New cell state drives colon cancer therapy resistance
An international group of researchers in collaboration with Dr. Gaetano Gargiulo, Group Leader of the Molecular Oncology lab at the Max Delbrück Center, have uncovered a mechanism by which some colorectal cancers (CRC) resist treatment. Tumor cells can switch into a fetal-like state, they found, enabling them to evade chemotherapy and continue growing. The study was published in “Nature Genetics.”
Colorectal cancer cells can exist in a variety of “states,” each with their own unique characteristics. These states include the well-known LGR5+cells, represented by orange, and the newly discovered aggressive fetal-like cells, represented by blue, and many in between. This diversity helps colorectal cancer spread and resist treatment.
A hidden escape mechanism
Colorectal cancer is the third most common cancer worldwide, according to the World Cancer Research Fund, and remains one of the deadliest malignancies. The five-year survival rate for CRC patients whose cancer has spread to distant sites in the body hovers around 15%, primarily because the cancer grows resistant to treatment.
In recent years, scientists have discovered that LGR5+ cancer stem cells fuel the progression of CRC. However, researchers have shown that destroying these cells alone does not lead to cancer remission. In this study, Dr. Slim Mzoughi and Dr. Ernesto Guccione and their colleagues at Mount Sinai’s Icahn School of Medicine identified another, previously unknown cell state that fuels CRC. The team named it Oncofetal (OnF) because it resembles fetal gut cells.
Genetic tracing yields clues
To confirm that these cells play an active role in tumor evolution and resistance to therapy, the Mount Sinai team partnered with Gargiulo and his team. In a mouse intestinal organoid model that mimics human CRC, the researchers used their proprietary synthetic genetic tracing technology to label and track OnF cells in real time. This provided direct evidence that these cells are not just passive bystanders, but key players in fueling tumor progression.
“We now know that rather than a single stem cell population, multiple cancer cell states coexist and cooperate, making tumors much harder to eliminate,” says Gargiulo. “With our versatile technology, we were well positioned to track a novel cell population and demonstrate their role in tumor evolution and therapy resistance. This study provides an unprecedented look at how tumors adapt to survive treatment and is a first step toward discovering new drugs that could dramatically improve patient outcomes and extend survival.”
