Divergent iron regulatory states contribute to heterogeneity in breast cancer aggressiveness
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
Affiliations
William D. Leineweber
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA
Maya Z. Rowell
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA
Sural K. Ranamukhaarachchi
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA
Alyssa Walker
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA
Yajuan Li
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA
Jorge Villazon
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA
Aida Mestre-Farrera
Department of Pharmacology, Moores Cancer Center, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA
Zhimin Hu
Department of Pharmacology, Moores Cancer Center, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA
Jing Yang
Department of Pharmacology, Moores Cancer Center, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA; Department of Pediatrics, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA
Lingyan Shi
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA
Stephanie I. Fraley
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; Corresponding author
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.
