Using Systems Biology Studies to Alter the Properties of Carcinogenic Cells in the Lung

Announced by KAIST (President Lee Kwang Hyung) on ​​January 30^th A research team led by Professor Kwang-Hyun Cho of the Department of Bio-Brain Engineering used research in systems biology to alter the properties of carcinogenic cells in the lungs, eliminating both drug resistance and their ability to proliferate to other areas. Succeeded in doing. body.

As the incidence of cancer increases with an aging population, cancer has become the deadliest disease threatening a healthy life. The fatality rate is particularly high if early detection is delayed and metastasis occurs in various organs. In order to solve this problem, a series of attempts have been made to remove cancer cells or reduce their ability to spread, but it is said that cancer cells in an intermediate state become unstable and become more malignant. There were serious therapeutic challenges.

Professor Kwang-Hyun Cho’s research team investigated various cancer cell states during the epithelial-to-mesenchymal transition (EMT) of lung cancer cells between non-metastatic epithelial cells and metastatic mesenchymal cells. simulated. We have established a mathematical model of molecular networks, and through computer simulation analysis and molecular cell experiments, we have discovered important regulatory factors that can restore the state of mesenchymal cells that have acquired invasiveness and drug resistance to epithelial cells. In particular, we succeeded in appropriately reverting mesenchymal lung cancer cells to a chemotherapy-sensitive state while avoiding the unstable EMT hybrid cell state in the intermediate process, which has been a challenge so far.

The results of this research are KAIST Ph.D. students Kim Nam-hee, Dr. Choi Young-hwan, and Taeyeon Kim researcher, Ph.D. A paper in which student Kim Hyun Jin participated was published online in the international journal Cancer Research published by the American Association for Cancer Research (AACR) on January 30. (Title of the article: A cell-fate reprogramming strategy reverses the epithelial-to-mesenchymal transition of lung cancer cells while avoiding the hybrid state)

EMT hybrid cells, which are produced by incomplete transition in the EMT process of cancer cells, have characteristics of both epithelial cells and mesenchymal cells, and have high drug resistance and metastatic potential by acquiring high stem cell ability. It is known that EMT, in particular, is further enhanced by factors such as transforming growth factor-β (TGF-β) secreted from the tumor microenvironment (TME), resulting in a variety of highly plastic cellular states. Due to the complexity of EMT, the migration process of mesenchymal cancer cells can be completely transformed into an epithelial cell state in which metastatic potential and drug resistance are eliminated while avoiding the EMT hybrid cell state with high metastatic potential and drug resistance. It was very difficult to reverse to . resistance.

Professor Kwang-Hyun Cho’s research team established a mathematical model of the gene regulatory network that governs the complex process of EMT and applied large-scale computer simulation analysis and complex system network control techniques to develop ‘p53’, Identified and verified “SMAD4”. , and ‘ERK1’ and ‘ERK2’ (collectively ERKs), through molecular cell experiments, have been identified as three important molecular targets that can convert lung cancer cells to the mesenchymal cell state and back to the epithelial cell state. Metastasize while avoiding the EMT hybrid cell state.

In particular, by analyzing the molecular regulatory mechanisms of the complex EMT process at the system level, key pathways associated with positive feedback that play an important role in fully reverting cancer cells to an epithelial cell state with metastatic potential has been identified. And drug resistance is eliminated.

This discovery proves that mesenchymal cells can be reverted to epithelial cells under the conditions in which TGF-β stimulation is present, similar to the actual environment in which cancer tissue is formed in the human body. It is important.

Abnormalities in the EMT of cancer cells cause various malignant traits, such as cancer cell migration and invasion, altered responsiveness to chemotherapy, enhanced stem cell function, and cancer dissemination. In particular, the acquisition of metastatic potential of cancer cells is an important factor that determines the prognosis of cancer patients. The EMT reversal technique for lung cancer cells developed in this study is a novel anti-cancer therapeutic strategy that reprograms cancer cells to eliminate high plasticity and metastatic potential and enhance responsiveness to chemotherapy.

By successfully reversing a state of highly metastatic and drug-resistant lung cancer cells back to a state of treatable epithelial cells with new susceptibility to chemotherapy, the results of the study will improve cancer prognosis. We propose new therapeutic strategies that can improve Patience. “

Professor Kwang-Hyun Cho

Professor Kwang-Hyun Cho’s research team announced the results of research on reverting colorectal cancer cells to normal colon cells in January 2020, and for the first time presented the principle of reversal therapy that reverts cancer cells to normal cells. bottom. We also present a successful reprogramming study in January 2022 that transformed the most malignant basal breast cancer cells into less malignant luminal breast cancer cells that can be treated with hormone therapy. This latest research result is his third result in the development of reversals. A technology that restores lung cancer cells that have acquired metastatic traits to a state in which the metastatic potential has been removed and enhances drug sensitivity.

This research was supported by the Ministry of Science, Technology and Information Communication and the National Research Foundation of Science and Technology Basic Research Program for Mid-career Researchers in South Korea.