Snail1 controls cooperative cell plasticity during metastasis

Mortality in cancer is strongly associated with the capacity of tumor cells to spread and critically affect other tissues and organs. Genetic mutations accumulated by tumor cells and cross-signaling between tumor and host cells underlie the formation of metastasis. Cancer-activated fibroblasts (CAFs), which are host fibroblasts activated by tumor signaling, can alter tumor cell behavior by both paracrine signaling (secreting diffusible molecules) and mechanical signaling (modifying the composition and organization of the stroma). These fibroblasts resemble myofibroblasts (MFs) of the granulation tissue generated during wound healing, which produce a rigid desmoplastic stroma rich in signaling molecules and cross-linked extracellular fibers. Desmoplasia favors malignant tumor cell properties such as mobility, stemness, and even resistance to pharmacological insults [1]. Our research group has been studying the role of Snail1 on tumor progression, a transcription factor involved in the epithelial-to-mesenchymal transition (EMT). EMT is a plasticity process by which epithelial cells exchange their structural determinants for mesenchymal ones. Thus, EMT promotes a transition from a static phenotype with apico-basal polarity towards a motile one with anterior-posterior polarity. EMT provides a simple explanation of how tumor cells escape from the primary tumor, via Snail1. Classically, Snail1 has been described as a transcriptional repressor of epithelial genes, particularly of those affecting the cell architecture. Thus, Snail1 expression in epithelial cells represses proteins in epithelial junctions, such as E-cadherin and claudin/occludin, and in epithelial intermediate filaments, such as cytokeratin 18, which then initiates EMT [2]. In tumors, EMT is incomplete because the majority of tumor cells that have gained mesenchymal markers have also retained some epithelial determinants. In this not-fully-differentiated state, cells acquire stem properties that allow them to behave as tumor-initiating and drug-resistant cells. In fact, the cancer stem cell (CSC) phenotype is comparable to a partial EMT status and is strongly dependent on signaling from the tumor stroma. Recent data indicate that Snail1 is also required for the trans-differentiation of fibroblasts. Indeed, in mammary and colonic tumors, Snail1-positive CAFs are more easily detected by histological studies than Snail1-positive tumor cells [3]. In these fibroblasts, the actions of Snail1 cannot be attributed to the repression of epithelial determinants, as these are constitutively repressed. Rather, Snail1 is required for the transcription [4] and the polymerization of extracellular molecules [3] involved in desmoplasia. Fiber polymerization is mediated by of RhoA, a GTPase activated by tumor secreted factors such as TGFβ in a Snail1-dependent manner. Thus, Snail1 is …