Divergent iron regulatory states contribute to heterogeneity in breast cancer aggressiveness

oleh: William D. Leineweber, Maya Z. Rowell, Sural K. Ranamukhaarachchi, Alyssa Walker, Yajuan Li, Jorge Villazon, Aida Mestre-Farrera, Zhimin Hu, Jing Yang, Lingyan Shi, Stephanie I. Fraley

Format: Article
Diterbitkan: Elsevier 2024-09-01

Deskripsi

Summary: Contact with dense collagen I (Col1) can induce collective invasion of triple negative breast cancer (TNBC) cells and transcriptional signatures linked to poor patient prognosis. However, this response is heterogeneous and not well understood. Using phenotype-guided sequencing analysis of invasive vs. noninvasive subpopulations, we show that these two phenotypes represent opposite sides of the iron response protein 1 (IRP1)-mediated response to cytoplasmic labile iron pool (cLIP) levels. Invasive cells upregulate iron uptake and utilization machinery characteristic of a low cLIP response, which includes contractility regulating genes that drive migration. Non-invasive cells upregulate iron sequestration machinery characteristic of a high cLIP response, which is accompanied by upregulation of actin sequestration genes. These divergent IRP1 responses result from Col1-induced transient expression of heme oxygenase I (HO-1), which cleaves heme and releases iron. These findings lend insight into the emerging theory that heme and iron fluxes regulate TNBC aggressiveness.