Understanding invasive cancer progression and metastasis formation are among the core open questions in cancer research. However, the limitations of current models lead to high failure rates in drug development. An EU-funded consortium has designed an organ-on-a-chip approach that could deliver new insights.
In metastasis, circulating tumor cells spontaneously shed from the primary site to the bloodstream, traveling to distant sites and forming secondary tumors. Current experimental approaches to investigate the underlying mechanisms and test drug candidates use animal models or in vitro cell culture assays.
Both approaches have their downsides. In cell culture assays, the cancer cells form a two-dimensional monolayer that does not reflect the heterogeneity of a three-dimensional tumor, often leading to an overestimation of the drug response.
Animal models allow studying tumors within the context of a living organism. However, the human-derived cancer tissue is surrounded by the animal’s physiological system, influencing both metastasis formation and drug response in a way that can differ significantly from the results obtained in humans.
As the existing models do not reflect actual in-patient conditions, therapy failures often occur once the drug development project moves to the clinical phase. For more relevant preclinical results and higher success rates, a new organ-on-a-chip system has been developed that provides a three-dimensional, fully human model.
Meet the Breast to Bone multi-chamber device
The Breast to Bone (B2B) multi-chamber device comprises two independent growth chambers that accommodate different tissue types. One is used to cultivate the primary breast cancer cells in an optimized extracellular matrix; the other contains bone tissue suitable for metastatic tumor growth.
A fluidic connection between the two chambers allows tumor cells to spread and infiltrate the bone tissue, similar to the situation in vivo. This connection was created by connecting the capillaries that were self-assembled by the two tissues with 3D-printed vessels in the fluidic device.
“Our goal was to create macro-to-micro bioprinted vessels that reproduce the different sizes, branching, and features of blood vessels,” explained Silvia Scaglione, CNR senior researcher, Project Coordinator B2B FET-OPEN, and Chief Research Officer at REACT4LIFE. “One of the biggest challenges was to create stable physiological adapters, especially as the diameter of the printed vessels is significantly larger than that of the capillaries.”
Demonstrating proof of principle
In the prototype B2B device, the researchers could observe spontaneous circulating tumor cell formation and circulation, and evidence of cancer cell infiltration and metastasis formation in the bone tissue.
“Most importantly, we demonstrated that certain compounds can suppress both the production of circulating tumor cells in the B2B device and tumor growth. These results are likely to pave the way toward larger drug screens for identifying compounds with anti-metastasis ability,” stressed Scaglione.
Tackling high-risk financing
The high financial risk of developing the B2B device was alleviated by the EU Pathfinder framework that supported the project with a total of 3.8 M€ over four years.
“The cost to develop prototype development and scientific validation would have been a major bottleneck if it hadn’t been for the EU funding. Venture capitalists usually demand a return on investment in five or seven years, a timeframe that does not match the development from the idea stage to commercialization of such a complex device,” Scaglione stated.
A team success
Besides funding, the collaboration of scientists from various fields made the B2B project possible:
- Nicola Aceto at the Cancer Metastasis lab, ETH Zurich, provided expertise in breast cancer metastasis
- Eric Farrell’s Bone Tissue Engineering Research lab at the Erasmus MC University Medical Center developed the ossicle model
- Andrea Banfi’s Cell and Gene Therapy lab at the Basel University Hospital and Lorenzo Moroni’s Complex Tissue Regeneration group at Maastricht University jointly designed the vascular network
- Greek biotech company BIOEMTECH provided high-resolution imaging to monitor cancer cell circulation and metastasis formation
- Cambridge Innovation Technologies Consulting Ltd (CITC) assessed the degree of maturity reached by the technology
- Italian research firm INsociety supported project management, communication, and dissemination of the B2B results
- Finally, the Engineering for Health and Wellbeing Group at the CNR-IEIIT institute, headed by Silvia Scaglione, integrated these components into the final device together with the R&D team at Italian biotech REACT4LIFE while constantly improving the prototype design based on the collected findings.
One of the project’s outcomes was the installation of the first microphysiological system summit, which brought together pharma companies, suppliers, regulatory agencies, and academia to promote the adoption of alternative organ-on-a-chip approaches.
On the road to commercialization
After the end of the project, its legacy will be to fine-tune the prototype and take the next steps toward commercialization. Within the consortium, REACT4LIFE, winner of the 2021 Innovation Radar Prize, has been chosen to take the B2B project to market. REACT4LIFE has patented and fully industrialized the MIVO® – Multi In Vitro Organ technology, demonstrating the need for complex organ-on-chip devices to solve challenges in drug discovery.
“Right now, we are working on optimizing the macro-to-micro connection, bone ossicle in vitro formation, and breast to bone cancer cell infiltration,” Scaglione said. “REACT4LIFE has already launched a pumping system compatible with both the MIVO® technology and the B2B device. In parallel, we are establishing the final parts of the supply chain for industrialization, which we expect to happen in about two years.”
Studying metastasis beyond breast and bone
Having mastered bone as one of the most demanding tissue types, the B2B approach can be adapted to studying metastasis of other cancer types, such as lung, pancreatic, or neuroblastoma tumors.
The multicompartmental chambers allow culturing of patient-derived biopsy tissue to test standard and personalized therapies. Another possible application is to add immune cells to the circulation to study the infiltration of tumor tissue with engineered immune cells and their capacity to kill tumor cells.
“We are confident that the B2B project will become an essential tool for the pharmaceutical and scientific community to improve basic research and drug discovery in cancer metastasis,” Scaglione concluded.
Learn more about REACT4LIFE and the legacy of the B2B project.
Images courtesy of REACT4LIFE and INsociety for B2B project.