Osteopontin is a therapeutic target that drives breast cancer recurrence

作者：Yu Gu, Tarek Taifour, Tung Bui, Dongmei Zuo, Alain Pacis, Alexandre Poirier, Sherif Samer Attalla, Anne-Marie Fortier, Virginie Sanguin‐Gendreau, Tien-Chi Pan, Vasilios Papavasiliou, Nancy U. Lin, Melissa E. Hughes, Kalie Smith, Morag Park, Michel L. Tremblay, Lewis A. Chodosh, Rinath Jeselsohn, William J. Muller · 发表于：Nature Communications · 年份：2024 · DOI：10.1038/s41467-024-53023-9 · 被引用次数：36 · 研究领域：Bone and Dental Protein Studies、Cancer Cells and Metastasis、Digestive system and related health

Recurrent breast cancers often develop resistance to standard-of-care therapies. Identifying targetable factors contributing to cancer recurrence remains the rate-limiting step in improving long-term outcomes. In this study, we identify tumor cell-derived osteopontin as an autocrine and paracrine driver of tumor recurrence. Osteopontin promotes tumor cell proliferation, recruits macrophages, and synergizes with IL-4 to further polarize them into a pro-tumorigenic state. Macrophage depletion and osteopontin inhibition decrease recurrent tumor growth. Furthermore, targeting osteopontin in primary tumor-bearing female mice prevents metastasis, permits T cell infiltration and activation, and improves anti-PD-1 immunotherapy response. Clinically, osteopontin expression is higher in recurrent metastatic tumors versus female patient-matched primary breast tumors. Osteopontin positively correlates with macrophage infiltration, increases with higher tumor grade, and its elevated pathway activity is associated with poor prognosis and long-term recurrence. Our findings suggest clinical implications and an alternative therapeutic strategy based on osteopontin's multiaxial role in breast cancer progression and recurrence.