In tissue biopsies, cancer cells are frequently observed to have nuclei (the cell's genetic information storage) larger than normal. Until now, this was considered a sign that the cancer was worsening, but the exact cause and effect had not been elucidated. In this study, the KAIST research team found that cancer cell nuclear hypertrophy is not a cause of malignancy but a temporary response to replication stress, and that it can, in fact, suppress metastasis. This discovery is expected to lead to the development of new diagnostic and therapeutic strategies for cancer and metastasis inhibition.
KAIST (President Kwang Hyung Lee) announced on the September 26th that a research team led by Professor Joon Kim of the Graduate School of Medical Science and Engineering, in collaboration with the research teams of Professor Ji Hun Kim and Professor You-Me Kim, discovered the molecular reason why the nucleus enlarges in cancer cells. This achievement provides an important clue for understanding nuclear hypertrophy, a phenomenon frequently observed in pathological examinations but whose direct cause and relationship with cancer development were unclear.
The research team confirmed that DNA replication stress (the burden and error signal that occurs when a cell copies its DNA), which is common in cancer cells, causes the 'actin' protein inside the nucleus to aggregate (polymerize), which is the direct cause of the nuclear enlargement.
This result suggests that the change in cancer cell nuclear size may not simply be a "trait evolved by the cancer cell for its benefit." Rather, it suggests that it is a temporary, makeshift response to stress, and that it may impose constraints on the cancer cell's potential for metastasis.
Therefore, future research needs to explore whether changes in nuclear size can become a target for cancer treatment or a clue related to the suppression of metastasis. That is, nuclear hypertrophy may be a temporary response to replication stress and should not necessarily be seen as indicating the malignancy of the cancer.
This conclusion was substantiated through: (1) Gene Function Screening (inhibiting thousands of genes sequentially to find the key genes involved in nuclear size regulation); (2) Transcriptome Analysis (confirming which gene programs are activated when the nucleus enlarges); (3) 3D Genome Structure Analysis (Hi-C), which revealed that nuclear hypertrophy is not just a size change but is connected to changes in DNA folding and gene arrangement; and (4) Mouse Xenograft Models (confirming that cancer cells with enlarged nuclei actually have reduced motility and metastatic ability).
Professor Joon Kim of the Graduate School of Medical Science and Engineering said, "We confirmed that DNA replication stress disrupts the nuclear size balance, explaining the underlying mechanism of long-standing pathological observations," adding, "The possibility of utilizing nuclear structural changes as a new indicator for cancer diagnosis and metastasis prediction has now opened up."
Dr. Changgon Kim (currently a Hematology and Oncology specialist at Korea University Anam Hospital) and Saemyeong Hong, a PhD candidate from the KAIST Graduate School of Medical Science and Engineering, participated as co-first authors in this study. The results were published online in the international journal PNAS (Proceedings of the National Academy of Sciences of the United States of America) on September 9th.
※ Paper Title: Replication stress-induced nuclear hypertrophy alters chromatin topology and impacts cancer cell fitness ※ DOI: https://doi.org/10.1073/pnas.2424709122
Meanwhile, this research was supported by the Mid-career Researcher Program and the Engineering Research Center (ERC) program of the National Research Foundation of Korea.