SOX9 and TCF transcription factors associate to mediate Wnt/ß-catenin target gene activation in colorectal cancer.

Activation of the Wnt/ß-catenin pathway regulates gene expression by promoting the formation of a ß-catenin-T-cell factor (TCF) complex on target enhancers. In addition to TCFs, other transcription factors interact with the Wnt/ß-catenin pathway at different levels to produce tissue-specific patterns of Wnt target gene expression. The transcription factor SOX9 potently represses many Wnt target genes by downregulating ß-catenin protein levels. Here, we find using colony formation and cell growth assays that SOX9 surprisingly promotes the proliferation of Wnt-driven colorectal cancer (CRC) cells. In contrast to how it indirectly represses Wnt targets, SOX9 directly co-occupies and activates multiple Wnt-responsive enhancers in CRC cells. Our examination of the binding site grammar of these enhancers shows the presence of TCF and SOX9 binding sites that are necessary for transcriptional activation. In addition, we identify a physical interaction between the DNA-binding domains of TCFs and SOX9 and show that TCF-SOX9 interactions are important for target gene regulation and CRC cell growth. Our work demonstrates a highly context-dependent effect of SOX9 on Wnt targets, with the presence or absence of SOX9-binding sites on Wnt-regulated enhancers determining whether they are directly activated or indirectly repressed by SOX9.

Tumour-host interactions through the lens of Drosophila.

There is a large gap between the deep understanding of mechanisms driving tumour growth and the reasons why patients ultimately die of cancer. It is now appreciated that interactions between the tumour and surrounding non-tumour (sometimes referred to as host) cells play critical roles in mortality as well as tumour progression, but much remains unknown about the underlying molecular mechanisms, especially those that act beyond the tumour microenvironment. Drosophila has a track record of high-impact discoveries about cell-autonomous growth regulation, and is well suited to now probe mysteries of tumour - host interactions. Here, we review current knowledge about how fly tumours interact with microenvironmental stroma, circulating innate immune cells and distant organs to influence disease progression. We also discuss reciprocal regulation between tumours and host physiology, with a particular focus on paraneoplasias. The fly's simplicity along with the ability to study lethality directly provide an opportunity to shed new light on how cancer actually kills.

Caenorhabditis elegans learning in a structured maze is a multisensory behavior.

We show that C. elegans nematodes learn to associate food with a combination of proprioceptive cues and information on the structure of their surroundings (maze), perceived through mechanosensation. By using the custom-made Worm-Maze platform, we demonstrate that C. elegans young adults can locate food in T-shaped mazes and, following that experience, learn to reach a specific maze arm. C. elegans learning inside the maze is possible after a single training session, it resembles working memory, and it prevails over conflicting environmental cues. We provide evidence that the observed learning is a food-triggered multisensory behavior, which requires mechanosensory and proprioceptive input, and utilizes cues about the structural features of nematodes' environment and their body actions. The CREB-like transcription factor and dopamine signaling are also involved in maze performance. Lastly, we show that the observed aging-driven decline of C. elegans learning ability in the maze can be reversed by starvation.