Developing in vitro models of tumor (tumor microenvironment) to evaluate and improve therapeutic approaches

Principal Investigator and Contact : Stéphanie Descroix,

A critical problem in the development and deployment of effective anti-cancer treatments is the lack of adequate in-vitro model systems and this is particularly true for combined therapies. Conventional cell cultures or animal models (such as nude mice for patient-derived xenograft) fail to accurately predict drug responses in humans as they do not properly mimic the complexity of human physiopathology, particularly the immune tumor-microenvironment; for instance, nude mice are severely immuno-compromised to allow human xenografting. This is why clinical trial success rate in oncology is dramatically low. The use of animal models also raises ethical problems regarding animal well-being especially in the 3R context.

Hence, there is an urgent need to develop new technologies that allow investigating the effect of anti-cancer therapies in particular when used in combination by being able to assess their influence on the tumor microenvironment as well as by controlling the composition of these humanized cellular tumor ecosystems for both research and treatment purposes. In the last decade, basic research showed how our understanding of the behavior of physiological and patho-physiological systems can be greatly increased thanks to a rational simplification of the human body in artificial microsystems. Microtechnology and specifically microfluidics, provided powerful tools, to interact with cells at their own scale, tailoring the artificial microenvironment on experimental needs. In this context, we have initiated a strong collaboration with the team of F. Mechta-Gregoriou at Institut Curie in particular with MC Parrini, G. Zalcman and J. Camonis to develop relevant in vitro microphysiological models of tumor microenvironment. We aim at pursuing in this research direction through both biological and biophysical approaches.

Despite already promising results, we still consider that our tumor on chip (ToC) platform could be further improved. In particular, we aim at integrating functional vessels on chip. Besides, in collaboration with Fluigent company, we also aim at implementing a new generation of ToC with a fine control of physioxic or hypoxic conditions.  Those improvements will both improve the completion of ToC biomimetism and allow for a better understanding of TME response to different drugs. With the team of F. Mechta-Gregoriou, we are currently implementing the on-chip reconstitution a simplified immunocompetent lung tumor microenvironment to quantify the effects of immune checkpoint inhibitor on the tumor ecosystem. We will use these models to dissect the response of the tumour microenvironment to therapeutic approaches combining nanoparticle-mediated hyperthermia and chemotherapy or immunotherapy.

In parallel, we also aim at further probing the biophysical properties of reconstituted tumor.  More specifically, tumor magnetic spheroid can be used as both rheological probes and biological actors of the tumor microenvironment. They can be either compressed in magnetic field gradient to measure in-depth rheological properties of these tumors-to-be or they can be manipulated by magnetic attractors within chips to probe the rheological properties of their environment to assess the effect of chemo- or photo-therapies on TME biophysical properties. Importantly, because these approaches involve the incorporation of exogenous nanoparticles in cells, we will also focus on the biological fate of these nanoparticles within the engineered tissues, and investigate their assimilation after playing their initial role as magnetic organizers and stimulators