The China University of Science and Technology has discovered a new mechanism of clonal proliferation in breast cancer tumor stem cells that regulates iron death and metastasis

On March 16th, Professor Zhu Tao of the School of Life Medicine, University of Science and Technology of China published a paper entitled Cancer Stem Cell Regulated Phenotypic Plasticity Protects Metastasized in Nature Communications Research paper on Cancer Cells from Ferroptosis.

Tumor stem cells have the ability of self-renewal, high metastasis and treatment resistance, which play a key role in the malignant progression of tumors. Tumor stem cells and non-tumor stem cell populations maintain a dynamic balance between subpopulations in the process of tumor development, and each subpopulation can reconstruct the entire tumor cell population. However, the mechanism of maintaining the homeostasis among tumor cell subsets and the role of this phenomenon in the tumorigenesis and development are still unclear.

Our research group first found that breast cancer stem cells can inhibit their own stem cell characteristics by secreting cytokine negative feedback through co-culture in vitro and co-transplantation in mice. Through high-throughput screening, luciferase reporting and other experiments, they found that DKK1 plays a key role in the tumor stem cell secretome. Further functional experiments showed that the autonomous inhibitory effect of tumor stem cell regulation could promote the release of tumor stem cells from the resting state and promote the clonal proliferation of metastasis. In a variety of breast cancer metastasis models, small molecule inhibitors of DKK1 can almost completely block the occurrence of lung metastasis.

Iron death is a non-apoptotic cell death process associated with abnormal cell metabolism and lipid peroxidation. Compared to in situ breast cancer, lung metastases are under the pressure of high reactive oxygen species and high iron death. This study shows that tumor stem cells are relatively enriched in lung metastases due to their highly invasive properties, and the enriched tumor stem cells can secrete DKK1 negative feedback to inhibit their stem cell properties. Since tumor stem cells are highly sensitive to iron death, DKK1-regulated inhibition of tumor stem cell properties can protect lung metastatic cells from iron death and promote the growth of metastases.

This study innovatively proposed that the metastatic cloning and proliferation step, rather than the tumor invasion step, could effectively inhibit the occurrence of tumor metastasis. Taken together, this work clarifies the role of phenotypic plasticity regulated by tumor stem cells in metastatic tumor colonization and provides innovative therapeutic strategies to inhibit metastasis.

Mingming Wu and Xiao Zhang, University of Science and Technology of China, are co-first authors of the paper. Professor Zhu Tao, Faculty of Life Medicine, University of Science and Technology of China, and Professor Peter E. Louie, adjunct Professor, Shenzhen International Graduate School, Tsinghua University, are co-corresponding authors of this paper. The research was supported by the National Natural Science Foundation of China and the New Medicine Foundation of the University of Science and Technology.

The article links: https://www.nature.com/articles/s41467-022-29018-9

(Department of Life Sciences and Medicine, Department of Scientific Research)