PO.ET02.13 · 实验与分子治疗
基底细胞来源的基质细胞蛋白SPON2通过阻断SLC38A1/mTOR代谢轴抑制腔上皮细胞的氧化磷酸化和癌症进展
The basal cell-derived matricellular protein SPON2 suppresses luminal cell oxidative phosphorylation and cancer progression by blocking the SLC38A1/mTOR metabolic axis
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摘要 Abstract
中文摘要
肿瘤耐药性在很大程度上由细胞异质性和肿瘤微环境（TME）内的复杂相互作用所驱动，仍是肿瘤学的核心挑战。在乳腺癌中，基底样癌症干细胞（bCSCs）与腔上皮龛细胞之间的串扰被假设为治疗耐药的关键驱动因素，但其潜在的分子机制尚不明确。在此，我们鉴定并表征了SPON2——一种由基底细胞分泌的基质细胞蛋白，作为腔上皮细胞代谢和功能的主调控因子。机制上，SPON2直接结合腔上皮细胞上的氨基酸转运体SLC38A1，从而阻断谷氨酰胺-亮氨酸交换，进而抑制PI3K-AKT-mTOR信号传导。这种抑制导致腔上皮细胞的氧化磷酸化（OXPHOS）和能量代谢显著降低。表型上，Spon2敲除小鼠表现出异常增多和加速的乳腺导管分支。相反，SPON2在体外过表达可强效抑制类器官形成、分支形态发生和上皮增殖。至关重要的是，SPON2在多种乳腺癌亚型（包括Luminal A和三阴性乳腺癌（TNBC））中均发挥强效的肿瘤抑制作用。我们的研究结果确立了SPON2作为一种基底细胞来源的旁分泌信号，对于维持乳腺和TME的代谢稳态至关重要。这项工作揭示了SPON2-SLC38A1-mTOR轴是细胞群体之间代谢通讯的一条基础通路，为理解乳腺癌异质性提供了新的概念框架，并为克服耐药性提供了一个有前景的治疗靶点。
查看英文原文 English 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.
利益披露 Disclosure
P. Lu, None.