June 10, 2020

What makes blood cancer cells tick

A masked lab employee examining petri dishes

Madison, Wis. — Peek into any biochemistry or molecular biology lab, and you’ll likely encounter dozens of petri dishes and plastic flasks filled with a thin layer of pinkish-orange liquid. Researchers handle these flasks delicately, careful to not disturb or contaminate the precious samples inside: cell cultures.

Cell cultures, or cells grown in a lab outside of an organism, are a key tool for biochemical research, allowing researchers to study and manipulate cells in a controlled setting. But the artificial environment the cells are kept in, a cocktail of nutrients, growth factors and salts, does not necessarily mimic recapitulate conditions encountered by cells in the human body.

“We’re trying to understand cell biology in conditions that cells are more likely to see in their natural context, especially as most now appreciate that the environment is a key factor in influencing cell physiology,” said Jason Cantor, PhD, assistant professor of biochemistry at UW-Madison.

A chemical engineer by training, Cantor first recognized this discrepancy in cell culture conditions during his post-doctoral training and decided to develop a new recipe for cell culture fluid that more closely reflects human plasma.

“I entered the world of cell culture in my post-doc with a clean slate, so to speak,” Cantor said. “An engineering approach led us to ask and begin to address what are arguably still somewhat fundamental questions.”

Cantor’s cell culture medium contains a collection of nearly 80 components – 30 to 40 more than in traditional culture mediums – at concentrations mimicking those in normal human plasma. In the initial study of this human plasma-like medium (HPLM), Cantor and his colleagues found that this medium had dramatic effects on the metabolism of cultured blood cancer cells.

Cantor joined the UW Carbone Cancer Center in 2018, and along with his research team, now works to understand how environmental factors affect the biology of human cells, particularly blood cancer cells and lymphocytes. One of their key questions is how the availability of different nutrients in the cells’ environment affects which genes are essential for those cells to grow and reproduce.

Not all genes – sections of DNA that code for specific protein products– are equal. Some can be deleted from a cell’s DNA without any change in how the cell grows and functions, while others are necessary, producing proteins without which a cell would die. Reality is much more complicated than this binary, however, and a cell’s environment has a say in how essential a gene really is.

For example, if a cell needs a specific nutrient to survive, it can take it up directly from the environment or the cell can produce the nutrient itself from other components in the environment.

“If a particular critical component is not available from the environment, then this de novo pathway in the cell then becomes really important,” Cantor said. “The environment is actually influencing the expression of a gene so that the cell can survive and proliferate.”

Cantor and his research team have identified a number of genes in blood cancer cells that appear to have this “conditional essentiality.” Now the question is how and why differences in composition between HPLM and conventional cell culture media recipes induce such effects.

“The fact that there’s something in the cell’s environment that’s dictating gene essentiality opens the door to identifying gene-nutrient interactions will allow us to better understand protein function, and potentially identify liabilities in cancer cells that are based on manipulation of metabolite levels found in the body,” Cantor said.

By using a more “human” culture medium, Cantor and his team hope to continue unraveling how environment contributes to the fundamental biology of how our cells function and survive.

“We are going to discover things that would not have been otherwise possible through the use of more conventional model systems.”