A few days ago, a message came from the Cancer Hospital Affiliated to Fudan University. The team of professors huxichun, wangbiyun and chenguangming of the hospital discovered for the first time the protective effect of adipocytes on iron death of triple negative breast cancer.
Studies have confirmed that breast cancer cells co cultured with adipocytes around tumors show resistance to iron death. Further experiments have found that adipocytes can induce iron death resistance of breast cancer cells by secreting specific fatty acids, and this process depends on fatty acid synthase acsl3. The research team also verified the iron death protection of adipocytes against triple negative breast cancer through animal models. The results were published online in the Journal of Hematology and oncology.
Elucidating the cause of cell death in triple negative breast cancer
Generally, breast cancer is the type with better prognosis among tumors. However, the triple negative breast cancer, which accounts for about 15% of all breast cancer, is called the "most toxic" breast cancer because of its high degree of malignancy, high risk of metastasis and recurrence, lack of corresponding targets and poor treatment effect.
Iron death is a newly discovered mode of programmed cell death. One of the important reasons why triple negative breast cancer is more invasive and tolerant to treatment is to avoid all kinds of cell death. However, there is no research report on triple negative breast cancer to avoid iron death.
The breast is in a unique microenvironment with a large number of fat cells infiltrating. Previous studies have shown that fat cells can regulate the fatty acid metabolism of breast cancer and enhance the invasion and metastasis of breast cancer, and iron death is closely related to fatty acid metabolism. Therefore, the researchers propose a scientific hypothesis, whether fat cells participate in the regulation of iron death of breast cancer?
Protection of adipocytes against iron death in triple negative breast cancer
In previous studies, the team found that the database showed that breast cancer was generally less sensitive to iron death, while adipocytes were closely associated with iron death related genes. Adipocytes are closely related to the occurrence and development of breast cancer. Are they also involved in the regulation of iron death?
Protection of adipocytes against iron death in triple negative breast cancer
The researchers then constructed the breast cancer adipocyte co culture system, and used different iron death inducers to detect the iron death level of breast cancer. The results showed that the co cultured cells were significantly resistant to iron death and could be reversed by iron death inhibitors, but not by apoptosis and other cell death inhibitors. At the same time, the results were verified from the aspects of protein expression, electron microscopy and cell proliferation. Furthermore, in order to simulate the real microenvironment of breast cancer in vivo, the research team constructed a mouse model and confirmed the protection of adipocytes against iron death in triple negative breast cancer.
To reveal the mechanism of adipocytes regulating iron death in breast cancer
What mechanism does adipocyte regulate iron death in breast cancer? The researchers then conducted a lipoomic analysis of co cultured and single cultured cells, and found that the phospholipid synthesis pathway in co cultured cells was significantly increased. Subsequently, they used exogenous fatty acids and fatty acid uptake inhibitors to explore and find that adipocytes regulate iron death of breast cancer cells by secreting fatty acid MUFA.
Schematic diagram of the mechanism of adipocyte protection against iron death in triple negative breast cancer
Literature review and pre validation showed that MUFA was bound to phospholipids through the enzyme acsl3 related to fatty acid synthesis. Therefore, subsequent acsl3 knockdown experiments were carried out and it was confirmed that the regulation of adipocytes and exogenous MUFA on iron death in breast cancer depended on acsl3.
Reversing iron death protection: the key to inhibiting fatty acid metabolism
This study first discovered the key role of adipocytes in regulating iron death in triple negative breast cancer and revealed its mechanism, improved the academic understanding of the relationship between breast cancer microenvironment and iron death, and provided potential therapeutic targets in the future.
In the follow-up work, the research group also found that specific drugs can effectively reverse the iron death protection of adipocytes against breast cancer, which may be achieved by inhibiting fatty acid metabolism. The relevant validation work is still in progress. In the future, it is expected to induce iron death in triple negative breast cancer through the combination of two drugs, so as to achieve the goal of reducing tumors.
Article link:
https://jhoonline.biomedcentral.com/articles/10.1186/s13045-022-01297-1
