Lung Cancer Organoids: The Rough Path to Personalized Medicine

Abstract

Lung cancer is the leading cause of cancer death worldwide. Despite significant advances in research and therapy, a dismal 5-year survival rate of only 10–20% urges the development of reliable preclinical models and effective therapeutic tools. Lung cancer is characterized by a high degree of heterogeneity in its histology, a genomic landscape, and response to therapies that has been traditionally difficult to reproduce in preclinical models. However, the advent of three-dimensional culture technologies has opened new perspectives to recapitulate in vitro individualized tumor features and to anticipate treatment efficacy. The generation of lung cancer organoids (LCOs) has encountered greater challenges as compared to organoids derived from other tumors. In the last two years, many efforts have been dedicated to optimizing LCO-based platforms, resulting in improved rates of LCO production, purity, culture timing, and long-term expansion. However, due to the complexity of lung cancer, further advances are required in order to meet clinical needs. Here, we discuss the evolution of LCO technology and the use of LCOs in basic and translational lung cancer research. Although the field of LCOs is still in its infancy, its prospective development will likely lead to new strategies for drug testing and biomarker identification, thus allowing a more personalized therapeutic approach for lung cancer patients.

Moving toward precision medicine with lung cancer organoids

“…With the development of methods for generating organoids, three-dimensional cultures of cancer specimens taken from the affected individual and grown in a basement membrane matrix, lung cancer organoids (LCOs) have come to the fore as an ex vivo system to determine therapy response phenotypes. 2 , 3 LCOs closely match the histopathology, mutational spectrum, and transcriptome of their parental tumors, 2 , 3 and so far, their in vitro responses appear to mirror what were found in the individuals they were derived from. 4 , 5 Several methods for establishing LCOs have been reported, and the derived organoids can be used for drug response phenotype testing, including in high-throughput systems, a clear advantage over such tests in patient-derived xenograft (PDX) systems in mice.…”

“…However, there are no agreed upon standard methods and validation criteria for generating, testing, and evaluating drug responses of LCOs. 2 , 3 Success rates for LCO generation from primary and metastatic sites and different lung cancer histologies are highly variable. A significant issue is that LCOs derived from primary lung tumors often are overrun by organoids composed of normal airway epithelial elements.…”

Clinical insights into small cell lung cancer: Tumor heterogeneity, diagnosis, therapy, and future directions

“…Nevertheless, despite these disadvantages, human SCLC cell lines still represent an important resource for preclinical research. In contrast to other tumor types, such as colon or breast cancer, three‐dimensional models that include organoids are rarely used in SCLC because of its extensive heterogeneity and complexity 114,115 …”

The Role of Patient-Derived Organoids in Triple-Negative Breast Cancer Drug Screening

“…Since their initial application, patient-derived organoids have provided great insights into the pathophysiology of numerous cancer entities and, especially, shed light on obscure and otherwise unexplainable aspects related to the pathogenesis of scarce or complex tumors [ 20 , 21 , 22 , 23 ]. TNBC belongs to the multifaceted and, consequently, aggressive subtypes of breast cancer, as it does not abide by the well-understood hormonal pathways that characterize the more common hormone-receptor positive breast cancer entities but develops and spreads through diverse and extremely complicated molecular mechanisms [ 24 ].…”