The origins of the mesenchymal cells participating in tissue repair and pathological processes, notably tissue fibrosis, tumor invasiveness, and metastasis, are poorly understood. However, emerging evidence suggests that epithelial-mesenchymal transitions (EMTs) represent one important source of these cells. As we discuss here, processes similar to the EMTs associated with embryo implantation, embryogenesis, and organ development are appropriated and subverted by chronically inflamed tissues and neoplasias. The identification of the signaling pathways that lead to activation of EMT programs during these disease processes is providing new insights into the plasticity of cellular phenotypes and possible therapeutic interventions.

/pdf/the-basics-of-epithelial-mesenchymal-transition-xe9crzoewf.pdf

The basics of epithelial-mesenchymal transition

Without epithelial–mesenchymal transitions, in which polarized epithelial cells are converted into motile cells, multicellular organisms would be incapable of getting past the blastula stage of embryonic development. However, this important developmental programme has a more sinister role in tumour progression. Epithelial–mesenchymal transition provides a new basis for understanding the progression of carcinoma towards dedifferentiated and more malignant states.

Epithelial–mesenchymal transitions in tumour progression

Tight control of cell-cell communication is essential for the generation of a normally patterned embryo. A critical mediator of key cell-cell signaling events during embryogenesis is the highly conserved Wnt family of secreted proteins. Recent biochemical and genetic analyses have greatly enriched our understanding of how Wnts signal, and the list of canonical Wnt signaling components has exploded. The data reveal that multiple extracellular, cytoplasmic, and nuclear regulators intricately modulate Wnt signaling levels. In addition, receptor-ligand specificity and feedback loops help to determine Wnt signaling outputs. Wnts are required for adult tissue maintenance, and perturbations in Wnt signaling promote both human degenerative diseases and cancer. The next few years are likely to see novel therapeutic reagents aimed at controlling Wnt signaling in order to alleviate these conditions.

/pdf/the-wnt-signaling-pathway-in-development-and-disease-z4j8s29ao8.pdf

The Wnt signaling pathway in development and disease.

https://www.cell.com/cell/pdf/S0092-8674(06)01344-4.pdf

Wnt/beta-catenin signaling in development and disease.

https://web.stanford.edu/group/nusselab/cgi-bin/wnt/sites/default/files/reviews/Cell%202012%20Clevers.pdf

Wnt/β-catenin signaling and disease.

The Wnt cell-cell signaling pathway plays a critical and evolutionarily conserved role in directing cell fates during embryogenesis. In addition, inappropriate activation of the Wnt signal transduction pathway plays a role in a variety of human cancers. Many recent studies of Wnt signaling have provided mechanistic insight into these dual roles. Here we focus on two areas of rapid advance: (i) the machinery that regulates the stability of the key signal transducer, β-catenin, and (ii) the effect of Wnt signaling on cellular targets outside the nucleus, the actin and microtubule cytoskeletons.

https://science.sciencemag.org/content/sci/287/5458/1606.full.pdf

Wnt Signaling in Oncogenesis and Embryogenesis--a Look Outside the Nucleus

https://pure.knaw.nl/ws/files/490699/17064.pdf

Armadillo Coactivates Transcription Driven by the Product of the Drosophila Segment Polarity Gene dTCF

Wingless/Wnt signalling directs cell-fate choices during embryonic development. Inappropriate reactivation of the pathway causes cancer. In Drosophila, signal transduction from Wingless stabilizes cytosolic Armadillo, which then forms a bipartite transcription factor with the HMG-box protein Drosophila Tcf (dTcf) and activates expression of Wingless-responsive genes. Here we report that in the absence of Armadillo, dTcf acts as a transcriptional repressor of Wingless-responsive genes, and we show that Groucho acts as a corepressor in this process. Reduction of dTcf activity partially suppresses wingless and armadillo mutant phenotypes, leading to derepression of Wingless-responsive genes. Furthermore, overexpression of wild-type dTcf enhances the phenotype of a weak wingless allele. Finally, mutations in the Drosophila groucho gene also suppress wingless and armadillo mutant phenotypes as Groucho physically interacts with dTcf and is required for its full repressor activity.

Drosophila Tcf and Groucho interact to repress Wingless signalling activity

A repeating amino acid motif shared by proteins with diverse cellular roles

The bithorax complex in Drosophila melanogaster is a cluster of homeotic genes that specify developmental pathways for many of the body segments of the fly. The DNA of the bithorax complex has been isolated, and a region of 195,000 base pairs that covers the left half of the complex is described here. The lesions associated with many of the bithorax complex mutants have been identified, and most are due to DNA rearrangements. Most of the spontaneous mutants have insertions of a particular mobile element named "gypsy." This element affects the functions of sequences removed from the site of insertion. Mutant lesions for a given phenotypic class are distributed over large DNA distances of up to 73,000 base pairs.

https://science.sciencemag.org/content/sci/221/4605/23.full.pdf

Mark Peifer

Papers

Wnt Signaling in Oncogenesis and Embryogenesis--a Look Outside the Nucleus

Armadillo Coactivates Transcription Driven by the Product of the Drosophila Segment Polarity Gene dTCF

Drosophila Tcf and Groucho interact to repress Wingless signalling activity

A repeating amino acid motif shared by proteins with diverse cellular roles

Molecular Genetics of the Bithorax Complex in Drosophila melanogaster