A groundbreaking approach that targets the degradation of membrane proteins in cancer cells has received funding from the European Innovation Council (EIC) Pathfinder program. The goal? To target previously “undruggable” cancer-related proteins by selectively degrading them and potentially offering a new way to overcome resistance to current cancer therapies.
Led by Madelon Maurice at the Center for Molecular Medicine, UMC Utrecht and the Oncode Institute, the OutMARCH project brings together experts in AI-based protein design, cancer biology, and antibody development. The team will work on the development of so-called SureTACs – bispecific antibodies designed to specifically degrade surface proteins that drive cancer growth. This technology could offer a more effective and targeted treatment option compared to traditional therapies, which are often limited due to resistance and side effects.
The OutMARCH team aims to unlock the potential of MARCH E3 ligases, specialized enzymes that can target and degrade specific proteins on cancer cells. By bringing these enzymes in close proximity to a target protein, the team aims to develop a therapy that can selectively attack cancer cells while minimizing damage to healthy tissue. A major technical challenge is to develop drugs that bind this class of enzymes. If successful, this approach may address some of the key challenges in oncology, including resistance to existing cancer treatments and the on-target off-tissue effects that can cause harm to healthy cells.
We’re happy to share that two new papers from our lab have just been published in iScience. A big team effort went into these studies, and we’re excited to finally share them. Read more about the work and find the full articles below.
Hepatocellular carcinoma (HCC) is the most common form of liver cancer and remains a major cause of cancer mortality worldwide. Genetic alterations in the Wnt/β-catenin pathway are frequently found in HCC, most notably mutations in CTNNB1 or AXIN1. While both mutation types were historically thought to activate Wnt signaling in similar ways, increasing evidence suggests that they define distinct tumor subtypes with different biological behavior.
In this study, we investigated how cancer-associated AXIN1 mutations influence signaling and growth of liver cancer cells and organoids. We found that AXIN1 mutations activate moderate levels of Wnt/β-catenin signaling, in contrast to CTNNB1 mutations which induce strong pathway activation. Surprisingly, many truncating AXIN1 mutations do not completely eliminate the protein but instead lead to alternative translation and expression of N-terminally truncated AXIN1 variants that retain partial tumor-suppressor activity. Despite this residual function, these AXIN1 variants similar to AXIN1 KO mutations allow liver progenitor organoids to grow independently of external Wnt signals, indicating that even low levels of Wnt pathway activation are sufficient to support tumor cell growth.
Importantly, we observed an inverse relationship between Wnt/β-catenin activity and YAP/TAZ signaling, suggesting that AXIN1 mutations create a signaling environment that permits YAP/TAZ activity while maintaining sufficient Wnt signaling for proliferation. These findings explain why AXIN1-mutant tumors represent a distinct and often more aggressive subtype of HCC.
Together, our work provides new insight into how different Wnt pathway mutations shape liver cancer biology and highlights potential therapeutic opportunities targeting Wnt and YAP/TAZ signaling pathways in AXIN1-mutant tumors.
WNT7B drives pancreatic cancer subtype switching and tumour progression
This publication by Sprangers et al describes how WNT7B drives pancreatic cancer subtype switching and tumour progression is now online at iScience. The full article can be found here: https://doi.org/10.1016/j.isci.2026.115050.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and is characterised by strong heterogeneity and resistance to therapy. Tumours are commonly classified into classical and basal like transcriptional subtypes, with basal like tumours associated with more aggressive disease and poorer patient outcomes. Elevated expression of several WNT ligands, including WNT7B and WNT10A, has been linked to this aggressive subtype, but how these ligands contribute to PDAC progression remained unclear.
Using patient derived PDAC organoids, we investigated how epithelial WNT signalling shapes tumour cell states and tumour growth. We found that WNT7B is expressed by a subset of tumour cells and marks a population that maintains a basal like transcriptional program. Importantly, these WNT7B high cells support the survival and growth of neighbouring WNT low cells through short range, cell cell contact dependent signalling, allowing distinct cellular states to coexist within the same tumour.
Transcriptional profiling revealed that WNT signalling suppresses a more differentiated classical PDAC program while maintaining basal like features. Inhibition of WNT secretion shifts tumour cells towards a more classical transcriptional state, suggesting that targeting WNT signalling may help push pancreatic tumours towards a less aggressive phenotype.
Together, these findings highlight how heterogeneous WNT ligand expression within the tumour epithelium can maintain pancreatic cancer cell states and drive tumour progression.
Our publication describing how LKB1 mutations drive a premalignant state in the intestine is now online at Gastroenterology. The full article can be found here.
Heterozygous mutations in the tumor suppressor LKB1 cause Peutz-Jeghers syndrome (PJS), a hereditary condition characterised by gastrointestinal polyps and increased cancer risk. While LKB1 loss in non-epithelial tissues was previously thought to drive polyp formation, how LKB1 deficiency alters the epithelial landscape to increase cancer susceptibility remained unclear.
Using mouse small intestinal and human colon organoids engineered with heterozygous or homozygous LKB1 loss, we discovered that even a single mutated copy of LKB1 pushes intestinal cells into a premalignant transcriptional program linked to serrated colorectal cancer. This effect is amplified when the remaining healthy LKB1 copy is lost. LKB1-deficient cells display persistent features of regeneration and increased expression of EGFR ligands and receptors, enabling growth that is independent of the usual niche signals.
Furthermore, our LKB1-mutant signature is enriched in sporadic serrated colorectal cancers, and cooperation between LKB1 loss and mutant Kras further accelerates organoid growth and transcriptional changes. These findings provide a mechanistic explanation for the increased colorectal cancer risk in PJS patients and highlight how partial loss of a tumor suppressor can prime cells for malignant transformation.
We are delighted to share that Dr. Jelte van der Vaart, a postdoctoral researcher in our lab, has been awarded the prestigious NWO Veni grant for his project “Adrenocortical organoids as human endocrinology avatars”.
This three-year grant will enable Jelte to develop the first human adrenocortical organoid models to study how hormone producing cells in the adrenal gland change identity and function. By recreating the adrenal cortex in vitro, his work will provide new insights into the molecular signals that regulate hormone production and control cell transitions between specialised zones. These processes are central to maintaining endocrine health, yet remain poorly understood in humans due to limitations of animal models.
The project will be conducted at the UMC Utrecht, within the Center for Molecular Medicine, and will combine advanced organoid culture with molecular and spatial profiling approaches. In the long term, the findings may provide a basis for improved diagnosis and treatment of conditions such as Cushing syndrome and other hormonal disorders.
We are proud to see this new research direction grow in our laboratory. Jelte’s expertise in organoid technology, combined with the lab’s strengths in molecular signalling and cancer biology, has made this success possible. The NWO Veni programme supports exceptional early career researchers in developing innovative, independent research, and we look forward to the contributions this project will bring to the field.
On Wednesday, May 7, Anton Venhuizen successfully defended his PhD thesis titled “Molecular Mechanisms of the β-Catenin Destruction Complex in Health and Disease”.
We congratulate Anton on this important achievement and wish him much success and enjoyment in his new postdoctoral position at the Cambridge Institute for Medical Research.
On Tuesday, March 11, Felix van der Krift successfully defended his PhD thesis titled “Folate metabolism in cancer: New opportunities and strategies to exploit metabolic vulnerabilities”.
We congratulate Felix on this significant achievement and wish him all the best in his new postdoctoral position at the Netherlands Cancer Institute (NKI).
We’re proud to share that Prof. Madelon Maurice and postdocs Michiel Boekhout and Jelte van der Vaart will be participating in Alpe d’HuZes 2025, representing the Center for Molecular Medicine and Oncode Institute.
On June 5th, they’ll be taking on the challenge of running or cycling up the legendary Alpe d’Huez—multiple times in one day—to raise funds for cancer research. Their motivation is deeply rooted in our shared mission to better understand and treat cancer. You can support their effort by donating via their team page:
On December 18th, Joep Sprangers from the Maurice group successfully defended his PhD thesis entitled: ‘WNT-mediated regulation of regeneration and oncogenesis’. We are very happy that Joep will stay on and help realize a green and sustainable CMM!
We are pleased to announce that Dr. Jelte van der Vaart, a postdoctoral researcher in the lab, has been honoured with the Unique High Risk Grant from KWF Kankerbestrijding for his project “Adrenal Cortical Organoids as Disease Models and Patient Avatars.” This grant facilitates his study into adrenocortical carcinoma organoids, with a particular focus on studying the Wnt signalling pathway’s dysregulation.
This project represents a collaborative effort as part of the Dutch Adrenal Network, with a shared goal of advancing our understanding of adrenal cancer and exploring new possibilities for treatment.
We proudly welcome this new line of research in our laboratory. The expertise within our team in the field of Wnt signalling and organoid culture has enabled us to secure this opportunity, marking a significant moment for both Jelte and the lab. Looking to the future, we are optimistic about the potential findings and contributions this research will bring to the scientific community.
The Maurice lab is proud to announce that Laigo Bio has launched their website!
Madelon is the co-founder and scientific lead of this startup that aims to develop SureTACs technology. Laigo Bio sprouted from the research of the Maurice lab, focused on degradation of target proteins at the cell surface, via redirection of transmembrane E3 ligases. How the induced proximity between target and E3 leads to ubiquitination, endocytosis and degradation of the target is actively being researched within the group.
Laigo Bio is dedicated to developing first-in-class therapeutics for patients with severe or life-threatening diseases by removing and degrading any cell surface targets with precision. Visit the website to learn how Laigo Bio is pioneering life-changing solutions in biotechnology: www.laigobio.com.
