Making healthy cells stronger might protect them against cancer cells

Cancer cells are known to take advantage of a mechanism called cell competition, a quality control system that ensures that our tissues are composed of healthy cells. Cellular biologist Ana Krotenberg Garcia and colleagues now show that the way cancer cells exploit this mechanism varies depending on the specific tissue and cell types involved. The findings suggest that besides focusing on weakening cancer cells to treat cancer, it could be beneficial to explore ways to strengthen healthy cells to protect them from the detrimental effects of nearby tumours. Krotenberg Garcia successfully defended her PhD dissertation on 26 June.

Cells in our body constantly compare how fit they are. The fittest cells, those that are more adaptable and stronger, remain in the tissue, while less fit cells are eliminated. Sometimes these less fit cells, or ’loser cells’ as Krotenberg Garcia calls them, are simply outcompeted by cells that are faster growing and more proliferative. But other times, the loser cells are actively triggered to kill themselves, forced to differentiate into a different cell type, or are forced out of the tissue.

This ’cell competition’ acts as a quality control mechanism that ensures that our tissues consist of the healthiest and strongest cells. But cancer cells can also hijack the mechanism, using it to make sure they survive and proliferate. Krotenberg Garcia: "In this context, the cancer cells are very fit: they are super competitors that outcompete healthy cells."

Organoids

Krotenberg Garcia wanted to know how cancer cells use cell competition to their own advantage in different environments. She decided to take a closer look at intestinal cancer cells in intestinal tissue, where they originate, and in liver tissue, the first place they grow after they break away from the intestine and form metastatic tumours.

If you look at cancer treatments from the point of competition, existing treatments try to make the cancer weaker. But instead of making the cancer weaker, you could also focus on strengthening healthy cells and transforming them into winners.

Ana Krotenberg Garcia

To be able to observe cell competition in intestinal tissue in the lab, the researcher grew mini-organs called organoids, in which she mixed cancer cells with healthy intestinal cells. In these organoids, the cancer cells caused the healthy intestinal cells to activate a stress reaction, which eventually lead to their death. The cancer cells benefited from this, proliferated even more vigorously and were able to take over the tiny organ.

In the liver

Krotenberg Garcia also created organoids consisting of intestinal cancer cells and bile duct cells, liver cells that form tubes that transport bile. Moreover, she created small bits of liver tissue called microtissues, consisting of intestinal cancer cells and hepatocytes, another type of liver cells that form most of the liver and are responsible for digestion and detoxification.

Here, the researcher saw that the cancer cells affected the two types of liver cells in different ways. Bile duct cells were forced to change their identity and became more similar to hepatocytes, while hepatocytes were forced to die.

Possible treatments

The intestinal cancer cells really seemed to benefit from the interactions with the liver cells. Krotenberg Garcia: "If you keep the cancer cells by themselves as microtissues, in the exact same conditions but without the healthy hepatocytes, they grow really poorly. When you look at them through the microscope, they do not look very ’happy’."

The researcher also found that if you manipulate the response of healthy cells to nearby cancer cells, you can protect them from losing the battle against the cancer cells. She points out that these insights could have implications for the development of new cancer treatments. Krotenberg Garcia: "If you look at cancer treatments from the point of competition, existing treatments try to make the cancer weaker. But instead of making the cancer weaker, you could also focus on strengthening healthy cells and transforming them into winners."

She emphasizes that such an approach could also lead to treatments with fewer side effects: "In chemotherapy, you kill the cancer cells, but you are also killing other cells, which is harmful to the body."

New opportunities

Krotenberg Garcia studied and worked in the Netherlands for nine years and decided that it was time to go back home after completing her PhD. Now she lives in Spain again, where she is looking for an opportunity to continue doing science.

She talks enthusiastically about her time as a PhD candidate, and especially about her supervisor Saskia Suijkerbuijk. Krotenberg Garcia: "Saskia is a real role model. She is a great scientist, very goal oriented, responsible and organised. When I started working with her, she had just started her own group and it was just the two of us. Saskia was very empathetic and we could talk about everything."

Suijkerbuijk was the one who developed the approach of working with organoids consisting of both healthy and cancer cells. But when it turned out impossible to create organoids with hepatocytes, Krotenberg Garcia developed the technique to create liver microtissues herself. Krotenberg Garcia: "I might be able to put my experience of working with organoids and microtissues to good use in Spain, but I would not mind doing something else. As long as I can keep on doing cancer research."