Abstract 1557: Loss of lncRNA XIST promote brain metastasis by reshaping tumor lipid metabolism via upregulation of ACSL4

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Abstract Metastatic disease is the main cause of cancer death, and the brain is one of the major sites of breast tumor metastasis. The median survival of breast cancer patients who developed brain metastases (BrM) is less than a year even with the advanced treatment such as stereotactic radiosurgery (SRS). Regardless of high clinical significance, the pathological mechanism of brain metastasis is still poorly understood. Previously, we found that loss of lncRNA XIST robustly promote metastasis and specially brain metastasis in breast cancer. However, the underlying molecular mechanism was not fully understood. In following study, we found that loss of XIST has significantly altered lipid metabolism of breast cancer cells specifically increasing lipid droplet amount and PUFA incorporation. Instead of de novo syntheses, XISTlow cancer cells acquire fatty acid by uptake from exogenous. We found that one X-linked gene, Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4) which are highly upregulated after loss of XIST is responsible for the altered lipid metabolism. ACSL4 activated the free polyunsaturated fatty acids (PUFAs) and lead to increased incorporation of PUFAs into phospholipids. On one hand, elevated ACLS4 expression leads to relative low PPAR pathway activation by decreasing the cellular free PUFA level which directly binds and activate PPAR. PPAR pathway is known to inhibit the expression of inflammatory cytokines which are important for cancer cells to establish brain metastasis. On the other hand, elevated ACSL4 expression enable cancer cells to metabolize the abundant PUFAs in the brain environment, thereby gaining survival advantage. However, increased PUFA incorporation into lipids especially phospholipids produce excess lipid ROS and sensitize cells to ferroptosis inducer such as RSL3. Our study has find out that brain microenvironment not only supports the outgrowth of XIST low cells by providing PUFAs for maintaining their metastatic properties but also sensitizes those cells to ferroptosis inducers, a potential therapy for treating this devastating disease. Citation Format: Yin Liu, Margaret R. Smith, Yuezhu Wang, Ralph D’Agostino, Jimmy Ruiz, Gregory L. Kucera, Lance D. Miller, Wencheng Li, Michael D. Chan, Michael Farris, Dawen Zhao, Fei Xing. Loss of lncRNA XIST promote brain metastasis by reshaping tumor lipid metabolism via upregulation of ACSL4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1557.