The Tisch Cancer Institute at Mount Sinai have uncovered a major reason why some colorectal cancers (CRC) resist treatment. Their groundbreaking study, published this week in Nature Genetics, reveals that cancer cells can revert to a fetal-like state, helping them survive and grow despite treatment. This phenomenon, termed “oncofetal reprogramming,” enables some tumour cells to diversify their molecular characteristics and behaviour, allowing them to evade chemotherapy.

Colorectal cancer remains one of the deadliest malignancies worldwide, with treatment resistance posing a significant barrier to long-term survival. Prior research has focused on targeting a harmful population of tumour cells known as “LGR5+ cancer stem cells”, but has failed to achieve durable tumour regression. The study suggests this failure is due to some LGR5+ cells transitioning into a fetal-like state, rendering them resistant to current chemotherapies.

“This discovery challenges the conventional belief that colorectal cancer is driven by a single, uniform cancer stem cell population,” said Slim Mzoughi, PhD, Assistant Professor of Oncological Sciences at the Icahn School of Medicine at Mount Sinai and Principal Investigator of the study. “Instead, we demonstrate that multiple distinct cancer stem cell states coexist and cooperate, significantly influencing tumour progression and therapy resistance.”

A New Understanding

Mount Sinai’s research team, in collaboration with several other leading institutions worldwide, found that oncofetal reprogramming helps colon cancer survive by making its cells more adaptable. They also discovered ways to block this process, which could make current cancer treatments work better.

“Our data suggest that inhibiting the oncofetal program in combination with current treatments may provide a powerful approach to overcoming therapy resistance,” said co-investigator Ernesto Guccione, PhD, Professor of Oncological Sciences at Mount Sinai. “This study lays the groundwork for the development of novel targeted therapies that could benefit CRC patients worldwide.”

For clinicians, these findings may offer a deeper understanding of why certain CRC patients experience treatment resistance and disease recurrence. Future therapeutic strategies integrating inhibitors of the oncofetal program with existing chemotherapy regimens could dramatically improve patient outcomes and extend survival.

The research team is now focusing on developing new drugs or repurposing ones already approved by the Food and Drug Administration to target the oncofetal program effectively.

Source: The Tisch Cancer Institute at Mount Sinai