Using a new innovative method to track down evasive cancer cells
One of the biggest challenges in cancer treatment is that some cancer cells manage to survive therapy. These cells hide in places where treatments, like chemotherapy and immunotherapy, struggle to reach them. In a recently published article in Nature, Scientific Reports, a team of SciLifeLab and Karolinska Institutet (KI) researchers decided to look into this topic to help identify why cancer cells survive cancer drugs. By combining two methods, they could reveal key survival strategies.
Cancer remains one of our deadliest diseases, disrupting families and causing significant pain and loss for loved ones. Many researchers attempt to bridge knowledge gaps and develop innovative theories and solutions. One angle is to look at how cancer cells evade and survive cancer drugs. A group of SciLifeLab and Karolinska Institutet (KI) researchers wanted to investigate a theory they had about how cancer cells evolve when they face trade-offs between tasks.
Elaborating on this theory, the corresponding author of the study and SciLifeLab researcher Jean Hausser (KI) said: “We can struggle to perform conflicting tasks at the same time, for example texting a colleague about a burning issue at work while listening to our significant other at dinner. Similarly, cancer cells need to perform several tasks to thrive, divide, survive the immune system, migrate, invade, and so on. Which can conflict with each other. When facing conflicting tasks, Darwin’s evolution theory suggests that cancer cells focus on the most important task in their current environment. Divide when in a favorable situation and survive when in a tough environment. Just as we would (hopefully) text our colleague after dinner and focus on our significant other during dinner”.
Understanding how cancer cells adjust the task they focus on based on their environment could inspire therapies that hinder these tasks and therefore be more effective at killing all cancer cells.
Why some cancer cells survive
For example, chemotherapy is designed to kill cancer cells that are actively dividing. These cells tend to be near blood vessels, where they get plenty of oxygen and nutrients. However, some cancer cells evade treatment by moving farther away from blood vessels.
A similar issue occurs with immunotherapy, which uses the body’s immune system to attack cancer cells. Immune cells travel through the bloodstream and work best in oxygen-rich environments. This means cancer cells hiding in low-oxygen areas are harder to detect and destroy.
Developing a new approach to understanding cancer cells
To better understand how these hidden cancer cells survive, the researchers combined a method to grow mini-tumors in the lab with a technique they specifically developed for this project called Diffusion Smart-seq3D. By doing this, they created environments where some cells receive plenty of oxygen while others get none. Using Diffusion Smart-seq3D, it allowed them to map individual cancer cells inside these tumors and analyze their gene activity.
They discovered thousands of differences between cells in oxygen-rich and oxygen-poor environments, revealing their survival strategies. These findings align with evolution theory, demonstrating how cancer cells adapt to their surroundings to improve their chances of survival.
“A nerdy eureka moment was when we finally cracked a mathematical model that explains how cells express their genes differently in different areas of tumors. Replacing random and chaotic data with mathematical order felt like a big advancement. While this step is not mentioned in our findings, it was the hardest part of this project and the one that made every finding possible,” Hausser explains.
Not letting the cancer cells escape
By figuring out how cancer tricks the immune system, they hope to develop smarter therapies that stop cancer in its tracks before it can return.
“The next step is to take advantage of this research to reveal how cancer cells manage to escape immune cells. Cancer cells often manage to tell immune cells not to kill them. We want to understand how they do this, so we can encourage immune cells to be better at finding and killing cancer cells. We are currently working on this together with immunologists at Karolinska Institutet,” Jean Hausser concludes.
All the computational work was done at SciLifeLab, which also supported key researchers in the study.
DOI: 10.1038/s41598-024-83989-x
The Diffusion Smart-seq3D method explained
Diffusion Smart-seq3D builds on Smart-seq3, an approach invented by Rickard Sandberg’s lab (KI) which reveals gene activity in individual cells at high sensitivity. One limitation of Smart-seq3D is that it requires researchers to break the tissue (like the mini-tumors of the study) down into single cells. Doing this, one cannot tell anymore where each cell was.
To recover information about where each cell was, a dye was added in the culture medium of mini-tumors. This dye stains well cells on the periphery of our mini-tumors. However, contacts between tumor cells make it hard for the dye to reach cells at the core. The result is that cells at the periphery of mini-tumors get a lot of dye while cells at the core get little.
By calculating how much dye each cell has right before measuring its gene activity by Smart-seq3, using a technique called flow cytometry. You can reveal both the position of individual cells and their gene activity in our mini-tumors.
