Hans, Carlon, Marianne S., Bost, Frédéric, Verhoeyen, Els, CMM, Cancer, Hubrecht Institute with UMC, Tiroille, Victor, Krug, Adrien, Bokobza, Emma, Kahi, Michel, Bulcaen, Mattijs, Ensinck, Marjolein M., Geurts, Maarten H., Hendriks, Delilah, Vermeulen, François, Larbret, Frédéric, Gutierrez-Guerrero, Alejandra, Chen, Yu, Van Zundert, Indra, Rocha, Susana, Rios, Anne C., Medaer, Louise, Gijsbers, Rik, Mangeot, Philippe E., Clevers, Hans, Carlon, Marianne S., Bost, Frédéric, and Verhoeyen, Els

Published
2023

23. SARS-CoV-2 Omicron entry is type II transmembrane serine protease-mediated in human airway and intestinal organoid models

Author

CMM, Cancer, Hubrecht Institute with UMC, Mykytyn, Anna Z., Breugem, Tim I., Geurts, Maarten H., Beumer, Joep, Schipper, Debby, van Acker, Romy, van den Doel, Petra B., van Royen, Martin E., Zhang, Jingshu, Clevers, Hans, Haagmans, Bart L., Lamers, Mart M., CMM, Cancer, Hubrecht Institute with UMC, Mykytyn, Anna Z., Breugem, Tim I., Geurts, Maarten H., Beumer, Joep, Schipper, Debby, van Acker, Romy, van den Doel, Petra B., van Royen, Martin E., Zhang, Jingshu, Clevers, Hans, Haagmans, Bart L., and Lamers, Mart M.

Published
2023

25. One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids

Author

Hubrecht Institute with UMC, CMM, Cancer, Geurts, Maarten H., Gandhi, Shashank, Boretto, Matteo G., Akkerman, Ninouk, Derks, Lucca L.M., van Son, Gijs, Celotti, Martina, Harshuk-Shabso, Sarina, Peci, Flavia, Begthel, Harry, Hendriks, Delilah, Schürmann, Paul, Andersson-Rolf, Amanda, Chuva de Sousa Lopes, Susana M., van Es, Johan H., van Boxtel, Ruben, Clevers, Hans, Hubrecht Institute with UMC, CMM, Cancer, Geurts, Maarten H., Gandhi, Shashank, Boretto, Matteo G., Akkerman, Ninouk, Derks, Lucca L.M., van Son, Gijs, Celotti, Martina, Harshuk-Shabso, Sarina, Peci, Flavia, Begthel, Harry, Hendriks, Delilah, Schürmann, Paul, Andersson-Rolf, Amanda, Chuva de Sousa Lopes, Susana M., van Es, Johan H., van Boxtel, Ruben, and Clevers, Hans

Published
2023

26. Patient-derived head and neck cancer organoids allow treatment stratification and serve as a tool for biomarker validation and identification

Author

MKA/BT Onderzoek, Pathologie Groep Brosens, Epi Kanker Team C, MS Radiotherapie, Cancer, Klinische Fysica RT, JC onderzoeksprogramma Kanker, DHS 3D Lab, MS Hoofd-Hals Chirurgische Oncologie, MS Medische Oncologie, Pathologie Pathologen staf, Lab Translational Oncology, Regenerative Medicine and Stem Cells, CMM, Hubrecht Institute with UMC, Millen, Rosemary, De Kort, Willem W.B., Koomen, Mandy, van Son, Gijs J.F., Gobits, Roán, Penning de Vries, Bas, Begthel, Harry, Zandvliet, Maurice, Doornaert, Patricia, Raaijmakers, Cornelis P.J., Geurts, Maarten H., Elias, Sjoerd G., van Es, Robert J.J., de Bree, Remco, Devriese, Lot A., Willems, Stefan M., Kranenburg, Onno, Driehuis, Else, Clevers, Hans, MKA/BT Onderzoek, Pathologie Groep Brosens, Epi Kanker Team C, MS Radiotherapie, Cancer, Klinische Fysica RT, JC onderzoeksprogramma Kanker, DHS 3D Lab, MS Hoofd-Hals Chirurgische Oncologie, MS Medische Oncologie, Pathologie Pathologen staf, Lab Translational Oncology, Regenerative Medicine and Stem Cells, CMM, Hubrecht Institute with UMC, Millen, Rosemary, De Kort, Willem W.B., Koomen, Mandy, van Son, Gijs J.F., Gobits, Roán, Penning de Vries, Bas, Begthel, Harry, Zandvliet, Maurice, Doornaert, Patricia, Raaijmakers, Cornelis P.J., Geurts, Maarten H., Elias, Sjoerd G., van Es, Robert J.J., de Bree, Remco, Devriese, Lot A., Willems, Stefan M., Kranenburg, Onno, Driehuis, Else, and Clevers, Hans

Published
2023

27. Uncovering the mode of action of engineered T cells in patient cancer organoids

Author

CTI, CTI Sebestyen, Infection & Immunity, Cancer, Hematologie ICAT, CTI Nierkens, MS Hematologie, CTI Straetemans, CTI Beringer, CDL Patiëntenzorg MI, CTI Research, CMM, Hubrecht Institute with UMC, CTI Kuball, Regenerative Medicine and Stem Cells, Dekkers, Johanna F., Alieva, Maria, Cleven, Astrid, Keramati, Farid, Wezenaar, Amber K.L., van Vliet, Esmée J., Puschhof, Jens, Brazda, Peter, Johanna, Inez, Meringa, Angelo D., Rebel, Heggert G., Buchholz, Maj Britt, Barrera Román, Mario, Zeeman, Amber L., de Blank, Sam, Fasci, Domenico, Geurts, Maarten H., Cornel, Annelisa M., Driehuis, Else, Millen, Rosemary, Straetemans, Trudy, Nicolasen, Mara J.T., Aarts-Riemens, Tineke, Ariese, Hendrikus C.R., Johnson, Hannah R., van Ineveld, Ravian L., Karaiskaki, Froso, Kopper, Oded, Bar-Ephraim, Yotam E., Kretzschmar, Kai, Eggermont, Alexander M.M., Nierkens, Stefan, Wehrens, Ellen J., Stunnenberg, Henk G., Clevers, Hans, Kuball, Jürgen, Sebestyen, Zsolt, Rios, Anne C., CTI, CTI Sebestyen, Infection & Immunity, Cancer, Hematologie ICAT, CTI Nierkens, MS Hematologie, CTI Straetemans, CTI Beringer, CDL Patiëntenzorg MI, CTI Research, CMM, Hubrecht Institute with UMC, CTI Kuball, Regenerative Medicine and Stem Cells, Dekkers, Johanna F., Alieva, Maria, Cleven, Astrid, Keramati, Farid, Wezenaar, Amber K.L., van Vliet, Esmée J., Puschhof, Jens, Brazda, Peter, Johanna, Inez, Meringa, Angelo D., Rebel, Heggert G., Buchholz, Maj Britt, Barrera Román, Mario, Zeeman, Amber L., de Blank, Sam, Fasci, Domenico, Geurts, Maarten H., Cornel, Annelisa M., Driehuis, Else, Millen, Rosemary, Straetemans, Trudy, Nicolasen, Mara J.T., Aarts-Riemens, Tineke, Ariese, Hendrikus C.R., Johnson, Hannah R., van Ineveld, Ravian L., Karaiskaki, Froso, Kopper, Oded, Bar-Ephraim, Yotam E., Kretzschmar, Kai, Eggermont, Alexander M.M., Nierkens, Stefan, Wehrens, Ellen J., Stunnenberg, Henk G., Clevers, Hans, Kuball, Jürgen, Sebestyen, Zsolt, and Rios, Anne C.

Published
2023

28. Rapid tissue prototyping with micro-organospheres

Author

Wang, Zhaohui, primary, Boretto, Matteo, additional, Millen, Rosemary, additional, Natesh, Naveen, additional, Reckzeh, Elena S., additional, Hsu, Carolyn, additional, Negrete, Marcos, additional, Yao, Haipei, additional, Quayle, William, additional, Heaton, Brook E., additional, Harding, Alfred T., additional, Bose, Shree, additional, Driehuis, Else, additional, Beumer, Joep, additional, Rivera, Grecia O., additional, van Ineveld, Ravian L., additional, Gex, Donald, additional, DeVilla, Jessica, additional, Wang, Daisong, additional, Puschhof, Jens, additional, Geurts, Maarten H., additional, Yeung, Athena, additional, Hamele, Cait, additional, Smith, Amber, additional, Bankaitis, Eric, additional, Xiang, Kun, additional, Ding, Shengli, additional, Nelson, Daniel, additional, Delubac, Daniel, additional, Rios, Anne, additional, Abi-Hachem, Ralph, additional, Jang, David, additional, Goldstein, Bradley J., additional, Glass, Carolyn, additional, Heaton, Nicholas S., additional, Hsu, David, additional, Clevers, Hans, additional, and Shen, Xiling, additional

Published
2022
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30. Nanoblades allow high-level genome editing in organoids

Author

Tirolle, Victor, primary, Krug, Adrien, additional, Bokobza, Emma, additional, Bulcaen, Mattijs, additional, Ensinck, Marjolein M., additional, Geurts, Maarten H., additional, Hendriks, Delilah, additional, Vermeulen, François, additional, Larbret, Frédéric, additional, Gutierrez-Guerrero, Alejandra, additional, Medaer, Louise, additional, Gijsbers, Rik, additional, Mangeot, Philippe E., additional, Clevers, Hans, additional, Carlon, Marianne S., additional, Bost, Frederic, additional, and Verhoeyen, Els, additional

Published
2022
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32. Uncovering the mode of action of engineered T cells in patient cancer organoids

Author

Dekkers, Johanna F., primary, Alieva, Maria, additional, Cleven, Astrid, additional, Keramati, Farid, additional, Wezenaar, Amber K. L., additional, van Vliet, Esmée J., additional, Puschhof, Jens, additional, Brazda, Peter, additional, Johanna, Inez, additional, Meringa, Angelo D., additional, Rebel, Heggert G., additional, Buchholz, Maj-Britt, additional, Barrera Román, Mario, additional, Zeeman, Amber L., additional, de Blank, Sam, additional, Fasci, Domenico, additional, Geurts, Maarten H., additional, Cornel, Annelisa M., additional, Driehuis, Else, additional, Millen, Rosemary, additional, Straetemans, Trudy, additional, Nicolasen, Mara J. T., additional, Aarts-Riemens, Tineke, additional, Ariese, Hendrikus C. R., additional, Johnson, Hannah R., additional, van Ineveld, Ravian L., additional, Karaiskaki, Froso, additional, Kopper, Oded, additional, Bar-Ephraim, Yotam E., additional, Kretzschmar, Kai, additional, Eggermont, Alexander M. M., additional, Nierkens, Stefan, additional, Wehrens, Ellen J., additional, Stunnenberg, Henk G., additional, Clevers, Hans, additional, Kuball, Jürgen, additional, Sebestyen, Zsolt, additional, and Rios, Anne C., additional

Published
2022
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33. Uncovering the mode of action of engineered T cells in patient cancer organoids

Author

Dekkers, Johanna F, Alieva, Maria, Cleven, Astrid, Keramati, Farid, Wezenaar, Amber K L, van Vliet, Esmée J, Puschhof, Jens, Brazda, Peter, Johanna, Inez, Meringa, Angelo D, Rebel, Heggert G, Buchholz, Maj-Britt, Barrera Román, Mario, Zeeman, Amber L, de Blank, Sam, Fasci, Domenico, Geurts, Maarten H, Cornel, Annelisa M, Driehuis, Else, Millen, Rosemary, Straetemans, Trudy, Nicolasen, Mara J T, Aarts-Riemens, Tineke, Ariese, Hendrikus C R, Johnson, Hannah R, van Ineveld, Ravian L, Karaiskaki, Froso, Kopper, Oded, Bar-Ephraim, Yotam E, Kretzschmar, Kai, Eggermont, Alexander M M, Nierkens, Stefan, Wehrens, Ellen J, Stunnenberg, Henk G, Clevers, Hans, Kuball, Jürgen, Sebestyen, Zsolt, Rios, Anne C, Dekkers, Johanna F, Alieva, Maria, Cleven, Astrid, Keramati, Farid, Wezenaar, Amber K L, van Vliet, Esmée J, Puschhof, Jens, Brazda, Peter, Johanna, Inez, Meringa, Angelo D, Rebel, Heggert G, Buchholz, Maj-Britt, Barrera Román, Mario, Zeeman, Amber L, de Blank, Sam, Fasci, Domenico, Geurts, Maarten H, Cornel, Annelisa M, Driehuis, Else, Millen, Rosemary, Straetemans, Trudy, Nicolasen, Mara J T, Aarts-Riemens, Tineke, Ariese, Hendrikus C R, Johnson, Hannah R, van Ineveld, Ravian L, Karaiskaki, Froso, Kopper, Oded, Bar-Ephraim, Yotam E, Kretzschmar, Kai, Eggermont, Alexander M M, Nierkens, Stefan, Wehrens, Ellen J, Stunnenberg, Henk G, Clevers, Hans, Kuball, Jürgen, Sebestyen, Zsolt, and Rios, Anne C

Abstract

Extending the success of cellular immunotherapies against blood cancers to the realm of solid tumors will require improved in vitro models that reveal therapeutic modes of action at the molecular level. Here we describe a system, called BEHAV3D, developed to study the dynamic interactions of immune cells and patient cancer organoids by means of imaging and transcriptomics. We apply BEHAV3D to live-track >150,000 engineered T cells cultured with patient-derived, solid-tumor organoids, identifying a 'super engager' behavioral cluster comprising T cells with potent serial killing capacity. Among other T cell concepts we also study cancer metabolome-sensing engineered T cells (TEGs) and detect behavior-specific gene signatures that include a group of 27 genes with no previously described T cell function that are expressed by super engager killer TEGs. We further show that type I interferon can prime resistant organoids for TEG-mediated killing. BEHAV3D is a promising tool for the characterization of behavioral-phenotypic heterogeneity of cellular immunotherapies and may support the optimization of personalized solid-tumor-targeting cell therapies.

Published
2022

34. Rapid tissue prototyping with micro-organospheres

Author

Wang, Zhaohui, Boretto, Matteo, Millen, Rosemary, Natesh, Naveen, Reckzeh, Elena S, Hsu, Carolyn, Negrete, Marcos, Yao, Haipei, Quayle, William, Heaton, Brook E, Harding, Alfred T, Bose, Shree, Driehuis, Else, Beumer, Joep, Rivera, Grecia O, van Ineveld, Ravian L, Gex, Donald, DeVilla, Jessica, Wang, Daisong, Puschhof, Jens, Geurts, Maarten H, Yeung, Athena, Hamele, Cait, Smith, Amber, Bankaitis, Eric, Xiang, Kun, Ding, Shengli, Nelson, Daniel, Delubac, Daniel, Rios, Anne, Abi-Hachem, Ralph, Jang, David, Goldstein, Bradley J, Glass, Carolyn, Heaton, Nicholas S, Hsu, David, Clevers, Hans, Shen, Xiling, Wang, Zhaohui, Boretto, Matteo, Millen, Rosemary, Natesh, Naveen, Reckzeh, Elena S, Hsu, Carolyn, Negrete, Marcos, Yao, Haipei, Quayle, William, Heaton, Brook E, Harding, Alfred T, Bose, Shree, Driehuis, Else, Beumer, Joep, Rivera, Grecia O, van Ineveld, Ravian L, Gex, Donald, DeVilla, Jessica, Wang, Daisong, Puschhof, Jens, Geurts, Maarten H, Yeung, Athena, Hamele, Cait, Smith, Amber, Bankaitis, Eric, Xiang, Kun, Ding, Shengli, Nelson, Daniel, Delubac, Daniel, Rios, Anne, Abi-Hachem, Ralph, Jang, David, Goldstein, Bradley J, Glass, Carolyn, Heaton, Nicholas S, Hsu, David, Clevers, Hans, and Shen, Xiling

Abstract

In vitro tissue models hold great promise for modeling diseases and drug responses. Here, we used emulsion microfluidics to form micro-organospheres (MOSs), which are droplet-encapsulated miniature three-dimensional (3D) tissue models that can be established rapidly from patient tissues or cells. MOSs retain key biological features and responses to chemo-, targeted, and radiation therapies compared with organoids. The small size and large surface-to-volume ratio of MOSs enable various applications including quantitative assessment of nutrient dependence, pathogen-host interaction for anti-viral drug screening, and a rapid potency assay for chimeric antigen receptor (CAR)-T therapy. An automated MOS imaging pipeline combined with machine learning overcomes plating variation, distinguishes tumorspheres from stroma, differentiates cytostatic versus cytotoxic drug effects, and captures resistant clones and heterogeneity in drug response. This pipeline is capable of robust assessments of drug response at individual-tumorsphere resolution and provides a rapid and high-throughput therapeutic profiling platform for precision medicine.

Published
2022

35. Differentiation and CRISPR-Cas9-mediated genetic engineering of human intestinal organoids

Author

Martinez-Silgado, Adriana, Yousef Yengej, Fjodor A, Puschhof, Jens, Geurts, Veerle, Boot, Charelle, Geurts, Maarten H, Rookmaaker, Maarten B, Verhaar, Marianne C, Beumer, Joep, Clevers, Hans, Martinez-Silgado, Adriana, Yousef Yengej, Fjodor A, Puschhof, Jens, Geurts, Veerle, Boot, Charelle, Geurts, Maarten H, Rookmaaker, Maarten B, Verhaar, Marianne C, Beumer, Joep, and Clevers, Hans

Abstract

Intestinal organoids are three-dimensional cultures that resemble key aspects of the epithelium of origin. Here, we describe how to differentiate human small intestinal organoids by combining growth media variations and genetic engineering. We detail the differentiation of human intestinal organoids in the presence and absence of BMP agonists to recapitulate a broader scope of functional cell states found in vivo. Using transient overexpression of the transcription factor Neurogenin-3, we describe the enhancement of differentiation toward rare enteroendocrine cells. For complete details on the use and execution of this protocol, please refer to Beumer et al. (2022).

Published
2022

36. Rapid tissue prototyping with micro-organospheres

Author

CMM, Cancer, Hubrecht Institute with UMC, Wang, Zhaohui, Boretto, Matteo, Millen, Rosemary, Natesh, Naveen, Reckzeh, Elena S., Hsu, Carolyn, Negrete, Marcos, Yao, Haipei, Quayle, William, Heaton, Brook E., Harding, Alfred T., Bose, Shree, Driehuis, Else, Beumer, Joep, Rivera, Grecia O., van Ineveld, Ravian L., Gex, Donald, DeVilla, Jessica, Wang, Daisong, Puschhof, Jens, Geurts, Maarten H., Yeung, Athena, Hamele, Cait, Smith, Amber, Bankaitis, Eric, Xiang, Kun, Ding, Shengli, Nelson, Daniel, Delubac, Daniel, Rios, Anne, Abi-Hachem, Ralph, Jang, David, Goldstein, Bradley J., Glass, Carolyn, Heaton, Nicholas S., Hsu, David, Clevers, Hans, Shen, Xiling, CMM, Cancer, Hubrecht Institute with UMC, Wang, Zhaohui, Boretto, Matteo, Millen, Rosemary, Natesh, Naveen, Reckzeh, Elena S., Hsu, Carolyn, Negrete, Marcos, Yao, Haipei, Quayle, William, Heaton, Brook E., Harding, Alfred T., Bose, Shree, Driehuis, Else, Beumer, Joep, Rivera, Grecia O., van Ineveld, Ravian L., Gex, Donald, DeVilla, Jessica, Wang, Daisong, Puschhof, Jens, Geurts, Maarten H., Yeung, Athena, Hamele, Cait, Smith, Amber, Bankaitis, Eric, Xiang, Kun, Ding, Shengli, Nelson, Daniel, Delubac, Daniel, Rios, Anne, Abi-Hachem, Ralph, Jang, David, Goldstein, Bradley J., Glass, Carolyn, Heaton, Nicholas S., Hsu, David, Clevers, Hans, and Shen, Xiling

Published
2022

37. Differentiation and CRISPR-Cas9-mediated genetic engineering of human intestinal organoids

Author

Nefro Vasculaire Geneeskunde, MS Nefrologie, Regenerative Medicine and Stem Cells, Circulatory Health, CMM, Cancer, Hubrecht Institute with UMC, Martinez-Silgado, Adriana, Yousef Yengej, Fjodor A., Puschhof, Jens, Geurts, Veerle, Boot, Charelle, Geurts, Maarten H., Rookmaaker, Maarten B., Verhaar, Marianne C., Beumer, Joep, Clevers, Hans, Nefro Vasculaire Geneeskunde, MS Nefrologie, Regenerative Medicine and Stem Cells, Circulatory Health, CMM, Cancer, Hubrecht Institute with UMC, Martinez-Silgado, Adriana, Yousef Yengej, Fjodor A., Puschhof, Jens, Geurts, Veerle, Boot, Charelle, Geurts, Maarten H., Rookmaaker, Maarten B., Verhaar, Marianne C., Beumer, Joep, and Clevers, Hans

Published
2022

38. Modelling of primary ciliary dyskinesia using patient‐derived airway organoids

Author

van der Vaart, Jelte, primary, Böttinger, Lena, additional, Geurts, Maarten H, additional, van de Wetering, Willine J, additional, Knoops, Kèvin, additional, Sachs, Norman, additional, Begthel, Harry, additional, Korving, Jeroen, additional, Lopez‐Iglesias, Carmen, additional, Peters, Peter J, additional, Eitan, Kerem, additional, Gileles‐Hillel, Alex, additional, and Clevers, Hans, additional

Published
2021
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40. A CRISPR/Cas9 genetically engineered organoid biobank reveals essential host factors for coronaviruses

Author

Beumer, Joep, primary, Geurts, Maarten H., additional, Lamers, Mart M., additional, Puschhof, Jens, additional, Zhang, Jingshu, additional, van der Vaart, Jelte, additional, Mykytyn, Anna Z., additional, Breugem, Tim I., additional, Riesebosch, Samra, additional, Schipper, Debby, additional, van den Doel, Petra B., additional, Lau, Wim de, additional, Pleguezuelos-Manzano, Cayetano, additional, Busslinger, Georg, additional, Haagmans, Bart L., additional, and Clevers, Hans, additional

Published
2021
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41. Behavioral-transcriptomic landscape of engineered T cells targeting human cancer organoids

Author

Dekkers, Johanna F., primary, Alieva, Maria, additional, Cleven, Astrid, additional, Keramati, Farid, additional, Brazda, Peter, additional, Rebel, Heggert G., additional, Wezenaar, Amber K.L., additional, Puschhof, Jens, additional, Buchholz, Maj-Britt, additional, Román, Mario Barrera, additional, Johanna, Inez, additional, Meringa, Angelo D., additional, Fasci, Domenico, additional, Geurts, Maarten H., additional, Ariese, Hendrikus C.R., additional, van Vliet, Esmée J., additional, van Ineveld, Ravian L., additional, Karaiskaki, Effrosyni, additional, Kopper, Oded, additional, Bar-Ephraim, Yotam E., additional, Kretzschmar, Kai, additional, Eggermont, Alexander M.M., additional, Wehrens, Ellen J., additional, Stunnenberg, Henk G., additional, Clevers, Hans, additional, Kuball, Jürgen, additional, Sebestyen, Zsolt, additional, and Rios, Anne C., additional

Published
2021
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42. Modelling of primary ciliary dyskinesia using patient-derived airway organoids

Author

van der Vaart, Jelte, Böttinger, Lena, Geurts, Maarten H, van de Wetering, Willine J, Knoops, Kèvin, Sachs, Norman, Begthel, Harry, Korving, Jeroen, Lopez-Iglesias, Carmen, Peters, Peter J, Eitan, Kerem, Gileles-Hillel, Alex, Clevers, Hans, van der Vaart, Jelte, Böttinger, Lena, Geurts, Maarten H, van de Wetering, Willine J, Knoops, Kèvin, Sachs, Norman, Begthel, Harry, Korving, Jeroen, Lopez-Iglesias, Carmen, Peters, Peter J, Eitan, Kerem, Gileles-Hillel, Alex, and Clevers, Hans

Abstract

Patient-derived human organoids can be used to model a variety of diseases. Recently, we described conditions for long-term expansion of human airway organoids (AOs) directly from healthy individuals and patients. Here, we first optimize differentiation of AOs towards ciliated cells. After differentiation of the AOs towards ciliated cells, these can be studied for weeks. When returned to expansion conditions, the organoids readily resume their growth. We apply this condition to AOs established from nasal inferior turbinate brush samples of patients suffering from primary ciliary dyskinesia (PCD), a pulmonary disease caused by dysfunction of the motile cilia in the airways. Patient-specific differences in ciliary beating are observed and are in agreement with the patients' genetic mutations. More detailed organoid ciliary phenotypes can thus be documented in addition to the standard diagnostic procedure. Additionally, using genetic editing tools, we show that a patient-specific mutation can be repaired. This study demonstrates the utility of organoid technology for investigating hereditary airway diseases such as PCD.

Published
2021

43. Evaluating CRISPR-based prime editing for cancer modeling and CFTR repair in organoids

Author

Geurts, Maarten H, de Poel, Eyleen, Pleguezuelos-Manzano, Cayetano, Oka, Rurika, Carrillo, Léo, Andersson-Rolf, Amanda, Boretto, Matteo, Brunsveld, Jesse E, van Boxtel, Ruben, Beekman, Jeffrey M, Clevers, Hans, Geurts, Maarten H, de Poel, Eyleen, Pleguezuelos-Manzano, Cayetano, Oka, Rurika, Carrillo, Léo, Andersson-Rolf, Amanda, Boretto, Matteo, Brunsveld, Jesse E, van Boxtel, Ruben, Beekman, Jeffrey M, and Clevers, Hans

Abstract

Prime editing is a recently reported genome editing tool using a nickase-cas9 fused to a reverse transcriptase that directly synthesizes the desired edit at the target site. Here, we explore the use of prime editing in human organoids. Common TP53 mutations can be correctly modeled in human adult stem cell-derived colonic organoids with efficiencies up to 25% and up to 97% in hepatocyte organoids. Next, we functionally repaired the cystic fibrosis CFTR-F508del mutation and compared prime editing to CRISPR/Cas9-mediated homology-directed repair and adenine base editing on the CFTR-R785* mutation. Whole-genome sequencing of prime editing-repaired organoids revealed no detectable off-target effects. Despite encountering varying editing efficiencies and undesired mutations at the target site, these results underline the broad applicability of prime editing for modeling oncogenic mutations and showcase the potential clinical application of this technique, pending further optimization.

Published
2021

44. The Organoid Platform: Promises and Challenges as Tools in the Fight against COVID-19

Author

Geurts, Maarten H, van der Vaart, Jelte, Beumer, Joep, Clevers, Hans, Geurts, Maarten H, van der Vaart, Jelte, Beumer, Joep, and Clevers, Hans

Abstract

Many pathogenic viruses that affect man display species specificity, limiting the use of animal models. Studying viral biology and identifying potential treatments therefore benefits from the development of in vitro cell systems that closely mimic human physiology. In the current COVID-19 pandemic, rapid scientific insights are of the utmost importance to limit its impact on public health and society. Organoids are emerging as versatile tools to progress the understanding of SARS-CoV-2 biology and to aid in the quest for novel treatments.

Published
2021

45. Evaluating CRISPR-based prime editing for cancer modeling and CFTR repair in organoids

Author

Longziekten onderzoek 2, CMM Groep Cuppen, Onderzoek, Child Health, Regenerative Medicine and Stem Cells, Hubrecht Institute with UMC, CMM Sectie Molecular Cancer Research, Geurts, Maarten H., de Poel, Eyleen, Pleguezuelos-Manzano, Cayetano, Oka, Rurika, Carrillo, Léo, Andersson-Rolf, Amanda, Boretto, Matteo, Brunsveld, Jesse E., van Boxtel, Ruben, Beekman, Jeffrey M., Clevers, Hans, Longziekten onderzoek 2, CMM Groep Cuppen, Onderzoek, Child Health, Regenerative Medicine and Stem Cells, Hubrecht Institute with UMC, CMM Sectie Molecular Cancer Research, Geurts, Maarten H., de Poel, Eyleen, Pleguezuelos-Manzano, Cayetano, Oka, Rurika, Carrillo, Léo, Andersson-Rolf, Amanda, Boretto, Matteo, Brunsveld, Jesse E., van Boxtel, Ruben, Beekman, Jeffrey M., and Clevers, Hans

Published
2021

46. A CRISPR/Cas9 genetically engineered organoid biobank reveals essential host factors for coronaviruses

Author

CMM Groep Maurice, Hubrecht Institute with UMC, Beumer, Joep, Geurts, Maarten H., Lamers, Mart M., Puschhof, Jens, Zhang, Jingshu, van der Vaart, Jelte, Mykytyn, Anna Z., Breugem, Tim I., Riesebosch, Samra, Schipper, Debby, van den Doel, Petra B., de Lau, Wim, Pleguezuelos-Manzano, Cayetano, Busslinger, Georg, Haagmans, Bart L., Clevers, Hans, CMM Groep Maurice, Hubrecht Institute with UMC, Beumer, Joep, Geurts, Maarten H., Lamers, Mart M., Puschhof, Jens, Zhang, Jingshu, van der Vaart, Jelte, Mykytyn, Anna Z., Breugem, Tim I., Riesebosch, Samra, Schipper, Debby, van den Doel, Petra B., de Lau, Wim, Pleguezuelos-Manzano, Cayetano, Busslinger, Georg, Haagmans, Bart L., and Clevers, Hans

Published
2021

47. Modelling of primary ciliary dyskinesia using patient-derived airway organoids

Author

Hubrecht Institute with UMC, van der Vaart, Jelte, Böttinger, Lena, Geurts, Maarten H., van de Wetering, Willine J., Knoops, Kèvin, Sachs, Norman, Begthel, Harry, Korving, Jeroen, Lopez-Iglesias, Carmen, Peters, Peter J., Eitan, Kerem, Gileles-Hillel, Alex, Clevers, Hans, Hubrecht Institute with UMC, van der Vaart, Jelte, Böttinger, Lena, Geurts, Maarten H., van de Wetering, Willine J., Knoops, Kèvin, Sachs, Norman, Begthel, Harry, Korving, Jeroen, Lopez-Iglesias, Carmen, Peters, Peter J., Eitan, Kerem, Gileles-Hillel, Alex, and Clevers, Hans

Published
2021

49. Modeling Breast Cancer Using CRISPR-Cas9-Mediated Engineering of Human Breast Organoids

Author

Dekkers, Johanna F., Whittle, James R., Vaillant, François, Chen, Huei Rong, Dawson, Caleb, Liu, Kevin, Geurts, Maarten H., Herold, Marco J., Clevers, Hans, Lindeman, Geoffrey J., Visvader, Jane E., Dekkers, Johanna F., Whittle, James R., Vaillant, François, Chen, Huei Rong, Dawson, Caleb, Liu, Kevin, Geurts, Maarten H., Herold, Marco J., Clevers, Hans, Lindeman, Geoffrey J., and Visvader, Jane E.

Published
2020

50. High-Resolution mRNA and Secretome Atlas of Human Enteroendocrine Cells

Author

Beumer, Joep, Beumer, Joep, Puschhof, Jens, Bauza-Martinez, Julia, Martinez-Silgado, Adriana, Elmentaite, Rasa, James, Kylie R., Ross, Alexander, Hendriks, Delilah, Artegiani, Benedetta, Busslinger, Georg A., Ponsioen, Bas, Andersson-Rolf, Amanda, Saftien, Aurelia, Boot, Charelle, Kretzschmar, Kai, Geurts, Maarten H., Bar-Ephraim, Yotam E., Pleguezuelos-Manzano, Cayetano, Post, Yorick, Begthel, Harry, van der Linden, Franka, Lopez-Iglesias, Carmen, van de Wetering, Willine J., van der Linden, Reinier, Peters, Peter J., Heck, Albert J. R., Goedhart, Joachim, Snippert, Hugo, Zilbauer, Matthias, Teichmann, Sarah A., Wu, Wei, Clevers, Hans, Beumer, Joep, Beumer, Joep, Puschhof, Jens, Bauza-Martinez, Julia, Martinez-Silgado, Adriana, Elmentaite, Rasa, James, Kylie R., Ross, Alexander, Hendriks, Delilah, Artegiani, Benedetta, Busslinger, Georg A., Ponsioen, Bas, Andersson-Rolf, Amanda, Saftien, Aurelia, Boot, Charelle, Kretzschmar, Kai, Geurts, Maarten H., Bar-Ephraim, Yotam E., Pleguezuelos-Manzano, Cayetano, Post, Yorick, Begthel, Harry, van der Linden, Franka, Lopez-Iglesias, Carmen, van de Wetering, Willine J., van der Linden, Reinier, Peters, Peter J., Heck, Albert J. R., Goedhart, Joachim, Snippert, Hugo, Zilbauer, Matthias, Teichmann, Sarah A., Wu, Wei, and Clevers, Hans

Abstract

Enteroendocrine cells (EECs) sense intestinal content and release hormones to regulate gastrointestinal activity, systemic metabolism, and food intake. Little is known about the molecular make-up of human EEC subtypes and the regulated secretion of individual hormones. Here, we describe an organoid-based platform for functional studies of human EECs. EEC formation is induced in vitro by transient expression of NEUROG3. A set of gut organoids was engineered in which the major hormones are fluorescently tagged. A single-cell mRNA atlas was generated for the different EEC subtypes, and their secreted products were recorded by mass-spectrometry. We note key differences to murine EECs, including hormones, sensory receptors, and transcription factors. Notably, several hormone-like molecules were identified. Inter-EEC communication is exemplified by secretin-induced GLP-1 secretion. Indeed, individual EEC subtypes carry receptors for various EEC hormones. This study provides a rich resource to study human EEC development and function.

Published
2020

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