Karner Emmet R, Wang Mengdie, Goel Hira Lal, Mercurio Arthur M
Departments of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605.
Proc Natl Acad Sci U S A. 2025 Aug 26;122(34):e2427304122. doi: 10.1073/pnas.2427304122. Epub 2025 Aug 19.
Understanding mechanisms that determine the response of cells to ferroptotic stress is a timely issue that has significant ramifications for biology and pathology. We investigated these mechanisms in the context of breast cancer where tumors are composed of diverse populations of cancer cells that differ in their ferroptosis sensitivity. Using single-cell RNA-sequencing, we determined that cancer cell populations with luminal differentiation are more resistant to ferroptosis than other cells within a heterogeneous tumor. Subsequent bioinformatic analysis and experimentation revealed that GATA3, a transcription factor that promotes luminal differentiation, has a causal role in ferroptosis resistance in luminal breast cancer cells. In pursuit of the mechanism involved, we found that GATA3 represses the expression of integrin β1 and its downstream signaling cascade. This observation led us to demonstrate that integrin β1 signaling is necessary for sensitivity to ferroptosis in basal breast cancer cells because it regulates a FAK/ROCK pathway that sustains the expression of ACSL4, a lipid-modifying enzyme that is essential for ferroptosis. The repression of integrin β1 by GATA3 inhibits this signaling pathway, rendering cells ferroptosis resistant. Together, these data provide insight into mechanisms of ferroptosis sensitivity and resistance that are linked to the cell biology and signaling pathways of the diverse types of cells present in breast tumors.
了解决定细胞对铁死亡应激反应的机制是一个适时的问题，对生物学和病理学具有重大影响。我们在乳腺癌的背景下研究了这些机制，在乳腺癌中，肿瘤由铁死亡敏感性不同的多种癌细胞群体组成。通过单细胞RNA测序，我们确定具有腔分化的癌细胞群体比异质性肿瘤中的其他细胞对铁死亡更具抗性。随后的生物信息学分析和实验表明，促进腔分化的转录因子GATA3在腔面乳腺癌细胞的铁死亡抗性中起因果作用。为了探究其中涉及的机制，我们发现GATA3抑制整合素β1及其下游信号级联的表达。这一观察结果使我们证明，整合素β1信号传导对于基底乳腺癌细胞对铁死亡的敏感性是必要的，因为它调节一条维持ACSL4表达的FAK/ROCK途径，ACSL4是一种对铁死亡至关重要的脂质修饰酶。GATA3对整合素β1的抑制作用会抑制该信号通路使细胞产生铁死亡抗性。总之，这些数据为与乳腺肿瘤中存在的不同类型细胞的细胞生物学和信号通路相关的铁死亡敏感性和抗性机制提供了见解。
