Metastatic Tumor-In-A-Dish: A Novel Multi-Cellular Organoid for Precision Medicine using Patient-Derived Cells

Metastasis is a major cause of cancer-related deaths. A dearth in preclinical models that recapitulates the metastatic microenvironment has impeded the development of therapeutic agents that are effective against metastatic disease. Since the majority of solid tumors metastasize to the lung, we developed multi-cellular organoid consisting of lung epithelial cells, fibroblasts, blood and lymph endothelial cells that mimics the lung microenvironment with air sac like structures and production of lung surfactant protein. We used these cultures called primitive lung-in-a-dish (PLiD), to recreate metastatic disease using primary and established cancer cells. The metastatic tumor-in-a-dish (mTiD) cultures resemble the architecture of metastatic tumors in the lung. We tested the response of primary and established cancer cells to current chemotherapeutic agents in mTiD vs 2-dimensional (2D) or 3D cultures containing only cancer cells. Interestingly, the response of primary patient-derived colon and ovarian tumor cells to chemotherapy in mTiD cultures but not 2D or single cell type 3D cultures, matched the response of the patient in the clinic. Sensitive mTiD cultures had low levels of secreted carcinoembryonic antigen that were similar to those seen in patients that responded to therapy. Thus, we have developed a novel method for identifying the appropriate therapeutic agent that specifically targets tumor tissues. More importantly, the technique has significant utility in precision/personalized medicine, wherein this phenotypic screen can be coupled with current DNA pharmacogenetics to identify the ideal therapeutic agent, thereby increasing the probability of response to treatment while reducing unnecessary side effects.