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| Format: | Artículo Open Access |
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Wiley
2024
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| Online-Zugang: | https://pathsocjournals.onlinelibrary.wiley.com/doi/10.1002/path.6366 |
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| author | Nolwenn Laborde Alexandre Barusseaud Muriel Quaranta Corinne Rolland Amélie Arrouy Delphine Bonnet Sylvain Kirzin Nuria Sola‐Tapias Dimitri Hamel Karl Barange Jean‐Pierre Duffas Marie‐Pierre Gratacap Julie Guillermet‐Guibert Anne Breton Nathalie Vergnolle Laurent Alric Audrey Ferrand Frédérick Barreau Claire Racaud‐Sultan Emmanuel Mas |
| author_facet | Nolwenn Laborde Alexandre Barusseaud Muriel Quaranta Corinne Rolland Amélie Arrouy Delphine Bonnet Sylvain Kirzin Nuria Sola‐Tapias Dimitri Hamel Karl Barange Jean‐Pierre Duffas Marie‐Pierre Gratacap Julie Guillermet‐Guibert Anne Breton Nathalie Vergnolle Laurent Alric Audrey Ferrand Frédérick Barreau Claire Racaud‐Sultan Emmanuel Mas Nolwenn Laborde Alexandre Barusseaud Muriel Quaranta Corinne Rolland Amélie Arrouy Delphine Bonnet Sylvain Kirzin Nuria Sola‐Tapias Dimitri Hamel Karl Barange Jean‐Pierre Duffas Marie‐Pierre Gratacap Julie Guillermet‐Guibert Anne Breton Nathalie Vergnolle Laurent Alric Audrey Ferrand Frédérick Barreau Claire Racaud‐Sultan Emmanuel Mas |
| collection | Wiley Open Access |
| contents | Human colonic organoids for understanding early events of familial adenomatous polyposis pathogenesis Nolwenn Laborde Alexandre Barusseaud Muriel Quaranta Corinne Rolland Amélie Arrouy Delphine Bonnet Sylvain Kirzin Nuria Sola‐Tapias Dimitri Hamel Karl Barange Jean‐Pierre Duffas Marie‐Pierre Gratacap Julie Guillermet‐Guibert Anne Breton Nathalie Vergnolle Laurent Alric Audrey Ferrand Frédérick Barreau Claire Racaud‐Sultan Emmanuel Mas The Journal of Pathology Abstract Patients with familial adenomatous polyposis (FAP) harbor mutations in the APC gene and will develop adenoma and early colorectal cancer. There is no validated treatment, and animal models are not sufficient to study FAP. Our aim was to investigate the early events associated with FAP using the intestinal organoid model in a single‐center study using biopsies from nonadenomatous and adenomatous colonic mucosa of FAP patients and from healthy controls (HCs). We analyzed intestinal stem cell (ISC) activity and regulation through organoid development and expression of mRNA and proteins, as well as within colonic crypts. We used several compounds to regulate the signaling pathways controlling ISCs, such as WNT, EGFR, PI3K‐AKT, TGF‐β, yes‐associated protein (YAP), and protease‐activated receptors. In addition to their high proliferative capacity, nonadenomatous and adenomatous organoids were characterized by cysts and cysts with buds, respectively, suggesting abnormal maturation. Adenomatous organoids were enriched in the stem cell marker LGR5 and dependent on EGF and TGF‐β for their growth. Downstream of EGFR, AKT, β‐catenin, and YAP were found to be activated in the adenomatous organoids. While the p110β isoform of PI3K was predominant in adenomatous organoids and essential for their growth, p110α was associated with the immature state of nonadenomatous organoids. We conclude that organoids offer a relevant model for studying FAP, and this work highlights abnormal behaviors of immature cells in both nonadenomatous and adenomatous mucosa of FAP patients, which could be targeted therapeutically. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. 10.1002/path.6366 http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| doi_str_mv | 10.1002/path.6366 |
| format | Artículo Open Access |
| id | wiley_oa_10_1002_path_6366 |
| institution | Wiley Open Access |
| license_str_mv | http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| publishDate | 2024 |
| publisher | Wiley |
| record_format | wiley_oa |
| spellingShingle | Human colonic organoids for understanding early events of familial adenomatous polyposis pathogenesis Nolwenn Laborde Alexandre Barusseaud Muriel Quaranta Corinne Rolland Amélie Arrouy Delphine Bonnet Sylvain Kirzin Nuria Sola‐Tapias Dimitri Hamel Karl Barange Jean‐Pierre Duffas Marie‐Pierre Gratacap Julie Guillermet‐Guibert Anne Breton Nathalie Vergnolle Laurent Alric Audrey Ferrand Frédérick Barreau Claire Racaud‐Sultan Emmanuel Mas The Journal of Pathology Human colonic organoids for understanding early events of familial adenomatous polyposis pathogenesis Nolwenn Laborde Alexandre Barusseaud Muriel Quaranta Corinne Rolland Amélie Arrouy Delphine Bonnet Sylvain Kirzin Nuria Sola‐Tapias Dimitri Hamel Karl Barange Jean‐Pierre Duffas Marie‐Pierre Gratacap Julie Guillermet‐Guibert Anne Breton Nathalie Vergnolle Laurent Alric Audrey Ferrand Frédérick Barreau Claire Racaud‐Sultan Emmanuel Mas The Journal of Pathology Abstract Patients with familial adenomatous polyposis (FAP) harbor mutations in the APC gene and will develop adenoma and early colorectal cancer. There is no validated treatment, and animal models are not sufficient to study FAP. Our aim was to investigate the early events associated with FAP using the intestinal organoid model in a single‐center study using biopsies from nonadenomatous and adenomatous colonic mucosa of FAP patients and from healthy controls (HCs). We analyzed intestinal stem cell (ISC) activity and regulation through organoid development and expression of mRNA and proteins, as well as within colonic crypts. We used several compounds to regulate the signaling pathways controlling ISCs, such as WNT, EGFR, PI3K‐AKT, TGF‐β, yes‐associated protein (YAP), and protease‐activated receptors. In addition to their high proliferative capacity, nonadenomatous and adenomatous organoids were characterized by cysts and cysts with buds, respectively, suggesting abnormal maturation. Adenomatous organoids were enriched in the stem cell marker LGR5 and dependent on EGF and TGF‐β for their growth. Downstream of EGFR, AKT, β‐catenin, and YAP were found to be activated in the adenomatous organoids. While the p110β isoform of PI3K was predominant in adenomatous organoids and essential for their growth, p110α was associated with the immature state of nonadenomatous organoids. We conclude that organoids offer a relevant model for studying FAP, and this work highlights abnormal behaviors of immature cells in both nonadenomatous and adenomatous mucosa of FAP patients, which could be targeted therapeutically. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. 10.1002/path.6366 http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| title | Human colonic organoids for understanding early events of familial adenomatous polyposis pathogenesis |
| topic | The Journal of Pathology |
| url | https://pathsocjournals.onlinelibrary.wiley.com/doi/10.1002/path.6366 |