Ana M. Vallés

Induction and regulation of epithelial–mesenchymal transitions

Herein we discuss the factors that bring about the transformation of epithelial cells into cells of fibroblastic phenotype. This type of transformation, referred to as epithelium-to-mesenchyme transition (EMT), allows cells to dissociate from the epithelial tissue from which they originate and to migrate freely. EMT is therefore thought to play a fundamental role during the early steps of invasion and metastasis of carcinoma cells. Among biological agents which have been identified as inducers of EMT are a number of cytokines and extracellular matrix macromolecules. The coordinated changes in cell morphology, associated with the induction of cell motility and the disruption of intercellular junctions, are the consequence of a signaling cascade emanating from the plasma membrane and leading to changes in gene expression. Understanding the mechanisms regulating EMT of normal and transformed epithelial cells may offer new perspectives for designing therapies for the treatment of metastatic cancers of epithelial origin.

Modulations of the epithelial phenotype during embryogenesis and cancer progression

In this chapter, we develop the idea that in order to be able to detach from the primary tumor, invade, and metastasize to distant organs, carcinoma cells must modify their adhesive status and change their cytoskeletal organization. Interestingly, such modifications of cell adhesion and communication systems have been shown to occur during embryogenesis and particulary during migratory process of epithelial-mesenchymal transition (EMT). These embryonic events therefore could represent the prototype of epithelial cell dispersion. Eventually, cells may switch back to a stable epithelial phenotype state that involves local growth and maintenance of this differentiated state, in coordination with the local environment. The delicate modulation of this equilibrium on a specific cell population represents a basic mechanism of embryogenesis. A similar mechanism of epithelial cell plasticity may apply to cancer cells. In this chapter, we first discuss this balance during a well-documented case of induced EMT in a bladder carcinoma. Then we expand the review to examples of EMT occurring during embryogenesis. Finally, we review cancer metastasis, with a special emphasis on breast cancer.

Model systems of epithelium-mesenchyme transitions.

This contribution discusses which factors bring about the transformation of epithelium to mesenchyme. Amongst biological agents which have this role are a number of cytokines (e.g. EGF, FGF-1, TGF-beta, HGF/SF) and extracellular matrix macromolecules, such as collagens. The coordinated changes in cell morphology, associated with the induction of cell motility and the loss of inter-cellular junctions, are under the control of signaling molecules that transduce the signal emanating from the plasma membrane, which ultimately lead to changes in gene expression.

tRNA processing defects induce replication stress and Chk2‐dependent disruption of piRNA transcription

RNase P is a conserved endonuclease that processes the 5′ trailer of tRNA precursors. We have isolated mutations in Rpp30, a subunit of RNase P, and find that these induce complete sterility in Drosophila females. Here, we show that sterility is not due to a shortage of mature tRNAs, but that atrophied ovaries result from the activation of several DNA damage checkpoint proteins, including p53, Claspin, and Chk2. Indeed, we find that tRNA processing defects lead to increased replication stress and de‐repression of transposable elements in mutant ovaries. We also report that transcription of major piRNA sources collapse in mutant germ cells and that this correlates with a decrease in heterochromatic H3K9me3 marks on the corresponding piRNA‐producing loci. Our data thus link tRNA processing, DNA replication, and genome defense by small RNAs. This unexpected connection reveals constraints that could shape genome organization during evolution.

Characterization of the signaling pathways Regulating α2β1 integrin-mediated events by a pharmacological approach

In certain instances of developing and adult organism, epithelial cells can change morphology and transform into mesenchynial-like type in order to move through the extracellular matrix. However, because of the multiplicity and complexity of signaling pathways that contribute to these processes, their molecular dissection has remained difficult. By using a pharmacological approach on the rat bladder carcinoma cell line NBT-II dispersion system, we have identified distinct signaling events for adhesion and motility in response to collagen, both activities depending on α2β1 integrin. Treatment of cells with PKC inhibitors markedly impaired initial attachment on collagen without affecting the capacity of cells to move, suggesting that PKC activity is required for initial adhesion strength during cell translocation. Both adhesion and motility were diminished by tyrosine kinase inhibitors herbimycin and tyrphostin whereas tyrosine phosphatase inhibitors amplified cell scattering. The collagen-induced dispersio...

The winding road from adhesive receptors to the nucleus Conference on molecular biology of cellular interactions: adhesion receptor signalling and regulation of gene expression

EURESCO conferences on adhesive interactions were established in 1993 in the Life Sciences programs of the European Science Foundation. Every 2 years, scientists involved in the different fields of adhesive interactions come for a 3‐day meeting and exchange their latest results in a conference format of about 40 invited speakers and a poster session. This format promotes discussion and a fruitful exchange of results and ideas and is considered by ‘old’ and ‘new’ investigators in the field to be one of the most attractive European meetings on cell adhesion. ![][1] Adhesive receptors are responsible for general tissue architecture and cell behaviour. They modulate mechanical adhesive interactions and regulate a cascade of intracellular signalling pathways (for reviews, see Giancotti and Ruoslahti, 1999; Gumbiner, 2000). In most cases, the end‐point of the receptor‐induced signalling cascade is the regulation of gene expression and corresponding modifications in cell metabolism, differentiation or proliferation. Adhesion receptor signalling, regulation of gene expression and their relevance to cell growth, differentiation, survival and development were the topics of the 2001 European Science Foundation Conference, organized by G. Tarone (Turin, Italy) and J.‐L. Duband (Paris, France). Adhesive receptors, which include integrins, cadherins, selectins and the immunoglobulin superfamily, have no catalytic function, and their interactions with other transducing molecules are crucial for signalling. Many examples of interactions of adhesive receptors with cellular effectors were presented, and the data generated from in vitro cell cultures were often corroborated in in vivo systems, designed to determine the contribution of each pathway to a given function. In this report, we highlight some of the salient themes that emerged. ### Pathways leading to gene expression: lessons from global expression analyses In the late 1980s, the pioneering work of S. Haskill (Eierman et al ., 1989) indicated that cell adhesion to the extracellular matrix (ECM) controls the expression of specific genes. It is now known that integrins are … [1]: /embed/graphic-1.gif