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–associated AXIN1 mutations drive low Wnt/β-catenin activity enabling niche-independent growth and YAP/TAZ signaling
This publication by Venhuizen et al, describes how AXIN1 mutations shape Wnt and YAP/TAZ signaling in liver cancer is now online at iScience. The full article can be found here: https://www.sciencedirect.com/science/article/pii/S2589004225027622?via%3Dihub
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.