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Mechanisms of tumorigenesis and tumor progression Antonio García de Herreros


Characterisation of mechanism controlling tumoural invasion: the role of transcriptional factor Snail1, the epithelial mesenchymal transition, and activation of tumour fibroblasts

Directed by Dr. García de Herreros

In 2000, our group published the characterisation of the transcription factor Snail1 as a repressor of E-cadherin expression, a protein that is key in determining the epithelial phenotype (Batlle et al., Nat Cell Biol 2000, 2:84 -89); Snail1 also induces the conversion of the epithelial cells into mesenchymal cells (epithelial-mesenchymal transition, EMT). This discovery led the group to study this factor and its function as a determinant of the EMT, a transition that not only gives the cells a major invasive capacity but also more resistance to apoptosis and even stem cell characteristics. Dr. García de Herreros's group is interested in studying the function of Snail1 in adult animals, with special emphasis on its role in mesenchymal cells and their relationship with neoplasms. In recent years, the group has analysed how Snail1 acts as a repressor in epithelial genes, as well as characterising the mechanism used to activate mesenchymal genes. Other significant results include the characterisation of RNA repeats in heterochromatin, both pericentromeric and telomeric, as a target for Snail1 that must be temporarily repressed so that the EMT occurs correctly and the mesenchymal genes are activated.

The group's recent work has focused on the importance of Snail 1 in the process of fibroblast activation. It is becoming increasingly clear that stromal cells play a crucial role in the development and progression of a tumour. Among these cells, fibroblasts seem to be especially significant, and those of the tumour stroma (Cancer-Associated fibroblasts, CAFs) have different characteristics to those of tissues. CAFs are more similar to active fibroblasts characteristic of fibrotic processes. Our results indicate that Snail1 is necessary for the activation of these cells by cytokines such as TGFβ. Fibroblasts that express or do not express Snail1 exhibit a different effect on the growth of tumour cells when both are co-implanted in mice, and they have a differential effect on their ability to invade in vivo and in vitro (Figure 1). Finally, Snail1 KO fibroblasts produce a poorer extracellular matrix, which is less rigid and unoriented, and that does not allow the directional migration of epithelial cells seeded at the top. These results also were observed in fibroblasts derived from tumours; the greatest expression of Snail1 correlates with a more ordered extracellular matrix. Moreover, presence of Snail1 in tumour stroma associates with a poor prognosis in colon or breast tumours. According to the results, the elimination of Snail1 in adult mice delays tumour growth in these animals, as well as making these tumours less invasive. The group's current goals are focused on the analysis of the signals produced by active fibroblasts involved in the invasion of epithelial tumour cells, as well as their effects on other components of tumoural stroma. We also look at the role of active fibroblasts in other phases of metastasis, such as in the implantation of metastatic cells in target tissues.

Figure 1: Cooperation of epithelial and mesenchymal cells during the invasion process. HT-29 M6 tumoural epithelial cells were seeded on a matrix of Matrigel/Collagen in the presence of mesenchymal cells marked with GFP. The sections were prepared one week after seeding and dyed with haematoxylin (left) or analysed using immunohistochemistry with an anti-GFP antibody (right).

The four most recent publications on this topic are:

  • Beltran M, Aparicio-Prat E, Mazzolini R, Millanes-Romero A, Massó P, Jenner RJ, Díaz VM, Peiró S, García de Herreros A. Splicing of a non-coding antisense transcript controls LEF1 gene expression. Nucl Acid Res 2015, 43, 5785-5797.
  • Alba-Castellón L, Olivera-Salguero R, Mestre-Farrera M, Peña R, Herrera M, Bonilla F, Casal JI, Baulida J, Peña C, García de Herreros A. Snail1-dependent activation of cancer-associated fibroblast controls collective tumor cell invasion and metastasis. Cancer Res 2016, 76, 6205-6217.
  • Moustakas A, Garcia de Herreros A. Epithelial to mesenchymal transition in cancer. Mol Oncol 2017, 11, 715-717.
  • Mazzolini R, Gonzàlez N, Garcia-Garijo A, Millanes-Romero A, Peiró S, Smith S, García de Herreros A*, Canudas S*. Snail1 transcription factor controls telomere transcription and integrity. Nucl Acid Res 2017, doi: 10.1093/nar/gkx958 (*corresponding authors). 

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