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Title: | Loss of enteric neuronal Ndrg4 promotes colorectal cancer via increased release of Nid1 and Fbln2 | Authors: | Vaes, Nathalie Schonkeren, Simone L. Rademakers, Glenn HOLLAND, Amy Koch, Alexander Gijbels, Marion J. Keulers, Tom G. de Wit, Meike Van der Meer, Jaleesa R. M. van den Boezem, Edith Wolfs, Tim G. A. M. Threadgill, David W. Demmers, Jeroen Fijneman, Remond J. A. Jimenez, Connie R. Vanden Berghe, Pieter Smits, Kim M. Rouschop, Kasper M. A. BOESMANS, Werend Hofstra, Robert M. W. Melotte, Veerle Moonen, Laura |
Issue Date: | 2021 | Publisher: | WILEY | Source: | EMBO REPORTS, 22(6), (Art N° e51913) | Abstract: | The N-Myc Downstream-Regulated Gene 4 (NDRG4), a prominent biomarker for colorectal cancer (CRC), is specifically expressed by enteric neurons. Considering that nerves are important members of the tumor microenvironment, we here establish different Ndrg4 knockout (Ndrg4(-/-)) CRC models and an indirect co-culture of primary enteric nervous system (ENS) cells and intestinal organoids to identify whether the ENS, via NDRG4, affects intestinal tumorigenesis. Linking immunostainings and gastrointestinal motility (GI) assays, we show that the absence of Ndrg4 does not trigger any functional or morphological GI abnormalities. However, combining in vivo, in vitro, and quantitative proteomics data, we uncover that Ndrg4 knockdown is associated with enlarged intestinal adenoma development and that organoid growth is boosted by the Ndrg4(-/-) ENS cell secretome, which is enriched for Nidogen-1 (Nid1) and Fibulin-2 (Fbln2). Moreover, NID1 and FBLN2 are expressed in enteric neurons, enhance migration capacities of CRC cells, and are enriched in human CRC secretomes. Hence, we provide evidence that the ENS, via loss of Ndrg4, is involved in colorectal pathogenesis and that ENS-derived Nidogen-1 and Fibulin-2 enhance colorectal carcinogenesis. | Notes: | Melotte, V (corresponding author), Maastricht Univ, GROW Sch Oncol & Dev Biol, Dept Pathol, Med Ctr, Maastricht, Netherlands.; Melotte, V (corresponding author), Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands. veerle.melotte@maastrichtuniversity.nl |
Other: | Melotte, V (corresponding author), Maastricht Univ, GROW Sch Oncol & Dev Biol, Dept Pathol, Med Ctr, Maastricht, Netherlands ; Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands. veerle.melotte@maastrichtuniversity.nl | Keywords: | colorectal cancer;enteric nervous system;Fibulin‐2;Ndrg4;Nidogen‐1 | Document URI: | http://hdl.handle.net/1942/34135 | ISSN: | 1469-221X | e-ISSN: | 1469-3178 | DOI: | 10.15252/embr.202051913 | ISI #: | WOS:000642444200001 | Rights: | 2021 The Authors. Published under the terms of the CC BY NC ND 4.0 license | Category: | A1 | Type: | Journal Contribution | Validations: | ecoom 2022 |
Appears in Collections: | Research publications |
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EMBO Reports - 2021 - Vaes - Loss of enteric neuronal Ndrg4 promotes colorectal cancer via increased release of Nid1 and.pdf | Published version | 5.37 MB | Adobe PDF | View/Open |
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