Cancer is insidious. Throughout tumor progression, the disease hijacks otherwise healthy biological processes鈥攍ike the body鈥檚 immune response鈥攖o grow and spread. When tumors elevate levels of an immune system molecule called Interleukin-6 (IL-6), it can cause severe brain dysfunction. In about 50%-80% of cancer patients, this leads to a lethal wasting disease called cachexia. 鈥淚t鈥檚 a very severe syndrome,鈥 says 抖阴黄版下载 (CSHL) Professor Bo Li. He explains:
鈥淢ost people with cancer die of cachexia instead of cancer. And once the patient enters this stage, there鈥檚 no way to go back because essentially there鈥檚 no treatment.鈥
Now, Li and a team of collaborators from four CSHL labs have found that blocking IL-6 from binding to neurons in a part of the brain called the area postrema (AP) prevents cachexia in mice. As a result, the mice live longer with healthier brain function. Future drugs targeting these neurons could help make cancer cachexia a treatable disease.
In healthy patients, IL-6 plays a crucial role in natural immune response. The molecules circulate throughout the body. When they encounter a possible threat, they alert the brain to coordinate a response. Cancer disrupts this process. Too much IL-6 gets produced, and it begins binding to AP neurons in the brain. 鈥淭hat leads to several consequences,鈥 Li says. 鈥淥ne is animals and humans alike will stop eating. Another is to engage this response that leads to the wasting syndrome.鈥
The team took a two-pronged approach to keeping elevated IL-6 out of the brain in mice. Their first strategy neutralized IL-6 with custom antibodies. The second used CRISPR to reduce the levels of IL-6 receptors in AP neurons. Remarkably, both tactics produced the same results鈥攖he mice started eating again, stopped losing weight, and lived longer.
For Li, the implications were mind-blowing:
鈥淭丑别 brain is so powerful in regulating the peripheral system. Simply changing a small number of neurons in the brain has a profound effect on whole-body physiology. I knew there was an interaction between tumors and brain function, but not to this extent.鈥
Li says his team is now determined to figure out how to translate this discovery to human patients. Their recent collaborations with CSHL Professor Adrian Krainer and former CSHL Professor Z. Josh Huang may bring them one step closer. 鈥淚f we can use what we鈥檝e learned to prevent or treat cachexia, we can dramatically increase patients鈥 quality of life,鈥 Li says. 鈥淭his could one day have a big impact on many people.鈥
Written by: Nick Wurm, Communications Specialist | wurm@cshl.edu | 516-367-5940
Funding
The Lustgarten Foundation, Thompson Family Foundation, Pershing Square Foundation, CSHL-Northwell Health Affiliation, Northwell Health, 抖阴黄版下载 Association, National Institutes of Health, Simons Foundation, National Cancer Institute, Cancer Grand Challenges, Mark Foundation for Cancer Research, Osprey Foundation, Fortune Footwear, Key Research and Development Program of Zhejiang Province
Citation
Sun, Q., et al., 鈥淎rea postrema neurons mediate interleukin-6 function in cancer cachexia鈥, Nature Communications, June 1, 2024. DOI:
Core Facilites
Principal Investigator
Bo Li
Professor
Robert Lourie Professor of Neuroscience
Ph.D., The University of British Columbia, 2003