癌症转移,铁死亡 z-bio 2024-11-28 635

　　Cancer metastasis refers to the process in which cancer cells detach from the primary tumor site, spread through the blood or lymphatic system to other parts of the body, and form new tumors in these new locations. This process is the main cause of most cancer-related deaths. The transfer process usually includes the following steps: local invasion, vascular infiltration (entering the bloodstream), survival in circulation, extravasation (leaving the bloodstream and entering the target tissue), and growth and proliferation in a new location.

　　Although certain lipid related changes are known to be crucial for the extravasation of cancer cells, there is still much unknown about which specific lipid components support the survival and growth of cancer cells in new environments.

　　On November 25, 2024, the team led by Zou Yilong and Wang Xi from Xihu University collaborated with Dr. Cao Jian from Nanjing Maternal and Child Health Hospital to publish a research paper titled "ACSL4 and polyunsaturated lipids support metastatic extravasation and colonization" in the top international academic journal Cell.

　　Dr. Wang Yuqi, Assistant Researcher at Xihu Laboratory, PhD student Hu Xize, and Dr. Cao Jian from Nanjing Maternal and Child Health Hospital/Nanjing Medical University Affiliated Obstetrics and Gynecology Hospital are co first authors of the paper.

　　This study revealed the association between metastatic potential and iron death sensitivity in various cancers. Cancer cells isolated from ovarian cancer patients with metastatic foci showed higher iron death sensitivity and polyunsaturated fatty acid (PUFA) - lipid content compared to cells from primary tumors. Furthermore, it was found that ACSL4 promotes blood transmission and metastasis, providing a new target for therapeutic development.

　　Research Highlights 

　　Pan cancer phenotype data mining reveals correlation between metastasis iron apoptosis sensitivity

　　In vivo CRISPR screening with a focus on metabolism reveals the role of ACSL4 in promoting metastasis

　　ACSL4 promotes metastatic extravasation by enhancing membrane fluidity and invasion

　　research contents 

　　Previous studies have found that cancer cells that reach distant organs may have evolved an optimal lipid metabolism profile that is favorable for their survival during circulation and extravasation. These cancer cells meet their high energy demands in low nutrient environments by activating mitochondrial biogenesis and oxidative phosphorylation. β - oxidation plays a crucial role in this process.

　　β - oxidation is the cleavage of fatty acids between alpha and beta carbon atoms under the action of a series of enzymes, producing acetyl CoA and fatty acyl CoA with two fewer carbon atoms than before. Beta oxidation plays a crucial role in supporting the growth of cancer cells in vivo by providing fuel for mitochondria with high flux of CoA.

　　The research team found through analysis of a pan cancer phenotype database that certain cancer types with high metastatic potential, such as ovarian cancer, liver cancer, and head and neck cancer, exhibit higher sensitivity to iron induced apoptosis. Further research has confirmed the susceptibility to ferroptosis and increased content of polyunsaturated fatty acyl (PUFA) - lipids in metastatic tumor cells.

　　Subsequently, through in vivo CRISPR screening, several metabolic genes promoting metastasis were identified in the established mouse model of ovarian cancer distant metastasis, including NMNAT 1 involved in NAD production and ACSL 4 involved in PUFA lipid biosynthesis. Among them, ACSL 4 can specifically mediate metastatic extravasation during hematogenous dissemination by enhancing membrane fluidity and promoting migration.

　　At the end of the ACSL 4 depletion experiment, ARA (a rich PUFA) pretreatment increased the PUFA lipid content of ES-2-GFP Luc parental cells and increased the tumor metastasis and extravasation rate in mice after intravenous implantation.

　　Researchers have found that ACSL4 enhances the iron death process by promoting the esterification of polyunsaturated fatty acids (PUFAs) to acyl CoA. In addition, metastatic cancer cells with high PUFA lipid content rely on β - oxidation of unsaturated fatty acids (UFA) to survive in the tumor microenvironment.

　　MDH1, ABHD6, ECI1, and ECH1 are key rate limiting enzymes involved in UFA β - oxidation, playing an important role in preparing UFA for metabolic breakdown.

　　Researchers have found that blocking UFA esterification (via ACSL4) and beta oxidation (via ECH1) can significantly reduce the growth and colonization of metastatic tumors. And this combined inhibition strategy is not only applicable to specific types of cancer, such as ovarian cancer, but also to other types of cancer, such as melanoma.

　　In summary, these findings suggest the possibility of inhibiting cancer metastasis by targeting lipid metabolism pathways. In addition, the study also demonstrated the broad applicability of this strategy in different cancer types and immune active environments, laying the foundation for further clinical applications.

　　This article is also a product of the strong collaboration between researchers and clinical doctors. Clinical doctors have a natural advantage in conducting scientific research. They directly face patients, understand their real clinical needs, and are able to transform clinical problems into scientific research topics. By collaborating with basic research scholars for in-depth basic research, research results can be quickly applied to clinical practice, accelerating the transformation of results and bringing more effective treatment plans to patients.

　　With the continuous emergence of research-oriented doctors, their status in the scientific research community will continue to rise. In the future, we have reason to believe that this closely integrated model of clinical and scientific research will bring more breakthroughs and innovations to the medical field.