Deep inside the intestinal lining, mature cells that should stay specialized are learning to become something they aren't supposed to be again—and that's how colorectal cancer gets a second chance at survival. A new study from Stevens Institute of Technology reveals a cellular sleight of hand that explains why colorectal tumors are so difficult to treat and why they so often return after therapy fails.
Colorectal cancer has become an increasingly urgent public health concern. As of 2010, it was the second leading cause of cancer death in the United States, and the situation has worsened in recent years. Rates are rising sharply among adults under 55, a trend researchers link to western diets high in processed foods, fat, and sugar, combined with sedentary lifestyles, obesity, and altered gut microbiomes—all factors that can trigger cellular mutation and malignant growth. Understanding how these tumors develop and resist treatment has become essential to creating better therapies.
Assistant Professor Ansu Perekatt and his team at Stevens School of Engineering and Science's Department of Chemistry and Chemical Biology published their findings in Cell Death & Disease, focusing on a process called dedifferentiation. The intestine normally maintains an orderly structure: Lgr5-positive stem cells live deep in pocket-like crypts, constantly dividing to create progenitor cells. These younger cells migrate upward to the villi—the finger-like projections that line the small intestine and absorb nutrients. During this journey, cells are supposed to stop dividing and become fully mature, specialized workers. But in colorectal cancer, something goes wrong.
Perekatt's research reveals that colon tumors can start in two distinct ways. The first is a "bottom-up" path where normal stem cells deep in the intestine acquire mutations and turn cancerous. The second is a "top-down" mechanism where mature cells near the intestinal surface reprogram themselves, shedding their specialization and becoming stem-like again before transforming into cancer cells. This process, which Perekatt calls acquiring "de-novo stemness," is the backup plan that makes cancer so dangerous.
"Mature cells can sometimes reverse course and become stem-like again, especially after injury or when normal stem cells are lost," Perekatt explains. "A similar process can happen in colon tumors, where mature, already specialized cells can acquire de-novo stemness and regain stem cell-like behavior."
When the Stevens team induced mutations into stem cells in a mouse model and observed their development, they discovered something alarming. While mutant stem cells were eventually replaced by healthy normal cells, some of the mutants' progenitor cells became cancerous and developed into tumors. More troubling still, tumors that arose from cells with acquired de-novo stemness displayed superior survival mechanisms, including the capacity to protect themselves against oxidative stress—damage from oxygen-containing molecules that would normally destroy cancer cells.
The randomness of which cells transform remains mysterious. "We don't know why they change and why only a subset changes," Perekatt says. "It's very random, very sporadic. But when they change, they develop tumors."
This finding fundamentally changes how researchers might approach colorectal cancer treatment. By understanding how mature cells revert to stem-like states and gain treatment resistance, scientists can now work toward therapies that specifically target this dedifferentiation process and prevent tumor relapse. For patients facing colorectal cancer diagnosis, that knowledge offers genuine hope.