Researchers at the University of Toronto‘s Faculty of Applied Science & Engineering have designed an innovative microfluidic platform that enables exceptional control and manipulation of tumor shapes — a largely uncharted territory that holds significant promise for advancing cancer research.
Led by Professor Edmond Young (MIE, BME), the research sheds light on how tumor shape can indicate the behavior and aggressiveness of cancer cells, paving the way for more personalized and targeted approaches to cancer treatment.
“While there are several platforms for in vitro modeling of spheroids — three-dimensional aggregates of cells that can mimic tissues and mini tumors — 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 (MIE PhD 2T4), the co-lead author of the study, which was recently published in Advanced Materials.
“So, researchers end up with this tumors-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 newly developed platform, named Recoverable-Spheroid-on-a-Chip with Unrestricted External Shape (ReSCUE), allows researchers to extract and release tumoroids for further analysis and characterization. Additionally, the platform provides the capability for researchers to cultivate cancer organoids in any desired shape. Kheiri emphasizes the significance of this feature, as much of the current focus in a cancer cell in vitro modeling is on tumors shaped like spheres, while tumors within the body can assume a variety of 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 modeling studies are limited to spherical tumor 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 behavior.”
Kheiri’s doctoral research was jointly overseen by Young and Professor Eugenia Kumacheva, who is affiliated with both the Department of Chemistry and the Institute of Biomedical Engineering.
The ReSCUE platform was developed alongside Dr. David Cescon, a distinguished clinical scientist and breast medical oncologist at the renowned Princess Margaret Cancer Centre in Toronto. With the invaluable support of Cescon’s team, access to vital cancer cells enabled the creation of advanced breast cancer organoids.
The multi-layer platform incorporates EKGel, a biomimetic hydrogel engineered by Kumacheva’s research group, which serves as a scaffold, enabling the patient-derived cancer cells to proliferate and organize similarly to how they would within human tissue.
The realization that the shapes of tumors influence the behavior of cancer cells was an unexpected finding for Kheiri. While fine-tuning and creating the microfluidic platform, he noticed that certain patient-derived tumoroids were developing positive curvatures due to the design 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 behavior.” 
The researchers investigated disk-, rod-, and U-shaped tumoroids and discovered increased cellular activity and greater proliferation in regions with positive curvatures — where the tumor’s shape is outwardly convex.
This observation suggests that cell growth in these areas may be more invasive than in regions of the tumor that exhibit 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 tumor shapes respond in anti-cancer drug treatment, radiotherapy, and chemotherapy.”
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.”
Journal reference:
- Sina Kheiri, Ilya Yakavets, Jennifer Cruickshank, Fatemeh Ahmadi, Hal K Berman, David W. Cescon, Edmond W.K. Young, Eugenia Kumacheva. Microfluidic Platform for Generating and Releasing Patient-Derived Cancer Organoids with Diverse Shapes: Insight into Shape-Dependent Tumor Growth. Advanced Materials, 2024; DOI: 10.1002/adma.202410547
