3D Microfluidic System to Study of Tumour Microenvironment
- Publication Type:
- Thesis
- Issue Date:
- 2022
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The tumour microenvironment (TME) plays a crucial role in cancer initiation, progression, and development. To better understand the cellular and molecular feature of TME, various in-vitro, ex-vivo and in-vivo models of TME have been developed, ranging from 2D cancer cells lines, 3D organoids to genetically engineered animal models. However, these models faced a series of challenges and drawbacks limiting the study of the particular feature of TME in a specific type of cancer. Recently, microfluidic technology introduced a new platform to mimic the TME ecosystem at the micro-scale through an advanced engineered system. This platform enables modelling a wide range of TME properties from ECM to the vasculature and the complex cellular structure by co-culturing 3D tumour cells cost-efficient, real-time, and controllable fashion. However, the major focus of the current microfluidic models of TME is on cancer cells rather than tumor-stromal cells and their effects on tumour immunity and immunotherapy. Moreover, these models unbale to provide a space for down-stream molecular analysis including cytokines analysis or RNA-sequencing. Additionally, the design of majority of these models is complex which might limit broad application of these models.16 This thesis focuses on addressing these challenges using a low-cost and easy to use microfluidic device which enable wide range of applications from in-vitro to ex-vivo and drug discovery and immune-oncology. Using developed model in this thesis, the most impactful contributions of this thesis was the discovery of the role of the tumor stromal cells including cancer-associated fibroblasts (CAFs) and tumour-associated mesenchymal stem cells (TAMs) in tumour immunity and that targeting these populations can significantly reduce immune-suppression capacity in TME. We discovered and introduced potential of an anti-fibrotic drug called Pirfenidone for targeting CAFs and secreted cytokines through a comprehensive in-silico data analysis at both bulk and single cell level in breast cancer for the first time. Using our developed microfluidic model of TME, we showed that how pirfenidone reduce CAFs and MSC activity, invasion, immune-suppression, and tumor initiation in breast carcinoma. Moreover, we modelled the effects of matrix stiffness which is regulated by CAFs on tumour immunity and expression of immune checkpoints.
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