Researchers Identify Promising New Target for Colorectal Cancer Treatment
Researchers at the University of Michigan Health Rogel Cancer Center have uncovered a critical metabolic process that could pave the way for a new generation of therapies against colorectal cancer, one of the leading causes of cancer-related deaths worldwide. The groundbreaking study, published in the prestigious journal Cell Metabolism, reveals how colorectal cancer cells are able to accumulate exceptionally high levels of iron without triggering the cell death that would normally occur under such conditions.
Scientists have long known that colorectal cancer cells rely heavily on iron to fuel their rapid growth and survival. In fact, the more aggressive the cancer becomes, the greater the amount of iron these cells accumulate. Under normal circumstances, excessive iron causes a specialized form of cell death known as ferroptosis. Surprisingly, cancer cells are able to bypass this protective mechanism, allowing iron to continue building up without damaging the tumor.
To better understand this phenomenon, the research team, led by Dr. Yatrik Shah, Horace W. Davenport Collegiate Professor of Physiology at Michigan Medicine, initially investigated the well-known ferroptosis pathways. When disabling these pathways failed to affect tumor growth, the team shifted its focus to mitochondrial metabolism—the process by which cells generate energy.
Using a metabolism-focused CRISPR genetic screening approach, the researchers discovered that heme, an iron-containing molecule, protects cancer cells from iron toxicity. They further identified that mitochondrial Complex II plays a crucial role by regulating coenzyme Q, effectively shielding tumor cells from iron-induced cell death.
The findings were striking. When researchers eliminated Complex II in laboratory cell lines and mouse models, the cancer cells could no longer protect themselves against the accumulated iron. As a result, the iron that once promoted tumor growth became toxic, causing the cancer cells to die.
“Complex II is absolutely critical for buffering iron toxicity in colon cancer,” said Dr. Shah. “When we removed Complex II, the cancer cells lost their ability to tolerate the high iron levels they depend on, ultimately leading to their death.
“One of the most encouraging aspects of the study is that normal cells contain significantly lower iron levels than cancer cells. This suggests that therapies targeting Complex II may selectively attack tumor cells while minimizing harm to healthy tissue. Researchers observed very few side effects when disabling Complex II in animal models.
The study also found that iron itself regulates Complex II, revealing another potential therapeutic target that could disrupt this cycle in multiple ways.
The Rogel Cancer Center team will now evaluate whether existing mitochondrial inhibitors can be adapted to treat colorectal cancer. Because many other cancers are also highly dependent on iron, future research will investigate whether similar mechanisms exist across different tumor types.
This discovery represents a significant step toward developing more precise, targeted cancer therapies that exploit the unique metabolic vulnerabilities of cancer cells while preserving healthy tissue.
For more information about the University of Michigan Rogel Cancer Center and its ongoing cancer research, visit www.rogelcancercenter.org.
