Researchers at the University of Toronto's Faculty of Applied Science & Engineering have designed a new microfluidic platform that allows forunprecedented control and manipulation of tumor shapes - a largely unexplored area with great potential to advance cancer research.
The work, led by Professor Edmond Young, offers new insights into how the shape of tumours can predict cancer cell behaviour and aggressiveness, which opens new pathways for more personalized and targeted cancer care.
"While there are several platforms for in vitro modelling of spheroids - three-dimensional aggregates of cells that can mimic tissues and mini tumours - a challenge in the cancer research field has been the inability to control the shape, recovery and location of these cancer organoids," says Sina Kheiri, the co-lead author of the study, which was recently published in Advanced Materials .
"So, researchers end up with these tumours-on-a-chip that can't be easily characterized because they are stuck on the device and can only be observed through optical microscopy."
The new platform, called Recoverable-Spheroid-on-a-Chip with Unrestricted External Shape (ReSCUE), gives researchers the ability to recover and release tumoroids to perform downstream analysis and characterization.
The platform also enables researchers to grow cancer organoids in any shape they want. This is important, Kheiri says, because much of the current research on cancer cell in vitro modelling is focused on spherical shaped tumors, but tumors in a body can take many different shapes.
"In many invasive cancers, the tumor shape is not spherical," he says. "For example, in a recent study of 85 patients with breast cancer , only 20% of tumors were spherical.
"If modelling studies are limited to spherical tumour shapes, then we are not looking at the full parametric space and scale of tumors that are seen in real life. We are only looking at a small portion of the whole answer to understand cancer cell behaviour."
Kheiri's PhD research was co-supervised by Young and Professor Eugenia Kumacheva, who is from the University of Toronto's Department of Chemistry and cross-appointed to the Institute of Biomedical Engineering.
The development of the ReSCUE platform was conducted in collaboration with Dr. David Cescon, a clinical scientist and breast medical oncologist at Princess Margaret Cancer Centre in Toronto. Cescon's team provided access to the cancer cells that were used to form breast cancer organoids.
The multi-layer platform also uses EKGel, a biomimetic hydrogel developed by Kumacheva's lab group , which acts as a scaffold, allowing the patient-derived cancer cells to grow and organize the way they would in vivo, inside human tissue.
The idea that tumour shapes determine cancer cell behaviour was a serendipitous discovery for Kheiri. When he was optimizing and developing the microfluidic platform, he discovered that some of the patient-derived tumoroids were forming positive curvatures because of the shape of the microwell.
"I was playing with the aspect ratio of the microwells and observed that when the wells had a more rod-like or elongated shape, rather than a circular or disc shape, the tissues formed cellular strands at the regions with positive curvature," he says.
"I didn't see that in tumoroids from the same cancer-cell sample that formed a spherical shape. So, we started to make different shapes and analyze the effects of shape or curvature on cancer behaviour."
The team looked at disk-, rod- and U-shaped tumoroids and they found higher cell activity and higher proliferation at the positive curvatures - where the tumour shape is convex, outward curving.
This could mean that the growth of cells in these areas is more invasive compared to areas of the tumour that have a flat curvature.
"Understanding the relationship between tumor shape and cell behavior is important for predicting tumor aggressiveness and planning appropriate treatment strategies, such as targeted radiation therapy or drug delivery," says Kheiri.
"We want to open this door and give researchers a platform that they can use to study how different tumour shapes respond in anti-cancer drug treatment, in radiotherapy and chemotherapy."
Kheiri is currently a postdoctoral researcher at the Massachusetts Institute of Technology (MIT), but he is continuing to provide support to the Young Lab on the continued development of the ReSCUE platform. The researchers have recently submitted a U.S. patent and are looking to build on their results.
"We hope that these uniquely shaped mini tumors can help biologists and cancer researchers better understand the biology of cancer cells and how they respond to drugs," says Young.
"We're going to add even more complex features, such as surrounding vasculature. The more control we have over the features we can include in our models, the more realistic they become, and the more accurate our drug testing will be."
