Nikolaos Doumpas

BCL9 and PYGO are β-catenin cofactors that enhance the transcription of Wnt target genes. They have been proposed as therapeutic targets to diminish Wnt signaling output in intestinal malignancies. Here we find that, in colorectal cancer cells and in developing mouse forelimbs, BCL9 proteins sustain the action of β-catenin in a largely PYGO-independent manner. Our genetic analyses implied that BCL9 necessitates other interaction partners in mediating its transcriptional output. We identified the transcription factor TBX3 as a candidate tissue-specific member of the β-catenin transcriptional complex. In developing forelimbs, both TBX3 and BCL9 occupy a large number of Wnt-responsive regulatory elements, genome-wide. Moreover, mutations in Bcl9 affect the expression of TBX3 targets in vivo, and modulation of TBX3 abundance impacts on Wnt target genes transcription in a β-catenin- and TCF/LEF-dependent manner. Finally, TBX3 overexpression exacerbates the metastatic potential of Wnt-dependent human colorectal cancer cells. Our work implicates TBX3 as context-dependent component of the Wnt/β-catenin-dependent transcriptional complex.

Organoids are self-organized three-dimensional (3D) multicellular tissue cultures which derive from cancerous and healthy stem cells, sharing a highly similarity to the corresponding in vivo organs. Since their introduction in 2009, they have emerged as a valuable model for studying early embryogenesis, organ and tissue development, as well as tools in drug screening, disease modeling and personalized therapy. Organoids can now be established for various tissues, including brain, retina, thyroid, gastrointestinal, lung, liver, pancreas, and kidney. These micro-tissues resemble the native organ in terms of gene expression, protein expression, tissue architecture and cell-cell interactions. Despite the success of organoid-based research and the advances in patient-derived organoid culture, important challenges remain. In this review, we briefly showcase the evolution from the primary 3D systems to complex, multilayered 3D structures such as assembloids, gastruloids and ETiX embryoids. We discuss current developments in organoid research and highlight developments in organoid culturing systems and analysis tools which make organoids accessible for high-throughput and high-content screening. Finally, we summarize the potential of machine learning and computational modeling in conjunction with organoid systems.

BACKGROUND: Wnt6 is an evolutionarily ancient member of the Wnt family. In Drosophila, Wnt6 loss-of-function animals have not yet been reported, hence information about fly Wnt6 function is lacking. In wing discs, Wnt6 is expressed at the dorsal/ventral boundary in a pattern similar to that of wingless, an important regulator of wing size. To test whether Wnt6 also contributes towards wing size regulation, we generated Wnt6 knockout flies. RESULTS: Wnt6 knockout flies are viable and have no obvious defect in wing size or planar cell polarity. Surprisingly, Wnt6 knockouts lack maxillary palps. Interestingly, Wnt6 is absent from the genome of hemipterans, correlating with the absence of maxillary palps in these insects. CONCLUSIONS: Wnt6 is important for maxillary palp development in Drosophila, and phylogenetic analysis indicates that loss of Wnt6 may also have led to loss of maxillary palps on an evolutionary time scale.