Divergent iron regulatory states contribute to heterogeneity in breast cancer aggressiveness
Year: 2024
Type: article
Abstract: Primary tumors with similar mutational profiles can progress to vastly different outcomes where transcriptional state, rather than mutational profile, predicts prognosis. A key challenge is to understand how distinct tumor cell states are induced and maintained. In triple negative breast cancer cells, invasive behaviors and aggressive transcriptional signatures linked to poor patient prognosis can emerge in response to contact with collagen type I. Herein, collagen-induced migration heterogeneity within a TNBC cell line was leveraged to identify transcriptional programs associated with invasive versus non-invasive phenotypes and implicate molecular switches. Phenotype-guided sequencing revealed that invasive cells upregulate iron uptake and utilization machinery, anapleurotic TCA cycle genes, actin polymerization promoters, and a distinct signature of Rho GTPase activity and contractility regulating genes. The non-invasive cell state is characterized by actin and iron sequestration modules along with glycolysis gene expression. These unique tumor cell states are evident in patient tumors and predict divergent outcomes for TNBC patients. Glucose tracing confirmed that non-invasive cells are more glycolytic than invasive cells, and functional studies in cell lines and PDO models demonstrated a causal relationship between phenotype and metabolic state. Mechanistically, the OXPHOS dependent invasive state resulted from transient HO-1 upregulation triggered by contact with dense collagen that reduced heme levels and mitochondrial chelatable iron levels. This induced expression of low cytoplasmic iron response genes regulated by ACO1/IRP1. Knockdown or inhibition of HO-1, ACO1/IRP1, MRCK, or OXPHOS abrogated invasion. These findings support an emerging theory that heme and iron flux serve as important regulators of TNBC aggressiveness.
Source: iScience
Institutions: University of California San Diego, Moores Cancer Center
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,150
Funders: Conrad Prebys Foundation, Illinois Humanities, National Science Foundation, American Cancer Society, American Heart Association, Tobacco-Related Disease Research Program, National Institutes of Health, University of California, San Diego, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Neurological Disorders and Stroke, School of Medicine, University of California, San Diego, Arena Pharmaceuticals
Awards: G1372536478, G1423100242, CAREER: A multi-scale, data-driven model of 3D cell motility, G2288160319, Regulation of Collective Breast Cancer Invasion and Metastasis, Novel Optical Imaging Approach to Study Neurovascular Coupling System, G4310190388, Apical-basal polarity in tumor progression and metastasis, Integrating Four-Dimensional Cell Migration Modeling with Quantitative Experiments, University of California San Diego Neuroscience Microscopy Imaging Core, G639426234, G6671297155, G6975997290, G7146094141, G8842412831, UCSD Cancer Center Training Program in Drug Development, The Cancer Cell Map Initiative v2.0, HIPC Data Coordinating Center, EPHA2 Receptor Signaling in Breast Cancer Mechanotransduction, Sugar Probed SRS Volumetric imaging of Metabolic Activities, Regulation of Tumor Invasion and Metastasis by Matrix Stiffness, Functional interplay between Hippo and estrogen receptor ESR1
OpenAlex ID: W4401297726