UCSF

Breast cancer is a heterogeneous disease in which a single oncogenic driver can give rise to divergent tumor phenotypes. Yet, how oncogenic mutations generate epithelial state plasticity and coordinately remodel the surrounding tissue remains incompletely understood. Here, we applied longitudinal single cell RNA-sequencing to trace the mammary landscape during Pik3ca(H1047R)-driven tumor progression in the mouse. We identify an expansion of the epithelial transcriptional state space, in which luminal cells lose lineage fidelity and acquire ciliated, basal, and squamous-like gene expression programs. While oncogenic cells lose features of luminal identity, they retain expression of hormone-sensing genes such as Esr1, Pgr, and Foxa1. These cell states are established early, and rather than reflecting further epithelial transformation, the transition to overt tumors is instead marked by the emergence of cancer-associated fibroblasts. We identify a Postn+ fibroblast population enriched at the epithelial interface, marked by ECM- remodeling programs and altered epithelial crosstalk in oncogenic glands, as a candidate source of cancer-associated fibroblasts. Altogether, these results characterize Pik3ca(H1047R)-driven oncogenesis as a tissue-level process in which epithelial lineage infidelity is accompanied by a remodeled microenvironment during tumor initiation.