A research team led by the Korea Advanced Institute of Science and Technology (KAIST) reported that they have succeeded in using systems biology research to change the properties of carcinogenic cells in the lungs as well as eliminate both drug resistance and their ability to proliferate out to other areas of the body.

Their findings are published in Cancer Research in an article titled, “A cell fate reprogramming strategy reverses epithelial-to-mesenchymal transition of lung cancer cells while avoiding hybrid states.”

“The epithelial-to-mesenchymal transition (EMT) of primary cancer contributes to the acquisition of lethal properties, including metastasis and drug resistance,” wrote the researchers. “Blocking or reversing EMT could be an effective strategy to improve cancer treatment. However, it is still unclear how to achieve complete EMT reversal (rEMT) as cancer cells often transition to hybrid EMT states with high metastatic potential. To tackle this problem, we employed a systems biology approach and identified a core-regulatory circuit that plays the primary role in driving rEMT without hybrid properties.”

Professor Kwang-Hyun Cho’s research team simulated various cancer cell states in the EMT of lung cancer cells, between epithelial cells without metastatic ability and mesenchymal cells with metastatic ability.

A molecular network mathematical model was established, and key regulators that could reverse the state of the mesenchymal cells back to the epithelial cells were discovered through computer simulation analysis and molecular cell experiments.

Due to the complexity of EMT, it has been difficult to completely reverse the transitional process of the mesenchymal cancer cells to an epithelial cell state in which metastatic ability and drug resistance are eliminated.

The research team established a mathematical model of the gene regulation network that governs the process of EMT. They then applied large-scale computer simulation analysis and system network control technology to identify and verify ‘p53’, ‘SMAD4’, and ‘ERK1’ and ‘ERK 2’ (collectively ERKs) through molecular cell experiments as the three key molecular targets that can transform lung cancer cells in the mesenchymal cell state, reverse back to an epithelial cell state that no longer demonstrates the ability to metastasize, while avoiding the EMT hybrid cell state.

The findings are significant in that they prove that mesenchymal cells can be reverted to the state of epithelial cells under conditions where TGF-β stimulation is present like it is in the actual environment where cancer tissue forms in the human body.

Cho said, “By succeeding in reversing the state of lung cancer cells that acquired high metastatic traits and resistance to drugs and reverting them to a treatable epithelial cell state with renewed sensitivity to chemotherapy, the research findings propose a new strategy for treatments that can improve the prognosis of cancer patients.”

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