Abstract
Abstract One of the biggest challenges in preclinical oncology is the lack of models faithfully recapitulating the physiological and pathophysiological features of the native tumor. PDXs (Patient-Derived Xenografts), developed in immune-compromised mice, have proven their relevance in the study of aberrations leading to the development and progression of cancer, to the mechanisms linked to tumor resistance and to the identification of novel therapies. Despite being a fundamental step to generate new knowledge on cancer, the use of PDXs shows some technical disadvantages such as long engraftment time and/or low growth rate, thus raising economic and ethical concerns. Huge efforts are being done to develop cell-based alternatives systems reproducing the tumor complexity combined with suitable methods. To this aim, we have developed 50+ PDX-derived cell lines (PDXDCs) from our proprietary 200+ PDX collection. These lines are currently used as two-dimensional (2D) cultures to perform drug screening in an affordable, timewise, and cost-effective way. While well designed, drug-tailored 2D screenings can predict drug behavior in vivo, they present limitations as they are unable to reproduce cell-cell and cell-extracellular matrix interactions, two important parameters that contribute to the regulation of drug accessibility and oxygen diffusion in vivo. To encompass those limitations and give access to a wider range of experimental methods we have generated three-dimensional (3D) cell culture models by taking advantage of LifeGel technology, consisting of protein-based hydrogels that modulate matrix density and stiffness to mimic the organ of origin-specific extracellular environment. Thanks to its versatility we successfully developed spheroid cultures from PDXDCs from various indications, including breast cancer cells from different histological subtypes. Tumor cells plated on LifeGel adopted 3D spheroid-like structures in a few days. These structures showed heterogeneous morphology and size depending on the tumor type and the hydrogel composition. As spheroids can be passaged in vitro by digestion, we could easily expand them and perform drug screening that will be presented and compared to 2D and in vivo results. The aim of this project is to develop a collection of PDX-derived spheroids recapitulating PDXs characteristics. This collection will give the opportunity to perform high-content drugs screening to select the best candidate drugs to be retained for further preclinical in vivo studies. Citation Format: Agnieszka Pietrzyk, Emilie Indersie, Olivier Deas, Jean-Gabriel Judde, Marcin Krzykawski, Stefano Cairo. Development of PDX-derived spheroids using LifeGel, an innovative 3D cell culture technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 176.
Published Version
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