Kill resistant cancer cells via their own metabolism

A certain type of resistant cancer cell defends itself against chemotherapy by using nutrients in a different manner. This has been discovered by Utrecht University biochemist Esther Zaal. The formation of tumours can therefore be inhibited by disrupting the resistant cells’ metabolism. Zaal will defend her dissertation at Utrecht University on 11 June.

Many cancer patients who receive chemotherapy for a period of time continue to harbour cancer cells that are resistant to treatment. Researchers around the world are looking for some way to deactivate these resistant cells. In so doing, they generally focus on changes to proteins and DNA in the resistant cells.

Building blocks instead of energy

Utrecht University PhD Candidate Esther Zaal approached the problem from a different angle. She studies characteristic that all sensitive and resistant cancer cells have in common: their changed metabolism. Metabolism is the way a cell converts nutrients into tiny cellular building blocks, such as amino acids. Zaal explains: “Cancer cells are generally extremely dependent on sugar. Most cancer cells use it to release the energy they need to quickly grow and multiply. Resistant cancer cells, on the other hand, prefer to use their sugar to make specific building blocks.”

Uncontrolled division

In her research, Zaal examined a variety of types of cancer, with a particular focus on multiple myeloma. In this type of cancer, plasma cells in bone marrow and other parts of the body divide in an uncontrolled and malignant manner. Healthy plasma cells grow to become white blood cells, which produce many thousands of types of antibodies found in the body. But this uncontrolled cell division produces an excessive amount of just one type of white blood cell, and therefore of one type of antibody, which is extremely harmful. Multiple myeloma can be successfully treated with chemotherapy, but in many patients the cancer becomes resistant to existing medications, such as the commonly used Bortezomib.

Virtual road map

Zaal used mass spectrometry at the molecular level to follow how cancer cells process nutrients. “With mass spectrometry, you can measure the presence of hundreds of tiny substances inside the cell based on their molecular weight. If you exchange the ordinary carbon atom ¹²C for the slightly heavier ¹³C, you can observe which nutrients are sent to which cell products. That enabled us to create virtual road maps of the complex metabolism inside cancer cells.”

Someday, cancer metabolomics will offer the opportunity to treat sensitive and resistant cancer cells.

Arm against chemotherapy

Using this virtual road map of Bortezomib-resistant multiple myeloma cells, Zaal was able to conclude that the amino acid serine plays a crucial role. “We were able to discover that the resistant cells use much more of their sugar to create the amino acid serine than the sensitive cells. We also observed that the medication works better when we remove serine from the patient’s food. Our hypothesis is therefore that resistant cells use serine to arm themselves against chemotherapy. And that is exactly the process in which you should intervene in order to prevent the cell from using serine, and therefore prevent cell growth and resistance.”

Metabolomics

Esther Zaal was lead by promotor Celia Berkers, professor of Metabolomics at Utrecht University. Metabolomics studies the role played by the smallest molecules in the cell. Zaals other promotor is Albert Heck, professor of Proteomics at the UU and one of the 2017 Spinoza Prize winners, the most prestigeous scientific prize in the Netherlands. Zaal: “I am convinced that cancer metabolomics will someday provide opportunities to treat both sensitive and resistant cancer cells.”