Glucose Metabolism May Play Key Role in Lung Cancer Resistance

Glucose Metabolism May Play Key Role in Lung Cancer Resistance
Credit: Lee Health

A new study suggests neutrophil metabolism determines how these immune cells support lung cancer tumors, making them more drug resistant. The researchers say this could point to a “Achille’s heel,” for lung tumors, allowing for novel treatment approaches.

The team was led by Etienne Meylan at EPFL’s School of Life Sciences. Their work is published in Cancer Research, a journal of the American Association for Cancer Research.

Since cell metabolism in cancer becomes deregulated, these researchers looked at whether the metabolism of cells in the tumor microenvironment also changes, and whether that could affect a cancer’s growth.

Using a genetically-engineered mouse model of lung adenocarcinoma, the scientists isolated tumor-associated neutrophils (TANs) and compared their glucose metabolism to that of neutrophils from healthy lungs.

They found that the TANs take-up and metabolize glucose much more efficiently than neutrophils from healthy lungs. The researchers also found that TANs express a higher amount of a protein called Glut1, which sits on the cell’s surface and enables increased glucose uptake and use.

“To understand the importance of Glut1 in neutrophils during lung tumor development in vivo, we used a sophisticated system to remove Glut1 specifically from neutrophils,” says Pierre-Benoit Ancey, the study’s first author. “Using this approach, we identified that Glut1 is essential to prolong neutrophil lifespan in tumors; in the absence of Glut1, we found younger TANs in the microenvironment.”

Using X-ray microtomography to monitor adenocarcinomas, the researchers found that removing Glut1 from TANs led to lower tumor growth rate but also increased the efficacy of radiotherapy, a common treatment for lung cancer. In other words, the ability of TANs to metabolize glucose efficiently seems to bestow the tumor with the ability to resist treatment – at least in lung cancer.

The scientists think that, because Glut1 loss diminishes the lifespan of TANs, their “age” determines whether they play a pro- or anti-tumor role. “Usually, we don’t know how to target neutrophils, because they are so important in innate immunity,” says Etienne Meylan. “Our study shows that their altered metabolism in cancer could be a new Achilles heel to consider in future treatment strategies. Undoubtedly, we are only beginning to learn about these fascinating cells in cancer.”

Lung cancer is the major cause of cancer related-death around the world. While there are a number of treatments for this condition, including chemotherapy, radiotherapy and immunotherapy, drug resistance is a major problem.  Small cell lung cancer (SCLC), the most malignant type of lung cancer, displays lower differentiation and rapid progression. Although SCLC patients are initially very sensitive to treatment methods drug resistance is still a major clinical challenge.