Making In Vitro Tumor Models Whole Again

As a reductionist approach, patient-derived in vitro tumor models are inherently still too simplistic for personalized drug testing as they do not capture many characteristics of the tumor microenvironment (TME), such as tumor architecture and stromal heterogeneity. This is especially problematic for assessing stromal-targeting drugs such as immunotherapies in which the density and distribution of immune and other stromal cells determine drug efficacy. On the other end, in vivo models are typically costly, low-throughput, and time-consuming to establish. Ex vivo patient-derived tumor explant (PDE) cultures involve the culture of resected tumor fragments that potentially retain the intact  TME of the original tumor. Although developed decades ago, PDE cultures have not been widely adopted likely because of their low-throughput and poor long-term viability. However, with growing recognition of the importance of patient-specific TME in mediating drug response, especially in the field of immune-oncology, there is an urgent need to resurrect these holistic cultures. In this Review, the key limitations of patient-derived tumor explant cultures are outlined and technologies that have been developed or could be employed to address these limitations are discussed. Engineered holistic tumor explant cultures may truly realize the concept of personalized medicine for cancer patients.