Skip to main content

Mouse Study Points to Driver Mutation, Tissue-Related Differences in Tumor Metabolism

NEW YORK (GenomeWeb News) – The metabolic profiles associated with cancer vary from one tumor to another depending on the tissue affected as well as the underlying genetic mutations involved, according to a study published online today in Cell Metabolism.

Researchers from the US and Spain did metabolic profiling on mouse liver tumors induced by elevated expression of either the MYC or the MET gene. They found that the metabolic properties differed between liver tumors driven by MYC over-expression compared to those induced by MET. Amongst the MYC-induced tumors, they also found evidence for tissue-specific metabolic differences based on comparisons between liver and lung tumors.

Together, the findings point to metabolic diversity across cancers that may ultimately be useful when selecting the most appropriate treatment for a given tumor.

"Cancer research is dominated now by genomics and the hope that genetic fingerprints will allow us to guide therapy," University of California at San Francisco researcher J. Michael Bishop, the study's senior author, said in a statement.

"The issue is whether that is sufficient," he added. "You may need to have the metabolome as well as the genome."

Past research has shown that metabolic patterns in cancer cells differ from those in normal cells, often involving changes to energy producing pathways based on glucose or amino acid glutamine, the team explained. Moreover, some of the same genes that contain driver mutations in certain cancers also code for proteins that interact with or even regulate metabolic pathway components.

But while members of such metabolic pathways have been proposed as treatment targets in some cancers, study authors noted, "the relationship between distinct tumor-initiating lesions and anomalies of tumor metabolism in vivo has not been addressed."

The researchers used a technique called stable isotope metabolic analysis to track changes to metabolic pathways related to the production and consumption of glucose and glutamine in mouse models of liver cancer involving one of two oncogenes.

Specifically, the mouse liver tumors had been generated through over-expression of either MYC, a proto-oncogene whose product interacts with some metabolic enzymes, or MET, a gene coding for a protein that contributes to carbohydrate metabolism.

Both the MYC- and MET-induced liver tumors showed lower-than-usual glucose levels and other patterns pointing to decreased glucose synthesis and increased energy production through aerobic glycolysis, researchers found.

But, they reported, there were metabolic differences between the tumors as well. For instance, based on the metabolites tested, researcher suspect that glucose gets broken down more quickly in the MYC-driven tumors than in those caused by excess MET.

"Altogether, our results suggest that glucose transport and catabolism may be increased in both types of tumors in comparison with normal liver," the team wrote. "However, MYC-induced liver tumors have significantly higher glucose uptake and catabolism than MET-induced liver tumors."

They found driver mutation-dependent differences in glutamine metabolism between the mouse liver tumors as well, with glutamine breakdown characterizing tumors driven by MYC compared to enhanced glutamine production in those driven by MET.

In addition, their analyses of data on mouse lung tumors linked to amped up MYC levels suggest a tumor's tissue of origin influences its metabolic profiles, since some of the metabolic properties of MYC-induced lung tumors were distinct from those in liver cancers driven by MYC over-expression.

Based on these and other findings, the study authors argued that "metabolic profiles of tumors are likely to depend on both the genotype and tissue of origin and have implications regarding the design of therapies targeting tumor metabolism."

"Our work shows that different tumors can have very different metabolisms," UCSF researcher Mariia Yuneva, first author on the study, added in a statement. "You can't generalize."

That realization may ultimately influence the treatment strategies used for these and other types of cancer, the researchers noted, particularly in instances where there are therapeutics available to curb the metabolic pathways that fuel cancer cell proliferation.

The Scan

Call to Look Again

More than a dozen researchers penned a letter in Science saying a previous investigation into the origin of SARS-CoV-2 did not give theories equal consideration.

Not Always Trusted

In a new poll, slightly more than half of US adults have a great deal or quite a lot of trust in the Centers for Disease Control and Prevention, the Hill reports.

Identified Decades Later

A genetic genealogy approach has identified "Christy Crystal Creek," the New York Times reports.

Science Papers Report on Splicing Enhancer, Point of Care Test for Sexual Transmitted Disease

In Science this week: a novel RNA structural element that acts as a splicing enhancer, and more.