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Articles
Articles
Kakiailatu, N. J. M., Zhang, W., Kuil, L. E., Bindels, E., Zink, J. T. M., Vermeulen, M., de Pater, E., Melotte, V., & Alves, M. M. (2025). Retinoic Acid Inhibition Alters Intestinal Composition in Zebrafish: A Non-genetic Model to Study Hirschsprung Disease? Neurogastroenterology and Motility, 37(11), Article e70155. doi.org/10.1111/nmo.70155
Thijssen, M. S., Massen, M., van der Meer, J. R. M., Gijbels, M. J., Samarska, I. V., van Engeland, M., Weijenberg, M. P., van den Brandt, P. A., Smits, K. M., Boesmans, W., & Melotte, V. (2025). Clinicopathological characterization of enteric glia in colorectal cancer: Insights from a population-based cohort. Journal of neuropathology and experimental neurology, 84(10), 892-901. doi.org/10.1093/jnen/nlaf067
Tasnády, K. R., Jehoul, R., de Ravé, M. G., Gijbels, M. J., Brône, B., Dewachter, I., Melotte, V., & Boesmans, W. (2025). Gastrointestinal Dysfunction and Low-Grade Inflammation Associate With Enteric Neuronal Amyloid-β in a Model for Amyloid Pathology. Neurogastroenterology and Motility, 37(5), Article e15016. doi.org/10.1111/nmo.15016
Windster, J. D., Kakiailatu, N. J. M., Kuil, L. E., Antanaviciute, A., Sacchetti, A., MacKenzie, K. C., Peulen-Zink, J., Kan, T. W., Bindels, E., de Pater, E., Doukas, M., van den Bosch, T. P. P., Yousefi, S., Barakat, T. S., Meeussen, C., Sloots, C. E. J., Wijnen, R. M. H., Parikh, K., Boesmans, W., ... Alves, M. M. (2025). Human enteric glia diversity in health and disease: new avenues for the treatment of Hirschsprung disease. Gastroenterology, 168(5), 965-979.e12. doi.org/10.1053/j.gastro.2024.12.011
Massen, M., Thijssen, M. S., Rademakers, G., Idris, M., Wouters, K. A. D., van der Meer, J. R. M., Buekers, N., Huijgen, D., Samarska, I. V., Weijenberg, M. P., van den Brandt, P. A., van Engeland, M., Gijbels, M. J., Boesmans, W., Smits, K. M., & Melotte, V. (2024). Neuronal distribution in colorectal cancer: associations with clinicopathological parameters and survival. Modern Pathology, 37(10), Article 100565. doi.org/10.1016/j.modpat.2024.100565
Schonkeren, S. L., Thijssen, M. S., Idris, M., Wouters, K., de Vaan, J., Teubner, A., Gijbels, M. J., Boesmans, W., & Melotte, V. (2024). Differences in enteric neuronal density in the NSE-Noggin mouse model across institutes. Scientific Reports, 14(1), Article 3686. doi.org/10.1038/s41598-024-54337-w
Idris, M., Coussement, L., Alves, M. M. M., De Meyer, T., & Melotte, V. (2023). Promoter hypermethylation of neural-related genes is compatible with stemness in solid cancers. Epigenetics & Chromatin, 16(1), Article 31. doi.org/10.1186/s13072-023-00505-7
Schonkeren, S. L., Seeldrayers, S., Thijssen, M. S., Boesmans, W., Langen, R. C. J., & Melotte, V. (2023). An optimization and refinement of the whole-gut transit assay in mice. Neurogastroenterology and Motility, 35(8), Article e014586. doi.org/10.1111/nmo.14586
Vaes N, Idris M, Boesmans W, Alves MM, Melotte V. (2022). Nerves in gastrointestinal cancer: from mechanism to modulations. Nat Rev Gastroenterol Hepatol. Dec;19(12):768-784. doi: 10.1038/s41575-022-00669-9. Epub 2022 Sep 2. PMID: 36056202.
Schonkeren SL, Küthe TT, Idris M, Bon-Frauches AC, Boesmans W, Melotte V. (2022). The gut brain in a dish: Murine primary enteric nervous system cell cultures. Neurogastroenterol Motil. Feb;34(2):e14215. doi: 10.1111/nmo.14215. Epub 2021 Jul 8. PMID: 34236124; PMCID: PMC9285479.
Vaes N, Schonkeren SL, Rademakers G, Holland AM, Koch A, Gijbels MJ, Keulers TG, de Wit M, Moonen L, Van der Meer JRM, van den Boezem E, Wolfs TGAM, Threadgill DW, Demmers J, Fijneman RJA, Jimenez CR, Vanden Berghe P, Smits KM, Rouschop KMA, Boesmans W, Hofstra RMW, Melotte V. (2021) Loss of enteric neuronal Ndrg4 promotes colorectal cancer via increased release of Nid1 and Fbln2. EMBO Rep. Jun 4;22(6):e51913. doi: 10.15252/embr.202051913. Epub 2021 Apr 23. PMID: 33890711; PMCID: PMC8183412.
Rademakers G, Massen M, Koch A, Draht MX, Buekers N, Wouters KAD, Vaes N, De Meyer T, Carvalho B, Meijer GA, Herman JG, Smits KM, van Engeland M, Melotte V. (2021) Identification of DNA methylation markers for early detection of CRC indicates a role for nervous system-related genes in CRC. Clin Epigenetics. Apr 15;13(1):80. doi: 10.1186/s13148-021-01067-9. PMID: 33858496; PMCID: PMC8048074.
Vaes N, Lentjes MHFM, Gijbels MJ, Rademakers G, Daenen KL, Boesmans W, Wouters KAD, Geuzens A, Qu X, Steinbusch HPJ, Rutten BPF, Baldwin SH, Sharkey KA, Hofstra RMW, van Engeland M, Vanden Berghe P, Melotte V. (2017) NDRG4, an early detection marker for colorectal cancer, is specifically expressed in enteric neurons. Neurogastroenterol Motil. Sep;29(9). doi: 10.1111/nmo.13095. Epub 2017 May 19. PMID: 28524415.
Melotte V, Lentjes MH, van den Bosch SM, Hellebrekers DM, de Hoon JP, Wouters KA, Daenen KL, Partouns-Hendriks IE, Stessels F, Louwagie J, Smits KM, Weijenberg MP, Sanduleanu S, Khalid-de Bakker CA, Oort FA, Meijer GA, Jonkers DM, Herman JG, de Bruïne AP, van Engeland M. (2009) N-Myc downstream-regulated gene 4 (NDRG4): a candidate tumor suppressor gene and potential biomarker for colorectal cancer. J Natl Cancer Inst. Jul 1;101(13):916-27. doi: 10.1093/jnci/djp131. Epub 2009 Jun 17. PMID: 19535783.
Thesis
Thesis
This thesis explores how nerve cells in the gut influence the development and progression of colorectal cancer (CRC). CRC is one of the most common and deadly cancers worldwide, and understanding how tumor cells interact with their surrounding cells is essential for improving diagnosis and treatment. One of the most recently identified members of the CRC environment are nerves and supporting glial cells. This research examined where these neural cells are located within tumors, how they communicate with the tumor environment and cancer cells, and whether their presence affects patient outcomes. Using cell models, animal studies, and analyses of human tumor samples, this thesis reveals that specific subtypes of nerves and glial cells can shape the immune environment, especially specific types of B cells, and can thereby influence clinical outcomes in colorectal cancer. These findings highlight that neural–immune communication is an important, yet underappreciated, driver of CRC biology, opens new avenues for understanding disease mechanisms and points to neural and glial subtypes as promising new therapeutic targets.
This PhD research explored how the enteric nervous system, which consists of specialized neurons and glial cells, interacts with colorectal cancer, a major health issue worldwide. The study reviewed cancer models and emphasized the importance of including components of the nervous system to gain better insights into colorectal tumor development. It developed protocols to isolate cells from the enteric nervous system and identified patterns of changes in neural-related DNA across various types of cancer, suggesting that these genes may play a role in cancer progression. Using mouse models, the research demonstrated that the loss of neurons did not directly promote colorectal tumor growth but instead altered the immune system’s response to colorectal cancer. Finally, single-cell RNA sequencing revealed that glial cells within colorectal tumors exhibit altered ratio of immune-specialized glia. This research enhances understanding of the role of the nervous system in colorectal cancer and highlights new approaches for treatment.
In this thesis, new biomarkers for both early detection and risk estimation of colon cancer patients were investigated. Here, special attention was paid to the potential role of the nervous system in the intestine (the enteric nervous system) as a new player in colon cancer. To complement this, we looked at improving research assay design for new biomakers and created guidelines for the future.
The enteric nervous system, also referred to as ‘the brain of the gut’, is important for gut functioning. In recent years, it has become evident that neurons can influence cancer, but how the brain of the gut influences colorectal cancer has hardly been investigated. This thesis focussed on the brain of the gut and its role in the development and progression of colorectal cancer. In addition, available models to study the brain of the gut were evaluated, with a focus on validating and improving these models for biomedical research. This research shows that neurons in the gut can influence colorectal cancer by sending signals to colorectal cancer cells on the one hand, and by influencing the immune system on the other hand.
This thesis investigates the role of the enteric nervous system, or 'the abdominal brain' in colon cancer. Through this study, it has been shown that there is an interaction between the nerve cells of the gut and the tumor cells, where certain proteins secreted by nerve cells can affect the growth of the tumor. It has also been shown that the presence or absence of nerve fibers in colon tumors may predict the life expectancy of colon cancer patients. Finally, it was discovered that many methylation markers, which can be used for early detection of colon cancer, are involved in nervous system processes. These studies indicate the importance of the enteric nervous system in colon cancer, which has not been extensively studied before. In the future, this research may lead to the development of new diagnostic and prognostic biomarkers as well as new therapies for colon cancer.
Despite improved early detection and treatment options, colorectal cancer (CRC) is one of the deadliest forms of cancer. I discovered that NDRG4, an established biomarker for the early detection of CRC (Cologuard®) is specifically expressed in the gut’s intrinsic nervous system: the enteric nervous system (ENS). While defects in the ENS have been implicated in life-threatening conditions, its contribution to CRC is hardly studied. This is remarkable as cells in the “tumor microenvironment” can contribute to (colorectal) carcinogenesis. I uncovered that NDRG4 affects ENS development and GI functioning. Moreover, the loss of NDRG4 enhanced colorectal tumorigenesis by the increased release of soluble factors. These findings implicate that the ENS is a new member of the (tumor) microenvironment which opens new perspectives for the development of clinical applications (biomarkers and/or treatment) for GI disorders.
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