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Mechanisms of tumorigenesis and tumor progression Antonio García de Herreros

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Molecular mechanisms that regulate pro-metastatic tumoural stroma

Directed by Dr. Josep Baulida

Just as if it were a wound, the connective tissue surrounding a tumour is activated to regenerate the affected epithelia. This is a common reaction of tumours in the epithelium of soft organs, such as the breast, the lungs, or the intestine, which is promoted by signalling molecules from tumour cells. The consequence is that a network rich in fibronectin fibres and collagen forms around the tumour that facilitates tumour cells to invade adjacent tissues and intravasate the circulatory systems (Fig.1). Our research examines the formation of this desmoplastic response and the influence of the tumour micro-environment properties on the formation of metastases.

Figure 1. The paracrine and mechanical signalling generated by CAF promotes the epithelial expression of transcription factors involved in mesenchymal EMT (EMT-TF). Homeostasis of the tissue in the mammary glands is maintained by means of signalling coordinated between epithelial (yellow) and stromal cells (orange). Oncogenic mutations in epithelial cells stimulate uncontrolled epithelial growth, generating primary tumour focuses (purple cells). Paracrine signalling in tumour cells (orange arrow in the zoomed box) promotes the expression of EMT-TFs in the nuclei of adjacent fibroblasts (red nuclei). Additional colour coding: luminal cells, yellow nuclei; basal epithelial cells, green nuclei; normal fibroblasts, orange nuclei; basal lamina, red lines; extracellular fibres, blue lines. (B) In metastatic tumours, the tumour cells escape from the primary focus (dark purple cells). This event is facilitated by micro-environmental changes promoted by CAF that express EMT-TFs (yellow cells with red nuclei), which include changes in the fibrillar architecture and the secreted factors (Orange arrows and text the amplified box). The signals generated by the local extracellular changes (black arrows) induce the expression of EMT-TF in adjacent tumour cells (dark purple cells with red nuclei), giving them malignancy-related cancer properties, such as the ability replicate limitlessly, increased the motility of tumour cells, and chemo-resistance.

The work done in the laboratory has allowed us to describe how cancer activated fibroblasts (CAFs) modulate the organization of the stromal compartment and how the new physical parameters facilitate oriented tumour cell invasion. At the molecular level we have described that CAF activation depends on a transcription factor called Snail1. In CAFs Snail1 behaves as an activator, despite having been described as a repressor in earlier works. Some molecular elements activated by TGFβ like subunit ReIA (p65) of nuclear factor-kB (NF-kB) and PARP1, collaborate with Snail1 to increase the transcription of genes coding for extracellular matrix molecules, such as fibronectin. In addition, Snail1 is necessary for the enzymatic activity of RhoA, which controls the reorganisation of the fibroblast cytoskeleton and enables the polymerisation of extracellular fibres. In infiltrating carcinomas of the breast we have described that the expression of this factor in tumour stromal fibroblasts is an indicator of poor prognosis.

The group's current research is focused on increasing our molecular knowledge of CAF regulation. We are characterising key regulatory enzymes whose activity can be inhibited in vivo. We hope to propose pharmacological tools for reducing desmoplasty that can complement the current antimetastatic treatments targeting tumour cell growth. The in vivo anti-metastatic activity of an inhibitor for an enzyme studied in the lab is shown in Fig. 2.

Figure 2. The inhibitor 1 prevents the stroma reaction and decreases metastasis in MMTV-PYMT mice. Primary tumours in MMTV-PYMT mice treated or untreated with the inhibitor 1 were analysed by immuno histochemistry (hematoxylin-eosin stain). The tumour stromal component was reduced in treated mice. Lung metastatic foci were counted. Plot shows that the inhibitor treatment promotes reduction of the metastatic burden.

The four most recent publications on this topic are:

  • Stanisavljevic J, Loubat-Casanovas J, Herrera M, Luque T, Peña R, Lluch A, Albanell J, Bonilla F, Rovira A, Peña C, Navajas D, Rojo F, García de Herreros A, Baulida J. Snail1-expressing fibroblasts in the tumor microenvironment display mechanical properties that support metastasis. Cancer Res 2015, 75, 284-295.
  • Baulida J, García de Herreros A.Snail1-driven plasticity of epithelial and mesenchymal cells sustains cancer malignancy. Biochim Biophys Acta. 2015,1856, 55-61.
  • Alba-Castellón L, Olivera-Salguero R, Mestre-Farrera A, Peña R, Herrera M, Bonilla F, Casal JI, Baulida J, Peña C, García de Herreros A.Snail1-Dependent Activation of Cancer-Associated Fibroblast Controls Epithelial Tumor Cell Invasion and Metastasis. Cancer Res 2016, 76, 6205-6217.
  • Baulida J. Epithelial-to-mesenchymal transition transcription factors in cancer-associated fibroblasts. Mol Oncol 2017, 11, 847-859.

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