Advanced lung organoids and lung-on-a-chip for cancer research and drug evaluation: a review

Abstract

Lung cancer has become the primary cause of cancer-related deaths because of its high recurrence rate, ability to metastasise easily, and propensity to develop drug resistance. The wide-ranging heterogeneity of lung cancer subtypes increases the complexity of developing effective therapeutic interventions. Therefore, personalised diagnostic and treatment strategies are required to guide clinical practice. The advent of innovative three-dimensional (3D) culture systems such as organoid and organ-on-a-chip models provides opportunities to address these challenges and revolutionise lung cancer research and drug evaluation. In this review, we introduce the advancements in lung-related 3D culture systems, with a particular focus on lung organoids and lung-on-a-chip, and their latest contributions to lung cancer research and drug evaluation. These developments include various aspects, from authentic simulations and mechanistic enquiries into lung cancer to assessing chemotherapeutic agents and targeted therapeutic interventions. The new 3D culture system can mimic the pathological and physiological microenvironment of the lung, enabling it to supplement or replace existing two-dimensional culture models and animal experimental models and realize the potential for personalised lung cancer treatment.

Keywords: 3D culture system; drug evaluation; lung cancer; lung organoid; lung-on-a-chip.

FIGURE 1

Comparison of the relevant characteristics and advantages of the four current lung cancer models, including 2D cell culture, animal models, lung organoid, and lung-on-a-chip. The illustrations are created with BioRender.com.

FIGURE 2

The progress of important events in lung organoids. Created with BioRender.com.

FIGURE 3

The progress of important events in lung-on-a-chip. Created with BioRender.com.

FIGURE 4

(A) 3D lung cancer organoids in a size-controllable manner and demonstrates for the production of lung cancer organoids from patients with small-cell lung cancer. Adapted from Jung et al. (2019). Copyright 2019, Royal Society of Chemistry. (B) Using genetic engineering techniques to obtain LCOs with specific Kras-, Trp53-deficient, and Eml53-Alk mutations, which significantly accelerated the study of the lung cancer genetic mechanisms. Adapted from Nakamura et al. (2019). Copyright 2019, Elsevier B.V. (C) By constructing long-term (greater than 3 months, more than 10 generations), and short-term (less than 3 months, less than 10 generations) NSCLC organoid models, Shi found that cancer organoids with breast cancer 2 gene, EGFR, and EGFR- and EGFR-mutation/MSC-epithelial-transformation (MET)-amplified mutations responded favourably to lapatinib, erlotinib, and crizotinib, respectively. Adapted from Shi et al. (2020). Copyright 2020, American Association for Cancer Research. (D) A LCO-based drug susceptibility test (LCO-DST) of osimertinib, paclitaxel, pemetrexed, carboplatin, etoposide, and cisplatin. Adapted from Wang et al. (2023). Copyright 2023, Cell Press.

FIGURE 5

(A) Schematic diagram of the alveolar structure. Its main structure comprises upper and lower microfluidic channels. Adapted from Tan et al. (2023). Copyright 2023, Elsevier B.V. (B) A multi-organ microarray can further be used to assess the mechanism of epithelial–mesenchymal transition (EMT) in lung cancer cells invading distant tissues and organs, such as the brain, bone, and liver. Adapted from Xu et al. (2016). Copyright 2016, American Chemical Society. (C) Co-cultured lung-on-a-chip models of A549 tumour cells and HFL1 to explore the effects of HFL1 on tumour cell metastasis and drug resistance. Adapted from Yang et al. (2018). Copyright 2018, Royal Society of Chemistry. (D) The three-dimensional-culture multiorgan microfluidic (3D-CMOM) platform for the cancer treatment effects of HIF-1α inhibitors (tirapazamine, SYP-5, and IDF-11774). Adapted from Zheng et al. (2021). Copyright 2021, American Chemical Society.