Organs-on-chips reveal breathing’s critical role in lung cancer development

Image of lung cancer cells grown alongside human lung small airway cells inside an organ-on-a-chip
Inside view of a lung cancer chip: Lung adenocarcinoma cells are grown as a tumor cell colony (blue) next to normal human lung small airway cells (purple). Credit: Wyss Institute at Harvard University

One of the biggest challenges facing cancer researchers — and lots of other medical researchers, in fact — is that experimental models cannot perfectly replicate human diseases in the laboratory.

That’s why human Organs-on-Chips, small devices that mimic human organ environments in an affordable and lifelike manner, have quickly been taken up into use by scientists in academic and industry labs and are being tested by the U.S. Food and Drug Administration.

Now, the chips have helped discover an important link between breathing mechanics and lung cancer behavior.

Developed by bioengineer Donald Ingber, MD, PhD, human Organs-on-Chips have now been adapted by Ingber’s team to develop a lung-cancer-on-a-chip platform. As published in Cell Reports, the team leveraged two chips representing different parts of the lung and then grew a common form of lung cancer inside them.

Organs-on-Chips are about the size of a computer memory stick and made of clear polymer. They are called microfluidic devices because they contain hollow channels that are perfused with a lifelike flow of blood substitute, nutrients and cells to mimic the microenvironment of human organs.

To do so, the two lung cancer chips — one of which mimics the small airways of the lung and the second which mimics the lung’s air sacs (called alveoli) responsible for oxygen and carbon dioxide exchange — were seeded with human adenocarcinoma cells, the most common variety of non-small cell lung cancer.

The resulting findings have illuminated how the mechanical forces of breathing might encourage the growth of “persister” cancer cells, which linger after treatment and become resistant to drugs, eventually spreading and causing metastasis.

The lung cancer chips “offer a literal window on the biological tumor complexities,” said Ingber, the study’s senior author, in a press release. Ingber is the director of the Wyss Institute for Biologically Inspired Engineering at Harvard University, and the Judah Folkman Professor of Vascular Biology in the Boston Children’s Hospital Vascular Biology Program and Harvard Medical School.

Unraveling the complexities of lung cancer

Inside the chips, the lung cancer cells behaved just like they have been known to do in human patients. In the lung airway chip, the cancer cells first remained dormant before they started to proliferate, while in the alveolus-on-a-chip they proliferated much more aggressively without any lag time.

Image of lung cancer cells alongside lung airway cells inside an organ-on-a-chip
Lung cancer cells alongside lung airway cells inside an airway-on-a-chip. Credit: Wyss Institute at Harvard University

“This approach allows us to recreate key hallmarks of this cancer, including its growth and invasion patterns, and to determine how they are influenced by cues from surrounding normal cells,” said Bryan Hassell, PhD, in the Wyss Institute press release. Hassel, the first author on the study, developed the lung-cancer-on-a-chip platform as a graduate researcher on Ingber’s team.

In mammals, the lung’s air sacs bring oxygen into the blood and expel carbon dioxide from it. The air sacs are called alveoli (singular: alveolus).

By applying cyclical mechanical forces to the alveolus chips to mimic breathing motions, the researchers noticed that both cancer cell growth and invasion were inhibited.

In human patients, they speculate that as lung cancer cells grow and fill the lung air sacs, the tumor mass interferes with the lung’s natural movements. In turn, this disruption could speed up tumor growth and facilitate invasive behavior leading to metastasis.

Breathing keeps us alive — but does it help lung cancer cells thrive, too?

Along this line of thinking, Ingber’s team wondered if breathing mechanics could also make lung cancer cells more sensitive to a type of clinically-used anti-cancer drug known as a TKI (tyrosine kinase inhibitor), which targets mutated enzymes that enable cancers to flourish. Although cancer researchers are trying to design better TKIs, it has so far been difficult to stay ahead of cancer cells, which can evolve very quickly, genetically rewiring themselves to thwart these drugs.

Using the lung-cancer-on-a-chip system, Ingber’s team discovered that cancer cells in the air sac — initially resistant to first-generation TKIs — could be controlled by third-generation TKIs.

But, interestingly, the success of the third-generation TKIs only occurred in the absence of breathing motions, as might occur when large tumors fill the lung’s alveoli and stop their motion, according to the Wyss release.

“The effects of breathing motions on cancer cell behavior in our models could explain how tumor cells, which remain from a shrinking tumor after therapy, could become persister cells, able to defy drug therapy, linger and eventually cause the cancer to relapse,” said Ingber.

Altogether, the findings underscore the complexities at play in lung cancer development and the important role that true-to-human laboratory models play in improving our understanding of those mechanisms — and in the future, our ability to outsmart them therapeutically.


This story was adapted from a press release issued by the Wyss Institute.

Other Wyss Institute authors on the study are Christopher Chen, Girja Goyal, Alexandra Sontheimer-Phelps, Esak Lee and Oren Levy.

The study was funded by the Wyss Institute for Biologically Inspired Engineering at Harvard University, Defense Advanced Research Projects Agency (DARPA), the National Institutes of Health (NIH), and fellowships from the International Foundation for Ethical Research (IFER) and the Lymphatic Education and Research Network.

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