Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC, Canada.
Department of Biochemistry, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada.
Nat Commun. 2024 Oct 24;15(1):9174. doi: 10.1038/s41467-024-53023-9.
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.
复发性乳腺癌常对标准治疗产生耐药性。确定导致癌症复发的可靶向因素仍然是改善长期预后的限速步骤。在这项研究中，我们确定肿瘤细胞衍生的骨桥蛋白是肿瘤复发的自分泌和旁分泌驱动因素。骨桥蛋白促进肿瘤细胞增殖，招募巨噬细胞，并与 IL-4 协同作用，进一步将其极化为促肿瘤状态。巨噬细胞耗竭和骨桥蛋白抑制可减少复发性肿瘤生长。此外，在原发性荷瘤雌性小鼠中靶向骨桥蛋白可预防转移，允许 T 细胞浸润和激活，并改善抗 PD-1 免疫治疗反应。临床上，复发性转移性肿瘤中的骨桥蛋白表达高于女性患者匹配的原发性乳腺癌肿瘤。骨桥蛋白与巨噬细胞浸润呈正相关，随着肿瘤分级的升高而增加，其升高的通路活性与预后不良和长期复发相关。我们的研究结果表明了临床意义和一种基于骨桥蛋白在乳腺癌进展和复发中的多轴作用的替代治疗策略。
