Interferon-Induced Bone Marrow Stromal Antigen 2 (BST2) Is A Functional Tumor-Initiating Cell Marker In Triple-Negative Breast Cancer

Abstract

SUMMARYTumor-initiating cells (TIC) are a tumor cell subpopulation thought to be responsible for therapeutic resistance and metastasis. Using aSignalTransducer andActivator ofTranscription (STAT) reporter, and a STAT-responsive lineage tracing system, we enriched for cells with enhanced mammosphere-forming potential in some, but not all, triple-negative breast cancer xenograft models (TNBC) indicating TIC-related and TIC-independent functions for STAT signaling. Single-cell RNA sequencing (scRNA-seq) of reporter-tagged xenografts identified a common interferon-associated transcriptional state, previously linked to inflammation and macrophage differentiation, in TIC. Similar transcriptional states exist in human breast cancer patient scRNA-seq datasets. Flow cytometric sorting using bone marrow stromal cell antigen 2 (BST2), a marker of this state, enriched for TIC, and BST2 knockdown reduced mammosphere-forming potential. These results suggest TIC may exploit the interferon response pathway to promote their activity in TNBC. Our results lay the groundwork to target interferon-associated pathways in TIC in a subset of TNBC.