Research database

Compared to conventional pre-clinical systems, such as the use of classical cell lines and animal models, organoid technology is a new extraordinary tool which can provide new keys about mechanisms underlying cellular dynamics, able to extend basic biological research into a more physiologically and also pathologically relevant human setting. Lung organoids have sprung up in more researching fields, because of their ability to recapitulate the 3D structure and functions of the in vivo counterpart organs. Unfortunately, in a cancer research setting, the culture system for lung cancer organoids is still immature, resulting in limited success rate and low tumor purity. The idea is that none of the established protocols was able to adequately simulate the tumor microenvironment, characterized by strong biophysical signaling mediated by cell contacts with the extracellular and biochemical stimulation mediated by stromal cells. The lack of these fundamental features relapse in defects of cell dynamics and, therefore, long-term propagation failure. In this scenario, our proposal (named ORiGAMi: Organoids in Gelatin-Methacrylate) aims to generate a platform of patient-derived organoids (PDO), established from both healthy and tumor tissues of patients affected by non-small cell lung cancer (NSCLC), mimicking NSCLC tumor microenvironment. The goal will be reached by developing a flexible and tunable ECM-like culture system based on Gelatin Methacrylate-based hydrogel (GelMA), in which organoids growth will be supported through soluble factors secreted by patient-derived stromal cells. GelMA is a promising alternative candidate to standard basement-membrane extract which has the main potential to be modulated in composition, geometry, stiffness and which can be functionalized with ad-hoc biomolecules, overcoming the main limitations in robustness and versatility common to the classical ECM-like matrices. Moreover, GelMA is a biocompatible, biodegradable, non-cytotoxic, and non-immunogenic gelatin-based hydrogel, already used for bioprinting applications. The ORiGAMi platform, including organoids generated by healthy and NSCLC cells of each patient, will allow investigations of in vivo-like fundamental biochemical signalling involved in cell growth and proliferation, biological and biophysical mechanisms regulating cell-cell and cell-matrix communication, as well as metabolic rewiring. The characterization of these healthy and NSCLC cell dynamics boost the employment of patient-derived organoids in personalized medicine, studying patient-specific pharmacological responses to adjuvant standard therapies and novel therapeutic approaches. A tumor type for which organoid-guided clinical decision making could be of particular value is NSCLC. This is in line with the main interest of our research consortium that will be committed to achieving a suitable tool for prospective therapeutic studies or to manage drug resistance.