Organs Synchronize Their Metabolic Response in Cancer Wasting Syndrome

Up to 80 percent of patients with cancer struggle with cachexia, often called wasting syndrome, which is a condition characterized by the inability to gain or maintain body weight. One of the reasons these patients lose weight so dramatically is because they are eating less. However, researchers are becoming increasingly aware that metabolic changes in multiple organs—not just malnutrition—likely underlie this condition.¹

To better understand how organs across the body influence cachexia, scientists recently performed transcriptomics and metabolomics in mice with tumors, profiling tissues that are commonly affected by cachexia.² When the researchers induced cachexia in the animals, they observed that these tissues shared one thing in common: the upregulation of one-carbon metabolism, which mediates many important biochemical processes such as protein and nucleotide biosynthesis. Findings from this study, published in Nature Metabolism, suggest that components of one-carbon metabolism could serve as biomarkers and therapeutic targets for cancer cachexia.

“Until now, it was completely unclear how the metabolic responses of different organs interact to drive cancer-related weight loss,” said Maria Rohm, a cancer metabolism researcher at Helmholtz Munich and a co-author of the study, in a statement.

Past work on cancer cachexia largely focused on the muscle—because that organ is most severely affected by the condition—or the serum to evaluate metabolites circulating in the bloodstream. The latter signified that cachexia results in a systemic response. So, in the present study, Rohm and her colleagues investigated metabolic changes in eight cachexia-targeted tissues: blood plasma, heart, liver, two types of muscle and adipose tissues, as well as the tumor itself.

“By analyzing multiple organs together, we aimed to better understand the systemic nature of weight loss,” Rohm said.

To evaluate metabolic changes due to cachexia, the researchers injected cachexia-inducing mouse colon cancer cells subcutaneously in mice, extracted metabolites from the selected organs, and then analyzed them using mass spectrometry. They compared the cachectic mice’s metabolic profiles to their counterparts that received saline injection or non-cachexia-inducing colon cancer cells.

Statistical analyses revealed that the cachectic tissues were metabolically more similar to each other than to the non-cachectic ones, supporting the researchers’ hypothesis of the body’s coordinated metabolic response to cachexia. Many of the shared metabolites were associated with nucleotide and amino acid metabolism.

To address whether a specific pathway underlay this response, Rohm and her colleagues identified metabolites whose levels differed significantly between cachectic and non-cachectic animals in two or more tissues. When the team performed pathway analysis on these metabolites, they discovered that cachexia significantly upregulated the levels of one-carbon metabolism products. Similarly, transcriptomic analyses revealed significant changes in the expression of multiple genes in the pathway. The researchers replicated these findings in other mouse models of cachexia, including one that involved human colon cancer cells, strengthening the result’s potential clinical relevance.

“It was surprising that all organs respond metabolically in the same way to cachexia,” Rohm said. “The organs lose their individual metabolic signatures and instead align with this coordinated metabolic process.”

In the future, Rohm hopes to understand why cancer cachexia leads to the upregulation of one-carbon metabolism as well as the molecular consequences of this reprogramming.