Lung cancer organoids analyzed on microwell arrays predict drug responses of patients within a week

Abstract

While the potential of patient-derived organoids (PDOs) to predict patients’ responses to anti-cancer treatments has been well recognized, the lengthy time and the low efficiency in establishing PDOs hamper the implementation of PDO-based drug sensitivity tests in clinics. We first adapt a mechanical sample processing method to generate lung cancer organoids (LCOs) from surgically resected and biopsy tumor tissues. The LCOs recapitulate the histological and genetic features of the parental tumors and have the potential to expand indefinitely. By employing an integrated superhydrophobic microwell array chip (InSMAR-chip), we demonstrate hundreds of LCOs, a number that can be generated from most of the samples at passage 0, are sufficient to produce clinically meaningful drug responses within a week. The results prove our one-week drug tests are in good agreement with patient-derived xenografts, genetic mutations of tumors, and clinical outcomes. The LCO model coupled with the microwell device provides a technically feasible means for predicting patient-specific drug responses in clinical settings.

Primary Lung Cancer Organoids for Personalized Medicine—Are They Ready for Clinical Use?

“…In a recent publication by Hu et al, a similar minimal medium composition was used for short-term organoid culture. The authors only used early-passage organoids for further analyses, but reported a high success rate of 79% in early lung cancer organoid establishment [ 17 ].…”

“…Based on morphological and immunohistochemical data, Dijkstra et al described different phenotypes of organoids derived from intrapulmonary NSCLC: NSCLC organoids can be both cystic or solid, although most cancer organoids appear to grow as irregularly formed, solid structures [ 16 ]. In general, there appears to be no clear association between the parental tumor histology and the general NSCLC organoid morphology and architecture [ 17 ]. p63 staining is either disorganized (in squamous cell carcinoma) or absent (in adenocarcinoma), but without a clear polarization within the organoid.…”

“…However, according to The Cancer Genome Atlas (TCGA), up to 15% of adenocarcinomas and 7% of squamous cell carcinomas present with a normal CN profile and are therefore difficult to distinguish from normal airway tissue based on this method [ 16 ]. Other groups used whole-exome sequencing (WES) or targeted sequencing for oncogenic drivers to verify the organoids’ malignant origin [ 11 , 12 , 14 , 15 , 17 , 18 ]. However, due to an inherent genetic drift during organoid passage, genetic alterations or an inconsistency in the present mutations was reported in several cases [ 12 , 18 ].…”

“…The time required to establish well-growing primary organoid cultures and the current rates of success and expansion limit the clinical application of organoids not only in NSCLC, but also in other cancer types such as colorectal cancer [ 28 ]. A promising solution for a faster and more straightforward drug screening is presented by Hu et al [ 17 ] The group used early-passage (mostly p0) organoids in a microwell array chip for high-throughput analysis in a nanoliter scale and obtained drug response profiles within a week [ 17 ]. Being aware of the occurrence of genetic drift and a potential selection of rapidly growing and pluripotent cancer cells in advanced passages, the use of early-passage organoids may furthermore help to faithfully recapitulate the tumor heterogeneity and in vivo drug response and additionally fit the short time frame for an early clinical application after surgical resection [ 23 ].…”

Scientific Validation and Clinical Application of Lung Cancer Organoids

“…Cancer organoids show promise for cancer research by recapitulating the tumor characteristics and heterogeneity [ 9 ]. The use of lung cancer organoids (LCOs) enable reliable high-throughput drug screening [ 10 , 11 , 12 ]. However, the success rate of LCO culture, the culture medium composition, and tissue processing differ among studies.…”