MetLung, an innovative 3D lung metastasis model

Metastasis is the leading cause of death for cancer patients. The most common location in pediatric solid tumor patients is the lung. Our failure to cure patients with metastasis is due to a lack of knowledge on the metastatic niche, resulting from scarcity of relevant tumor models. Animal models are still a gold standard in preclinical research, although they often fail to recapitulate human biology and poorly predict patient response to drugs. Recent technological advances propel alternative approaches: Organoids are established in vitro from tissue stem cells and mimic architectural and functional characteristics of their corresponding in vivo organ, while 3D-bioprinted constructs can mimic the physical and chemical properties of the tissue microenvironment. We aim at constructing versatile and scalable in vitro alternatives to animal models of solid tumor lung metastasis for pre-clinical drug testing. The models will be designed in a stepwise fashion from less to more complex. To achieve the best possible in vitro approximation of the metastatic site we will inform the design of our models by analyzing actual lung metastases of various pediatric solid tumors by single-cell and spatial genomics. Cellular complexity and physical properties of the lung niche will be simulated through airway organoids and 3D-printed constructs. The models will be populated with pediatric patient- derived cells from the metastatic site and used to screen for drug sensitivities. This way, we will provide proof of concept for patient-specific 3D-models of lung metastatic pediatric tumors as an alternative to animal studies to guide personalized drug selection for patients with advanced disease. For the first time, state-of-the-art single cell genomics, organoid and 3D- bioprinting technologies will be combined to mimic tumor growth in its metastatic niche in vitro. Through specific targeting of the tumor/niche interactions we aim to develop more efficient, biology-based, personalized treatments for lung metastatic disease.