ULSAN — Korean researchers have identified how colon cancer cells adapt in the early stage of taking root in a new organ after spreading, along with an Achilles' heel that could be targeted to stop them. The work is expected to mark an important turning point in developing treatments tailored to the traits that metastatic cancer takes on in each organ.
The Ulsan National Institute of Science and Technology, or UNIST, said on Sept. 17 that research teams led by professors Cho Seung-woo and Park Tae-eun of its department of biomedical engineering had built an in-vitro culture system that closely reproduces the surrounding tissue of individual organs, and had confirmed both the early adaptation process of colon cancer cells and a vulnerable signaling pathway in colon cancer that has spread to the liver.
Metastasis to other organs is the main cause of death among cancer patients, but tumors are often found only after they have grown, making it difficult to study how cancer cells settle into an unfamiliar organ in the first place. Matrigel, a material derived from mouse tumors and long used in such experiments, also failed to reflect the microenvironment specific to each human organ.
The teams removed cells from colon, liver, lung and brain tissue taken from pigs, whose tissue composition is similar to that of humans, and extracted only the extracellular matrix, or ECM, to produce four gel-type culture materials. They then placed patient-derived colon cancer organoids, or mini organs, in each environment and tracked changes in gene regulation over time using ATAC-seq, a technique that measures chromatin accessibility.
The analysis showed that colon cancer cells rapidly rewired their gene regulation to match the organ environment in which they had settled. Colon cancer cells placed in the liver tissue environment sharply increased production of HNF4A, a key protein that controls how genes operate, and suppressing it markedly reduced the formation of tumor masses.
The teams also found that in the liver environment, the cancer cells became far more dependent on c-MET, a protein that acts as a receiver for survival signals. When a drug blocking c-MET signaling was administered, cancer cells that had barely responded in an ordinary culture environment saw their survival rate plunge in the liver-mimicking environment and died. That amounts to a clue toward targeted therapy that could effectively attack colon cancer that has spread to the liver.
The teams plan to upgrade the system into a platform for assessing the efficacy and toxicity of immuno-oncology drugs by adding microenvironment components such as immune cells and blood vessels step by step.
"We have demonstrated that gene expression and survival strategies differ depending on the organ in which cancer cells settle," the researchers said. "We will broaden the research to various cancer types and contribute to establishing precision, tailored treatment strategies that target the vulnerabilities of each site of metastasis."
The findings, with UNIST researchers Yoon Hee-jung and Kim Da-young as first authors, were published in the online edition of Bioactive Materials, a leading journal in the field of biomaterials. The research was supported by the Ministry of Health and Welfare's Korean ARPA-H Project and the National Research Foundation of Korea.
