Cancer researchers have come to understand that generating human tumors in mice by injecting cancer cell lines under the skin does not recapitulate how tumors normally emerge and spread to specific organs in the human body, nor how they respond to anti-cancer drugs. So, they turned to injecting tumor cells at the organ sites where they originated from in humans, so-called ‘orthotopic’ sites. Orthotopic tumors, such as those created by injecting breast cancers into the mammary fat pads of mice, exhibit growth and metastatic behaviors more like those seen in patients, however, these organ environments are still not human. It is also not possible to visualize how tumor cells grow, move and respond to therapeutics in these orthotopic animal models, which restricts our ability to understand how different organ microenvironments influence tumor behavior and thereby develop better drugs.

As reported in the journal Cell Reports, a team at the Wyss Institute for Biologically Inspired Engineering led by Founding Director and Wyss Core Faculty member Donald Ingber, now has leveraged its human Organs-on-Chips technology to confront this challenge. In previous work, the team successfully modelled two different regions of the lung—the air-conducting small airway and the oxygen and carbon dioxide-exchanging alveoli at the tips of the small airways—in microfluidic devices that are created with microchip manufacturing methods. The different lung cells inhabit one of two microchannels that run parallel through the chip, separated by a thin porous membrane from a microvessel lined by human lung endothelium in the second channel. Like in the human lung, the resulting small airway epithelium is thicker, stiffer and covered with moving cilia, while the thinner alveolar epithelium is more permeable to enable efficient gas exchange and it is exposed to cyclic mechanical deformations to mimic breathing motions in the chip. The researchers continuously stream cell culture medium through the vascular channel to support the epithelial and endothelial cell layers over many weeks as occurs with blood-flow in living lung. In addition to having engineered the basic tissue architecture and functionalities of these two lung regions on chips, the team previously showed that they can successfully model lung diseases, including chronic obstructive pulmonary disease (COPD), asthma and pulmonary edema.

In this new study, the team developed human orthotopic lung cancer models using these two lung chips. Approximately 85% of all lung cancers are diagnosed as non-small cell lung cancer (NSCLC), and the team focused on the adenocarcinoma form of this cancer which roughly accounts for 40% of all NSCLCs. In the human body, NSCLC adenocarcinoma cells are known to arise at the interface between the lung’s small airways and alveoli, but the tumor then primarily grows within the alveolar structures.

Ingber’s team showed that when NSCLC adenocarcinoma cells are grown in the Lung Airway and Alveolus Chips, the tumor cells grow rampantly in the microengineered alveolar microenvironment whereas they remain quiescent in the Airway Chip, just as is observed in human patients. “Our lung cancer-on-chip platforms can model central aspects of orthotopic NSCLC in real time and high-resolution, and much more closely than other in vivo and in vitro approaches. They offer a literal window on the biological tumor complexities,” said Ingber. Ingber also is the Judah Folkman Professor of Vascular Biology at HMS and the Vascular Biology Program at Boston Children’s Hospital, as well as Professor of Bioengineering at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS).

To achieve this, the researchers developed co-plating and injection strategies that enabled them to stably integrate a small number of NSCLC cells into the two lung chips. “This approach allows us to recreate key hallmarks of this cancer, including its growth and inv