Occluding junctions and epithelial wound repair

In epithelial tissues, cells tightly connect to each other through cell–cell junctions, but they also present the remarkable capacity of reorganizing themselves without compromising tissue integrity. Upon injury, simple epithelia efficiently resolve small lesions through the action of actin cytoskeleton contractile structures at the wound edge and cellular rearrangements. However, the underlying mechanisms and how they cooperate are still poorly understood. By using live imaging of wound repair in the fly Drosophila melanogaster and theoretical modeling Carvalho and collaborators reveal a novel and indispensable role for occluding junctions (OJs) in this process. They demonstrate that OJ loss of function leads to severe defects in wound-closure dynamics: instead of contracting, wounds dramatically increase their area. OJ mutants exhibit phenotypes in cell shape, cellular rearrangements, and mechanical properties as well as in actin cytoskeleton dynamics at the wound edge. The authors propose that OJs are required for wound closure by impacting on tissue mechanical properties, which in turn is crucial for the correct regulation of the cellular events occurring at the wound edge.

The article entitled “Occluding junctions as novel regulators of tissue mechanics during wound repair”was published in The Journal of Cell Biology.

Unscheduled expression of embryonic genes can lead to tumor formation

Tumor initiation is often linked to a loss of cellular identity. While key instructive genes are crucial during embryogenesis, many of these are then silenced during later developmental stages and in adulthood. Polycomb group proteins are among the main epigenetic silencing complexes and ensure appropriate silencing of many developmental genes in many cell types. In this work, Joana Torres, Jorge Beira and other collaborators at ETHZürich and Univ. Basel (Switzerland)investigated the gene signature of tumors caused by disruption of the Drosophila epigenetic regulator, polyhomeotic (ph). In larval tissue ph mutant cells show a shift towards an embryonic-like signature. Using loss- and gain-of-function experiments we uncovered the embryonic transcription factor knirps (kni) as a new oncogene. The oncogenic potential of kni lies in its ability to activate JAK/STAT signaling and block differentiation. Conversely, tumor growth in ph mutant cells can be substantially reduced by overexpressing a differentiation factor. This demonstrates that epigenetically derailed tumor conditions can be reversed when targeting key players in the transcriptional network. Overall, it also shows the importance of maintaining the OFF state for many embryonic genes after their function has been fulfilled. Read more about how genes that have key functions in the embryo can start to drive tumor formation at later stages, if they are not correctly turned off, in the published eLIFE paper entitled "switch in transcription and cell fate governs the onset of an epigenetically-deregulated tumor in Drosophila".

 

 

Context-dependent signalling

Signalling pathways modulate cellular responses in developmental and regenerative processes but can also be misused by cancer cells to promote tissue invasion and growth. How signalling outputs are integrated to direct a variety of responses ranging from organ repair to tumour onset remains elusive. Jorge Beira and collaborators at ETH Zürich (Switzerland) revealed that similar signals and pathways are differentially regulated during tissue regeneration on the one hand, and tumorigenesis on the other. Interestingly, signalling hierarchies active in Drosophila ph tumours are distinct from the role these same pathways have in protecting normal tissues undergoing stress or injury, thus promoting regeneration.

The paper entitled "Signalling crosstalk during early tumorigenesis in the absence of Polycomb silencing" was published in PLoS Genetics.

 

Zebrafish larvae xenografts for precision medicine

Despite advances in targeted cancer treatments, methods to predict how a specific cancer will respond to a given therapy are still lacking. Consequently, patients go through rounds of trial-and-error approaches based on guidelines to find the best treatment, often subjected to unnecessary toxicity. Using cell lines, Rita Fior and collaborators at the Champalimaud Centre for the Unknown, used zebrafish larvae xenografts as sensors for cancer behavior and therapy guideline screening. Their data show not only sufficient resolution to distinguish functional tumor behaviors in just 4 days but also differential sensitivity to colorectal cancer therapy. As proof-of-principle, they provide evidence for similar behavior response to therapies in patients as in zebrafish patient-derived xenografts. Altogether, their results suggest zebrafish larvae xenografts as a promising in vivo screening platform for precision medicine.

See the article entitled “Single-cell functional and chemosensitive profiling of combinatorial colorectal therapy in zebrafish xenografts” published in PNAS. 

Notch decides numbers of motile versus nonmotile cilia in the LR Organizer

Foxj1a is necessary and sufficient to specify motile cilia. Using transcriptional studies and slow-scan two-photon live imaging capable of identifying the number of motile and immotile cilia, Bárbara Tavares and collaborators at CEDOC established that the final number of motile cilia depends on Notch signalling (NS). They found that despite all left-right organizer (LRO) cells express foxj1aand the ciliary axonemes of these cells have dynein arms, some cilia remain immotile. They found that this decision is taken early in development in the Kupffer’s Vesicle (KV) precursors the readout being her12 transcription. They further demonstrated that overexpression of either her12 or Notch intracellular domain (NICD) increases the number of immotile cilia at the expense of motile cilia, and leads to an accumulation of immotile cilia at the anterior half of the KV. This disrupts the normal fluid flow intensity and pattern, with consequent impact on left-right (L-R) axis establishment.

See the article entitled “Notch/Her12 signalling modulates, motile/immotile cilia ratio downstream of Foxj1a in zebrafish left-right organizer” published in eLIFE.