Ancestry-linked stromal variations impact breast epithelial cell invasion

Madison G Schmidtmann; Victoria Elliott; James W Clancy; Zachary T Schafer; Harikrishna Nakshatri; Crislyn D'Souza-Schorey

doi:10.1016/j.isci.2025.112686

Ancestry-linked stromal variations impact breast epithelial cell invasion

iScience. 2025 May 16;28(6):112686. doi: 10.1016/j.isci.2025.112686. eCollection 2025 Jun 20.

Authors

Madison G Schmidtmann¹, Victoria Elliott¹, James W Clancy¹, Zachary T Schafer¹, Harikrishna Nakshatri², Crislyn D'Souza-Schorey¹

Affiliations

¹ Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA.
² Department of Surgery, Indiana University School of Medicine, and the VA Roudebush Medical Center, Indianapolis, IN, USA.

Abstract

Breast cancer disproportionately affects women of African ancestry (AA) in part due to biological factors that affect disease outcome. A cell population that expresses PROCR, ZEB1, and PDGFRα (PZP) was recently found to be enriched in breast stroma from healthy AA donors, but only in tumor-adjacent tissues from donors of European ancestry (EA). Here, we show that PZP cells conferred invasive capacity to epithelial cells of both AA and EA origin in 3D cell models wherein cells exhibited leader-follower behaviors during extracellular matrix invasion. Epithelial cell invasion stemmed from a combination of AKT activation and fibronectin deposition by PZP cells. Although AKT activation in epithelial cells alone was insufficient to enhance invasion, blocking AKT activation markedly reduced invasive capacity. These findings point to the germaneness of intrinsic differences in normal breast tissues, such as PZP cell enrichment, in furthering understanding of the molecular basis for worse prognosis in patient cohorts.

Keywords: Cancer; Genomics; Human Genetics.