"Patient-Derived Organoids" Reveal Cancer Cell Evolution in Metastatic Colorectal Cancer

National Cancer Center-KAIST joint study

More chemotherapy-related mutations accumulate in rapidly proliferating cancer cells

Lays groundwork for clarifying recurrence and treatment resistance in dormant cancer cells

The process by which cancer cells in metastatic colorectal cancer accumulate different genetic changes and evolve independently during chemotherapy has been uncovered. In particular, cancer cells that proliferate faster were found to accumulate more chemotherapy-related mutations.

Professor Kim Beon (left) of the Colorectal Cancer Center at the National Cancer Center and Professor Lee Wonhee of KAIST. National Cancer Center

Professor Kim Beon of the Colorectal Cancer Center at the National Cancer Center and a joint research team from the Korea Advanced Institute of Science and Technology (KAIST) identified how cancer cells in metastatic colorectal cancer evolve using patient-derived organoids, the National Cancer Center said on October 12. The findings were published in the international journal Nature Communications.

Even after colorectal cancer spreads to other organs, the genetic characteristics of cancer cells can change during treatment. However, previous studies have mainly analyzed entire tumor tissues containing a mixture of different types of cancer cells, making it difficult to track how individual cancer cells change over time.

To address this limitation, the researchers established patient-derived tumor organoids, or tumoroids, from primary and metastatic tumor tissues of six patients with metastatic colorectal cancer. Organoids are three-dimensional cell models created by culturing a patient's tumor cells outside the body.

The researchers isolated individual cancer cells from the organoids and cultured them separately, obtaining organoid clones that allowed them to analyze the genetic characteristics of individual cancer cells. They then conducted whole-genome sequencing on these clones and 18 tumor tissues, and reconstructed the order in which the cancer cells accumulated genetic changes in the form of a phylogenetic tree.

The analysis showed that cancer cells in metastatic colorectal cancer did not behave as a single, uniform population. Instead, they divided into multiple cell lineages and accumulated different genetic changes. In particular, metastatic cancer cells shared as a common ancestor a specific cell lineage that had emerged during cancer progression. This suggests that some cancer cells may selectively survive and cause metastasis.

The researchers also analyzed the genetic traces left by anticancer drugs in cancer cells. In cancer cells from patients treated with 5-fluorouracil (5-FU) and oxaliplatin, two commonly used colorectal cancer drugs, they found an average of 1,400 drug-related mutations per cell. These accounted for about 8% of all mutations.

The extent of mutation accumulation also varied with the rate at which cancer cells proliferated. In rapidly proliferating cancer cells, more frequent cell division was associated with the accumulation of more drug-related genetic mutations. By contrast, relatively few drug-related mutations were found in cancer cells that had stopped dividing or were growing very slowly in a dormant state.

These findings suggest that actively proliferating cancer cells and dormant cancer cells may respond differently to chemotherapy. In particular, if dormant cancer cells survive treatment, they may later contribute to cancer recurrence.

This study is significant because it tracked genetic changes and evolution at the level of individual cancer cells, going beyond the conventional approach of analyzing entire tumor tissues. The researchers plan to expand functional studies using organoids to clarify the relationship between cancer cell dormancy and treatment resistance, and to develop research that can predict treatment responses for individual patients.

"We established a research platform that enables us to create organoids from patients' primary and metastatic tumor tissues, isolate and culture them at the level of individual cancer cells, and analyze each cancer cell lineage," Professor Kim Beon said. "Going forward, we will work to clarify the relationship between cancer cell dormancy and treatment resistance and develop research to predict treatment responses for individual patients."

The study was conducted with support from research and development programs of the Ministry of Health and Welfare and the Korea Health Industry Development Institute, as well as research programs of the National Cancer Center.

This content was produced with the assistance of AI translation services.