Kidney cancer accounts for approximately 4% of all cancers worldwide, with clear cell renal cell carcinoma (ccRCC) representing the most common histological subtype. Highly metastatic, ccRCC is associated with very poor five-year survival rates, once dissemination has occurred. Current treatments, including tyrosine kinase inhibitors and immunotherapies, often prove ineffective. This therapeutic failure can be attributed to several factors, including the lack of reliable predictive markers, intra-tumoral heterogeneity, and the limitations of traditional preclinical models (2D cultures or animal models).
In this context, the aim of this thesis was to design a biomimetic microfluidic device capable of assessing the metastatic potential of ccRCC tumor cells, with a specific focus on their invasion and intravasation abilities. As a first step, I optimized a 3D invasion model based on tumor spheroids cultured in a permissive hydrogel that closely mimics the mechanical properties of renal tumor tissue. This system allowed us to assess the aggressiveness of different ccRCC cell lines and to correlate their invasive potential with their in vivo behavior.
This invasion model was then integrated into a microfluidic chip designed to replicate the first two steps of the metastatic cascade: matrix invasion and intravasation through a reconstructed endothelial monolayer. This device, still under validation with various cell lines to test its robustness and relevance, represents an innovative tool with both predictive and therapeutic applications, in line with a personalized medicine approach for ccRCC patients.
Finally, with a long-term goal of developing a microfluidic system that models the entire metastatic dissemination process, a parallel study was conducted to simulate the bone niche, a preferential site for ccRCC metastases. We developed a co-culture system involving ccRCC cells and mesenchymal stem cells, either undifferentiated or differentiated into osteoblasts. This approach revealed a structural effect of osteoblasts, which were able to slow down tumor cell migration, highlighting the critical role of cellular interactions in metastatic colonization.
This work thus lays the foundation for the development of a modular and biomimetic platform, paving the way for a better understanding of ccRCC metastatic mechanisms and the design of personalized therapeutic strategies.
Supervision of the thesis :Odile FILHOL-COCHET
Claude COCHET