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Project

Multi-omic validation of a next generation organoid co-culture platform: can we recreate an individualized tumor microenvironment?

Over the last few decades, most of our knowledge regarding the biology and treatment of cancer has been derived from in vitro and in vivo tumor models. The use of 2-dimensional (2D) cancer cell lines has been considered as the golden standard in both basic and translational oncological research. Unfortunately, 2D in vitro models are not able to recapitulate the complexity and cellular heterogeneity of the in vivo setting. Moreover, numerous studies have demonstrated that 2D in vitro models fail to prospectively predict individual treatment responses. Accordingly, the inevitable limitations of pre-existing cancer models in combination with the urgent need for more physiologically relevant predictive platforms have eventually fostered the development of patient-derived tumor organoids. These three-dimensional (3D) multicellular constructs do not only hold great promise to elucidate the underlying molecular mechanisms of cancer growth (basic and translational relevance), but also significantly enhance the concept of personalized medicine (clinical relevance). Moreover, the main advantage of using patient-derived tumor organoids is their preservation of the genetic profile, cellular heterogeneity and clinical response of the primary tissue they originate from. Combining these auspicious features with their high-throughput potential, provides this tool promising applications for future cancer research. In accordance with this promising future, our group recently developed a more advanced pancreatic ductal adenocarcinoma (PDAC) organoid in vitro model (i.e. micro-tumor platform) that incorporates a stromal compartment. Given the numerous advantages of this innovative in vitro platform (compared to the traditional organoid cultures), we are convinced that this model will be the seed for a novel era in preclinical and clinical oncological research. Nevertheless, it should be addressed that, prior to its implementation, further research is of unmet need. Accordingly, this project will focus on validating the physiological relevance of this micro-tumor platform by comparing the concordance in terms of transcriptional profile and fibroblast heterogeneity between our platforms and parental tumors (N=7). Additionally, we aim to comprehensively characterize each micro-tumor (activated pathways, proteome, secretome, single cell transcriptome) and map the bi-directional communication/rewiring of both the PDAC and stromal cells in a co-culture setting. To explore this crosstalk, we will combine a single-cell RNA-seq analysis with a mass spectrometry analysis and subsequently implement the state-of-the-art bioinformatic algorithms (CytoTalk and CellRank). In the end, this validation study allows the previously planted seed to sprout and find its way towards the upcoming era of oncological research.
Date:1 Apr 2022 →  31 Mar 2023
Keywords:3D CELL CULTURE, PANCREATIC CANCER, ORGANOID, TUMOR BIOLOGY
Disciplines:Cancer biology