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Morphological and functional adaptation of osteosarcoma cells during the invasive process
Tumor initiation and progression are accompanied by complex changes in the cyto-architecture that at the cellular level involve remodeling of the actin cytoskeleton. Its central role in cellular functions such as adhesion and migration makes the study of the reorganization of the actin cytoskeleton
Keywords: Cancer, actin cytoskeleton, osteosarcoma, 3D culture, synthetic hydrogels
Osteosarcoma is the most frequent bone cancer in children and young adults with approximately 60% cases being diagnosed in patients between 10 and 20 years of age [World Health Organization, 2013; Fagioli et al., 2002]. In the case of early detected/localized osteosarcoma, standard treatment comprises surgical removal followed by chemotherapy, and achieves a 5-year survival rate of 70%. Nevertheless, survival of patients with advanced or metastatic tumors at diagnosis remains low with an average life expectancy of only 23 months [Fagioli et al., 2002; Allison et al., 2012]. Because of their mesenchymal origin osteosarcomas do not follow standard epithelial-to-mesenchymal transition (EMT), a process by which malignant cells gain invasive and metastatic capabilities. This difference invalidates many of the invasion observations made in the more frequent carcinomas, which have epithelial origin. In the present project we plan to analyze the phenotypic and functional changes that osteosarcoma cells undergo during the invasive process. Three-dimensional synthetic hydrogels represent an unique model to mimic biological processes, including pathological ones, under controlled conditions. With this in mind in the present project we propose the use of polyethyleneglycol (PEG) hydrogels as three-dimensional (3D) cell culture and migration/invasion platforms [Ehrbar et al., 2007; Milleret et al., 2014].
Osteosarcoma is the most frequent bone cancer in children and young adults with approximately 60% cases being diagnosed in patients between 10 and 20 years of age [World Health Organization, 2013; Fagioli et al., 2002]. In the case of early detected/localized osteosarcoma, standard treatment comprises surgical removal followed by chemotherapy, and achieves a 5-year survival rate of 70%. Nevertheless, survival of patients with advanced or metastatic tumors at diagnosis remains low with an average life expectancy of only 23 months [Fagioli et al., 2002; Allison et al., 2012]. Because of their mesenchymal origin osteosarcomas do not follow standard epithelial-to-mesenchymal transition (EMT), a process by which malignant cells gain invasive and metastatic capabilities. This difference invalidates many of the invasion observations made in the more frequent carcinomas, which have epithelial origin. In the present project we plan to analyze the phenotypic and functional changes that osteosarcoma cells undergo during the invasive process. Three-dimensional synthetic hydrogels represent an unique model to mimic biological processes, including pathological ones, under controlled conditions. With this in mind in the present project we propose the use of polyethyleneglycol (PEG) hydrogels as three-dimensional (3D) cell culture and migration/invasion platforms [Ehrbar et al., 2007; Milleret et al., 2014].
The objectives of the present project are:
1. Optimization of the cell culture conditions of tumor cells in 3D synthetic hydrogels: 2 paired osteosarcoma cell lines composed each of a low metastatic variant (SaOs-2 and HuO9) and two experimentally derived highly metastatic forms (LM5 and M132, respectively.
2. Characterization of a tumorigenic actin mutation while 3D cell culture and migration (Rat-2 and Rat2sm9 [Blache et al., 2013]).
3.- Characterization and quantification of the invasive process for each cell line using live microscopy and fixed samples. In addition to single cells cell aggregates will be used as surrogates of solid tumors.
4.- Characterization of morphological changes at the actin cytoskeleton and focal adhesions during the invasive process.
The objectives of the present project are:
1. Optimization of the cell culture conditions of tumor cells in 3D synthetic hydrogels: 2 paired osteosarcoma cell lines composed each of a low metastatic variant (SaOs-2 and HuO9) and two experimentally derived highly metastatic forms (LM5 and M132, respectively.
2. Characterization of a tumorigenic actin mutation while 3D cell culture and migration (Rat-2 and Rat2sm9 [Blache et al., 2013]).
3.- Characterization and quantification of the invasive process for each cell line using live microscopy and fixed samples. In addition to single cells cell aggregates will be used as surrogates of solid tumors.
4.- Characterization of morphological changes at the actin cytoskeleton and focal adhesions during the invasive process.
Dr. Unai Silvan, unai.silvan@hest.ethz.ch / Institute for Biomechanics, ETH Zürich / Professorship
Dr. Unai Silvan, unai.silvan@hest.ethz.ch / Institute for Biomechanics, ETH Zürich / Professorship