TY - JOUR
T1 - Loss of enteric neuronal Ndrg4 promotes colorectal cancer via increased release of Nid1 and Fbln2
AU - Vaes, Nathalie
AU - Schonkeren, Simone L.
AU - Rademakers, Glenn
AU - Holland, Amy M.
AU - Koch, Alexander
AU - Gijbels, Marion J.
AU - Keulers, Tom G.
AU - de Wit, Meike
AU - Moonen, Laura
AU - Van der Meer, Jaleesa R. M.
AU - van den Boezem, Edith
AU - Wolfs, Tim G. A. M.
AU - Threadgill, David W.
AU - Demmers, Jeroen
AU - Fijneman, Remond J. A.
AU - Jimenez, Connie R.
AU - Vanden Berghe, Pieter
AU - Smits, Kim M.
AU - Rouschop, Kasper M. A.
AU - Boesmans, Werend
AU - Hofstra, Robert M. W.
AU - Melotte, Veerle
PY - 2021/6/4
Y1 - 2021/6/4
N2 - 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.
AB - 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.
KW - colorectal cancer
KW - enteric nervous system
KW - Fibulin‐
KW - 2
KW - Ndrg4
KW - Nidogen‐
KW - 1
U2 - 10.15252/embr.202051913
DO - 10.15252/embr.202051913
M3 - Article
C2 - 33890711
VL - 22
JO - Embo Reports
JF - Embo Reports
SN - 1469-221X
IS - 6
M1 - e51913
ER -