Human Organ Chip Models Recapitulate Orthotopic Lung Cancer Growth, Therapeutic Responses, and Tumor Dormancy In Vitro

Abstract

Here, we show that microfluidic organ-on-a-chip (organ chip) cell culture technology can be used to create in vitro human orthotopic models of non-small-cell lung cancer (NSCLC) that recapitulate organ microenvironment-specific cancer growth, tumor dormancy, and responses to tyrosine kinase inhibitor (TKI) therapy observed in human patients in vivo. Use of the mechanical actuation functionalities of this technology revealed a previously unknown sensitivity of lung cancer cell growth, invasion, and TKI therapeutic responses to physical cues associated with breathing motions, which appear to be mediated by changes in signaling through epidermal growth factor receptor (EGFR) and MET protein kinase. These findings might help to explain the high level of resistance to therapy in cancer patients with minimal residual disease in regions of the lung that remain functionally aerated and mobile, in addition to providing an experimental model to study cancer persister cells and mechanisms of tumor dormancy in vitro.

In vitro and ex vivo systems at the forefront of infection modeling and drug discovery

“…To date, several types of 3D in vitro tumor-on-a-chip models have been established in an effort to elucidate tumor-microvascular interactions while mimicking the tumor microenvironment. One study employed previously described organon-a-chip technology to recapitulate and investigate human non-smallcell lung cancer (NSCLC) growth and invasion patterns as well as the tumor cell responses to therapeutic cues associated with breathing motions [213]. In addition to single organ-on-a-chip, multi-organs-ona-chip, also known as body-on-a-chip, have been developed to understand the physiological coupling between different organs in vitro, study drug metabolism, and generate pharmacokinetic (PK) and pharmacodynamics (PD) models [214][215][216][217][218] (Fig.…”

From Shape to Function: The Next Step in Bioprinting

“…On the other hand, 3D in vitro models that are intended to be used for drug screening, may only need to display a certain salient feature of the replicated biological structure. This concept is well exemplified by the current state‐of‐the‐art of organ‐ and body‐on‐a‐chip technology, involving soft lithography and replica molding as production processes . Such models are often composed by horizontally or vertically aligned microfluidic channels, each representing a tissue compartment, which are interfaced to allow intercompartment cell communication.…”

Stem cell-based Lung-on-Chips: The best of both worlds?

“…However, their potential to recapitulate complex human organ-level functions became rapidly evident and led to an array of advanced models of human lung tissue, such as the "lung-on-a-chip", "alveolus-on-a-chip" and "small airway-on-a-chip" [50,52,80,82,[121][122][123]. Applications include the study of lung cells growth and injury [122,123], modeling of alveolar tissue-tissue interaction and inflammatory processes [50], responses of the alveolar epithelium to drugs, mechanical stresses [81,121], and pulmonary thrombotic events [82], as well as lung cancer [124]. Most recently, a functional dynamic model of human airways comprising well-differentiated airway epithelial cells at air-liquid interface has been developed.…”