Michigan Identifies New Colorectal Cancer Vulnerability
University of Michigan researchers discovered a mechanism that allows tumor cells to accumulate unusually high levels of iron without dying, potentially opening a new avenue for future cancer therapies.
A new study from the University of Michigan Health Rogel Cancer Center is helping scientists understand one of colorectal cancer’s unusual survival strategies: how tumor cells can accumulate extremely high levels of iron without triggering cell death.
The discovery could have important implications for future treatments. Researchers identified a metabolic pathway that essentially serves as a protective system for colorectal cancer cells. When scientists disrupted that mechanism, the cancer cells became vulnerable to iron toxicity and began to die.
Researchers have long known that colorectal cancer cells require substantial amounts of iron. As the disease becomes more aggressive, cancer cells can accumulate even higher levels. In normal cells, however, excessive iron can trigger ferroptosis, a form of cell death associated with iron-dependent oxidative damage.
The question was how cancer cells managed to escape that fate.In the study, published in Cell Metabolism, researchers initially examined pathways already known to be involved in ferroptosis. Surprisingly, knocking out typical enzymes associated with the process did not affect tumor growth, prompting the team to investigate mitochondrial metabolism more closely.
Using a metabolism-focused CRISPR screen, scientists found that heme — an iron-containing cellular molecule — was helping protect tumor cells from iron toxicity.
That discovery led researchers to mitochondrial complex II. The study found that complex II plays a critical role in buffering iron-induced cell death by regulating coenzyme Q.“Complex II in colon cancer was absolutely critical for buffering iron toxicity,” said senior study author Yatrik Shah, Ph.D., Horace W. Davenport Collegiate Professor of Physiology at Michigan Medicine.
When researchers eliminated complex II in cancer cell lines and mouse models, the cancer’s dependence on iron became a weakness. Without its protective mechanism, iron became increasingly toxic and cancer cells began dying.
Another encouraging finding was that researchers observed few side effects after disrupting complex II in mouse models. Because colorectal cancer cells carry substantially more iron than normal cells, scientists believe this mechanism could potentially provide a more selective therapeutic target.
The research remains at an early stage and does not yet represent a new treatment for patients. The Rogel Cancer Center team will next investigate whether inhibitors targeting this mitochondrial process could be effectively applied to colorectal cancer.
Researchers also plan to examine other cancers with a strong dependence on iron.Ultimately, the discovery raises an intriguing possibility: turning one of cancer’s metabolic advantages — its extraordinary appetite for iron — into a vulnerability that future therapies could exploit.
