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Published on: January 5, 2021
Cholangiocarcinoma-on-a-chip: A human 3D platform for personalised medicine
Michela Anna Polidoro1, Erika Ferrari2, Cristiana Soldani1
1Hepatobiliary Immunopathology Laboratory, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
Background & Aims:
Cholangiocarcinoma (CCA) is a primary liver tumour characterised by a poor prognosis and limited therapeutic options. Available 3D human CCA models fail to faithfully recapitulate the tumour niche. We aimed to develop an innovative patient-specific CCA-on-chip platform.
Methods:
A CCA tumour microenvironment was recapitulated on a microfluidic three-channel chip using primary CCA cells, cancer-associated fibroblasts (CAFs), endothelial cells, and T cells isolated from CCA specimens (n = 6). CAF and CCA cells were co-cultured in the central channel, flanked by endothelial cells in one lateral channel, recreating a tubular structure. An extensive characterisation of this platform was carried out to investigate its diffusion ability, hydrogel properties, and changes in matrix composition. Cell phenotype and functional properties were assessed.
Results:
Primary cells seeded on the microfluidic device were shown to reproduce the architectural structure and maintain the original phenotype and functional properties. The tumour niche underwent a deep remodelling in the 3D device, with an increase in hydrogel stiffness and extracellular matrix deposition, mimicking in vivo CCA characteristics. T cells were incorporated into the device to assess its reliability for immune cell interaction studies. Higher T cell migration was observed using cells from patients with highly infiltrated tumours. Finally, the drug trial showed the ability of the device to recapitulate different drug responses based on patient characteristics.
Conclusions:
We presented a 3D CCA platform that integrates the major non-immune components of the tumour microenvironment and the T cell infiltrate, reflecting the CCA niche. This CCA-on-chip represents a reliable patient-specific 3D platform that will be of help to further elucidate the biological mechanisms involved in CCA and provide an efficient tool for personalised drug testing.
Impact And Implications:
An innovative patient-specific cholangiocarcinoma (CCA)-on-chip platform was successfully developed, integrating the major components of the tumour microenvironment (tumour cells, cancer-associated fibroblasts, endothelial cells, and immune infiltrate) and faithfully mimicking the CCA niche. This CCA-on-chip represents a powerful tool for unravelling disease-associated cellular mechanisms in CCA and provides an efficient tool for personalised drug testing.
Insights
Researchers developed a patient-specific cholangiocarcinoma (CCA)-on-chip platform to better model liver cancer. This 3D model accurately mimics the tumor microenvironment, aiding in personalized drug testing for CCA.
Area of Science:
- Oncology
- Biotechnology
- Microfluidics
Background:
- Cholangiocarcinoma (CCA) is an aggressive liver cancer with poor prognosis and limited treatment options.
- Existing 3D models fail to accurately represent the complex tumor microenvironment.
- There is a critical need for improved models to study CCA biology and test therapies.
Purpose of the Study:
- To develop an innovative, patient-specific cholangiocarcinoma (CCA)-on-chip platform.
- To create a 3D model that faithfully recapitulates the CCA tumor microenvironment.
- To establish a tool for personalized drug testing in CCA.
Main Methods:
- A microfluidic three-channel chip was used to co-culture primary CCA cells, cancer-associated fibroblasts, endothelial cells, and T cells.
- The platform mimicked the tubular structure of liver vasculature.
- Characterization included diffusion, hydrogel properties, matrix composition, cell phenotype, and functional assessments.
Main Results:
- The CCA-on-chip platform successfully reproduced the architectural structure and maintained cell phenotype and function.
- The 3D model showed increased hydrogel stiffness and extracellular matrix deposition, mimicking in vivo CCA.
- The platform demonstrated reliable T cell migration and differential drug responses based on patient characteristics.
Conclusions:
- A 3D CCA-on-chip platform integrating key tumor microenvironment components and immune infiltrate was developed.
- This patient-specific model faithfully mimics the CCA niche.
- The platform serves as a reliable tool for elucidating CCA mechanisms and for personalized drug testing.
