Shutting Down Cancer’s Engines
We've learned a lot about cancer over the past few decades, and one startling revelation has been just how diverse cancers are — divided into ever more specific subtypes, defined by location in the body, appearance under a microscope, protein markers, genetic mutations, and more. But for all their diversity, there's one thing all cancers have in common: they need energy, in the form of glucose. And lots of it.
But for all their diversity, there's one thing all cancers have in common: they need energy, in the form of glucose. And lots of it.
The process by which living things, including cancer cells, utilize energy to sustain themselves is known as metabolism. Because glucose is so central to cancer's growth, it makes sense that understanding metabolic processes would be crucial in the fight against cancer.
However, even though we know cancer cells have unusually high glucose demands, we know very little about how exactly their metabolism is altered and how this might guide treatment. Even more challenging is being able to predict which cancers have specific metabolic features and how this might change under different conditions.
Under the Hood
To understand this challenge, let’s imagine cancer cells as microscopic cars. Just like cars can have different types of engines and are powered by different kinds of fuel – gasoline, diesel, natural gas, electricity, biofuels, etc. – specific cancers may rely on different metabolic processes and have different preferred energy sources.
For both cars and cancer cells, it's basically impossible to know the power source just by looking at the outside. We have to get under the hood, so to speak.
In a new study, our scientists did just that. They looked at the metabolic profiles of cancer cells to see if they could identify distinct metabolic "engines" driving different cells.
They began by studying cell lines derived from pancreatic cancer – one of the most deadly cancers and a disease known to have altered metabolism. They assessed more than 250 metabolites to reveal the unique profile of each cell line, and found three distinct classes of cells, each with a defining mix of metabolic markers (specifically representing glycolysis, lipogenesis, and redox pathways).
When they examined the glycolytic and lipogenic groups more deeply, they found that these two classes of cells differed in their engine type and how they utilized their fuel. To confirm the identity of these cellular engines, the team then tested a variety of metabolic inhibitors, drugs known to be precise tools for dismantling the machinery of specific metabolic engines. Indeed, the different classes of cells they identified showed differential sensitivity to metabolic drugs, including inhibitors of aerobic glycolysis, lipid synthesis, and redox balance.
Many Makes and Models
These findings in pancreatic cancer cell lines were intriguing, but of course that’s just one example of the disease. When it comes to cancer, there are hundreds of different “makes and models,” with vastly different characteristics. They wondered what they would find if they took what they learned from pancreatic cancer and looked under the hood of a diverse set of cancers?
The team tested this theory by examining about 200 different cancer cell lines, representing a wide range of cancer types. The results were clear: cells broke out into the same types of groups, with similar energy signatures and corresponding sensitivity to specific metabolic inhibitors.
The Road Ahead
We have a longstanding commitment to exploring the basic science of cancer and sharing our discoveries with the field. Metabolomic signatures have the potential to become one of the tools used in the development of diagnostics hypotheses and guiding personalized treatment choices in the clinic. Although there is still much work to be done to dissect cancer cell metabolism, these newest findings will provide important new insights about the biology of cancer and will be a valuable resource for many scientists as they continue to investigate this important hallmark of cancer.
Read more about these important findings in the following paper from Genentech scientists:
Proceedings of the National Academy of Science. “Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors.”