Our group studies the molecular mechanisms that drive the development of gastrointestinal cancers, with a particular focus on colorectal cancer. As one of the most common malignancies and a leading cause of cancer-related death worldwide, this disease remains a major health challenge. In most cases, tumor development is triggered by genetic changes that activate the Wnt/β-catenin signaling pathway. While mutations in the APC gene and β-catenin were long considered the main drivers of this process, research in the last decade has revealed RNF43 and ZNRF3 as key regulators frequently altered in colorectal cancer. Our work aims to uncover how defects in these genes affect Wnt signaling and promote tumor formation.
A second focus of our research is understanding why colorectal tumors that develop on the right and left sides of the colon behave differently. These tumors are increasingly recognized as distinct disease entities, displaying differences in their clinical characteristics, pathology, and molecular features. We aim to uncover the biological mechanisms underlying these location-specific differences and their impact on disease progression.
Key Publications
1) Li S, Niu J, Zhang R, Massaar S, Neves Cabrita M, van Merode J, de Schipper N, van de Kamp L, Peppelenbosch MP, Smits R (2025). Lack of dominant-negative activity for tumor-related ZNRF3 missense mutations at endogenous levels. Oncogene 44: 805-819.
2) Zhang R, Li S, Schippers K, Li Y, Eimers B, Lavrijsen M, Wang L, Cui G, Chen X, Peppelenbosch MP, Lebbink JHG, Smits R (2024). Analysis of Tumor-Associated AXIN1 Missense Mutations Identifies Variants That Activate beta-Catenin Signaling. Cancer Res 84: 1443-1459.
3) Li S, Niu J, Smits R (2024). RNF43 and ZNRF3: Versatile regulators at the membrane and their role in cancer. Biochim Biophys Acta Rev Cancer 1879: 189217.
4) Li S, Lavrijsen M, Bakker A, Magierowski M, Magierowska K, Liu P, Wang W, Peppelenbosch MP, Smits R (2020). Commonly observed RNF43 mutations retain functionality in attenuating Wnt/beta-catenin signaling and unlikely confer Wnt-dependency onto colorectal cancers. Oncogene 39: 3458-3472.
5) Liu P, Liang B, Liu M, Lebbink JHG, Li S, Qian M, Lavrijsen M, Peppelenbosch MP, Chen X, Smits R (2020). Oncogenic Mutations in Armadillo Repeats 5 and 6 of beta-Catenin Reduce Binding to APC, Increasing Signaling and Transcription of Target Genes. Gastroenterology 158: 1029-1043 e1010.