Abstract Tumor resistance, largely driven by cellular heterogeneity and complex interactions within the tumor microenvironment (TME), remains a central challenge in oncology. In breast cancer, the crosstalk between basal-like cancer stem cells (bCSCs) and luminal niche cells is hypothesized to be a critical driver of therapy resistance, yet the underlying molecular mechanisms are poorly defined. Here, we identify and characterize SPON2, a matricellular protein secreted by basal cells, as a master regulator of luminal cell metabolism and function. Mechanistically, SPON2 directly binds to the amino acid transporter SLC38A1 on luminal cells, thereby blocking the glutamine-leucine exchange and consequently suppressing PI3K-AKT-mTOR signaling. This inhibition leads to a profound reduction in oxidative phosphorylation (OXPHOS) and energy metabolism in luminal cells. Phenotypically, Spon2-knockout mice exhibit aberrantly increased and accelerated mammary ductal branching. Conversely, SPON2 overexpression in vitro potently inhibits organoid formation, branching morphogenesis, and epithelial proliferation. Crucially, SPON2 exerts potent tumor-suppressive effects across multiple breast cancer subtypes, including Luminal A and triple-negative breast cancer (TNBC). Our findings establish SPON2 as a basal-derived paracrine signal that is essential for maintaining metabolic homeostasis in the mammary gland and the TME. This work unveils the SPON2-SLC38A1-mTOR axis as a fundamental pathway of metabolic communication between cell populations, providing a novel conceptual framework for understanding breast cancer heterogeneity and a promising therapeutic target for overcoming drug resistance. Citation Format: Pengfei (Paul) Lu. The basal cell-derived matricellular protein SPON2 suppresses luminal cell oxidative phosphorylation and cancer progression by blocking the SLC38A1/mTOR metabolic axis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4528.
Pengfei (Paul) Lu (Fri,) studied this question.