麻豆传媒社区

Cancer cells have voracious appetites. And there are certain nutrients they can鈥檛 live without. Scientists have long hoped they might stop tumors in their tracks by cutting off an essential part of cancer cells鈥� diet. But these cells are crafty and often find a new way to get what they need. How? By reprogramming their metabolism and switching to backup food supplies.

Now, Laboratory(麻豆传媒社区) Assistant Professor Michael Lukey has found a way to deprive cancer cells of both a vital nutrient and their backup supply. In lab experiments with breast cancer cells, patient-derived tissue models, and mice, this strategy killed breast cancer cells and shrank tumors.

How does this work? Let鈥檚 go back to cancer metabolism. Aggressive cancer cells avidly consume an amino acid called glutamine. They use this vital nutrient to generate the energy and materials needed to grow and replicate.

Previous studies have shown that starving cancer cells of glutamine or preventing its conversion into metabolites can stop the cells鈥� growth in the lab. However, in recent clinical trials, breast cancer patients didn鈥檛 benefit from a drug taking this approach. This suggests that breast cancer cells can adapt and find a way to live without glutamine.

Lukey and postdoc Yijian Qiu saw the same thing in their lab. They noticed that breast cancer cells adapt to glutamine starvation by switching on a pathway that generates a critical metabolite called alpha-ketoglutarate, normally derived from glutamine. This enables cancer cells to continue producing the energy and building materials they would otherwise get from glutamine. It was a lightbulb moment for Lukey鈥檚 lab. He recalls:

鈥淭hat made us think, could we exploit this for cancer therapy? Could we target glutamine metabolism? We know the cells adapt to that. So, could we simultaneously target their adaptive response by inhibiting the pathway?鈥�

The approach was successful, killing breast cancer cells in lab dishes and effectively treating tumors in mice. Lukey鈥檚 team saw tumors stop growing and even shrink with the combination treatment. The animals remained healthy.

Inhibitors of both metabolic pathways are now under further investigation. Lukey notes that these pathways might be especially important for breast cancer metastasis to different tissues, including some that are very difficult to treat. He explains:

鈥淏rain metastases in particular lack any effective therapies.鈥�

Lukey hopes his lab鈥檚 combination therapy could ultimately improve the efficacy of glutamine metabolism inhibitors in the clinic. This could mean effective new treatments that target cancer鈥檚 metabolic addictions.

Written by: Jennifer Michalowski, Science Writer | publicaffairs@cshl.edu | 516-367-8455

Funding

National Institutes of Health, Department of Defense Breast Cancer Research Program, METAvivor, The Elsa U. Pardee Foundation

Citation

Qiu, Y., et al., 鈥淭丑别 unique catalytic properties of PSAT1 mediate metabolic adaptation to glutamine blockade鈥�, Nature Metabolism, August 27, 2024. DOI:

Core Facilites

鈥淭丑别 Mass Spectrometry Core Facility provides state-of-the-art quantitative analysis of proteins and peptides, protein-protein interactions, and post-translational modifications. The resource also offers the ability to detect lipids, metabolites, and other small molecules. The facility supports experimental design, sample preparation, LC-MS analyses, and data analysis and interpretation.鈥� 鈥� Director Paolo Cifani, Ph.D.

鈥淭丑别 Sequencing Technologies and Analysis Shared Resource provides access to an array of high throughput Next Generation Sequencing (NGS) technologies. We offer cutting-edge technology alongside convenient in-house services for a broad range of genetic analysis.鈥� 鈥� Project Manager Sara Goodwin, Ph.D.