Identifying gene mutations in cancer patients to predict clinical outcome has been the cornerstone of cancer research for nearly three decades, but now researchers at the Kimmel Cancer Center at Jefferson have invented a new approach that instead links cancer cell metabolism with poor clinical outcome. This approach can now be applied to virtually any type of human cancer cell.
The researchers demonstrate that recurrence, metastasis, and poor clinical outcome in breast cancer patients can be identified by simply gene profiling cancer cells that are using ketones and lactate as a food supply.
These findings are reported in the April 15th online issue of Cell Cycle. The investigators are calling this new approach to personalized cancer medicine “Metabolo-Genomics.”
High-energy metabolites have long been suspected to “fuel” aggressive tumor cell behavior. The researchers used this premise to generate a gene expression signature from genetically identical cancer cells, but one cell group was fed a diet of high-energy metabolites. These lactate- and ketone-induced “gene signatures” then predicted recurrence, metastasis, and poor survival.
So, it appears that what cancer cells are eating determines clinical outcome, not necessarily new gene mutations.
Genetic markers, like expression of the mutationally activated HER2 gene, provide biomarkers that can be used to identify breast cancer patients at high-risk for recurrence or metastasis, and to modify their subsequent treatment with targeted therapies (i.e., herceptin, a drug used in aggressive breast cancers). But with “Metabolo-Genomics,” it is now about using “global” cancer cell metabolism for these predictions.
“Just by feeding cancer cells a particular energy-rich diet, it changes their character, without introducing mutations or altering their genetic profile,” Dr. Lisanti said. “We’ve only fed them high energy nutrients that help them to use their mitochondria, and this changes their transcriptional profile. It’s a new biomarker for “lethal” cancers that we can now treat with the right drugs, such as the anti-oxidant metformin.”
Dr. Lisanti and his colleagues believe that tumor metabolism is the new big picture for understanding how cancers undergo recurrence and metastasis.