Cancer spreading beyond the primary tumor – a process known as metastasis – is responsible for at least two-thirds of cancer deaths. Drugs targeting the metastatic progression have largely failed, in part due to the lack of predictive models that would help identify the underlying mechanisms of metastasis.
While animal models have led to key advances in the understanding of metastasis-related mechanisms, the persistent clinical failures of drugs targeting metastatic progression suggest that the differences between human and rodent biology cannot be discounted.
In a study published on August 19 in Science Translational Medicine, Columbia Engineering professor Gordana Vunjak-Novakovic and her team report the development of a multi-organ chip that mimics how cancer cells spread from vascular flow to distant organs, the first model of cancer metastasis of its kind. The chip includes compartments with millimeter-sized engineered human bone and lung tissues, and the vascular flow that contains circulating breast cancer cells and allows the dynamic cross-talk of the tissues being colonized.
"The pressing need for developing human tissue models of metastasis has been a key motivation for our study," said Vunjak-Novakovic, who is a University Professor at Columbia University and the Mikati Foundation Professor of Biomedical Engineering and Professor of Medical Sciences (in Medicine). "Our objective was to probe the ability of cancer cells to adhere to and traverse across endothelium [inner lining of blood vessels], and to determine their capacity to survive in the tissues they are colonizing through cell reprogramming and niche remodeling."
The study sheds light on a critical phase of metastasis, known as organ colonization, which is difficult to study using animal models. As cancer cells break away from the original tumor, they travel through the bloodstream and settle into the tissue of distant organs. From there, these cells grow until a tumor forms in a new location. The process is highly complex, requiring the cancer cells to evade tissue defense and adapt to the specific organs they invade.
This multi-organ chip allows scientists to investigate, in detail, metastatic progression with actual patient cells and tissues, as opposed to using animal models that don't always reflect human biology. The platform enables controlled experimentation of cancer cell-tissue interactions within organ-specific microenvironments, towards revealing molecular pathways and therapeutic targets for metastasis. To demonstrate the chip's capabilities, Vunjak-Novakovic and her colleagues examined the colonization of circulating human breast cancer cells into bone and lung.
"Cancer is very smart, unfortunately. We learned how the cells cross barriers to get from blood circulation into the tissues," said Vunjak-Novakovic. "We were also able to reproduce something that happens in patients, where cancer cells condition the target tissues, even before they colonize them, to make them more receptive."
Vunjak-Novakovic, who heads the Laboratory for Stem Cells and Tissue Engineering , focuses on tissue engineering approaches to improving human health. Her lab was part of the first wave of the development of micro-sized human tissue platforms — called microphysiological systems or organs-on-a-chip — for modeling human pathophysiology and drug response. For this study, the engineers teamed up with colleagues at Columbia's Herbert Irving Comprehensive Cancer Center: Andrea Califano , the Clyde and Helen Wu Professor of Chemical and Systems Biology, Peter Sims , associate professor of systems biology, and Hanina Hibshoosh , professor of pathology & cell biology.
Ilaria Baldassarri, a PhD student at Columbia Engineering and one of the lead authors of the study, said she is excited about what the work demonstrates for the future of preclinical research: engineered human tissues that can complement what is learned from animal models. "As the FDA and NIH place growing emphasis on new approach methodologies, this study is a concrete example of what that shift can look like in practice, applied to one of cancer's most challenging hallmarks: metastasis," Baldassarri said.
Bone and lung, common sites of metastasis for breast cancer, and the vascular endothelium were engineered from induced pluripotent stem cells (iPSCs) using tissue-specific scaffold-bioreactor culture systems. The engineered tissues were maintained in individual compartments of the chip, which were each optimized for tissue maturation and long-term maintenance of functionality, and linked to each other by vascular circulation.
A selectively permeable endothelial barrier is a critical feature of this chip, as it separates tissue compartments from the vascular channel, as in the human body. Once the platform was established, the researchers introduced breast cancer cells into the vascular circulation to observe patterns of organ-specific colonization. In line with what happens inside the human body, cancer cells that typically gravitate towards the bone showed stronger bone colonization and induced more pronounced bone degeneration. In contrast, cancer cells that typically gravitate towards the lung caused greater disruption in the lung tissue and only modest colonization of bone. Distinct patterns of tissue colonization and secreted factors demonstrate that this device mimics key features of organ-specific metastasis observed in the human body.
In addition, a post-analysis of the engineered tissue revealed that cancer cells condition the distant organs to be more receptive to colonization. The team saw signs of this process — called pre-metastatic niche formation — across both tissue compartments.
"The key advantages of this advanced model of metastasis are that it is human and can be patient-specific," Vunjak-Novakovic said. "It faithfully mimics some of the key aspects of human metastasis that are otherwise largely inaccessible for direct study."
