Osteopontin is a therapeutic target that drives breast cancer recurrence

Nat Commun. 2024 Oct 24;15(1):9174. doi: 10.1038/s41467-024-53023-9.

Abstract

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.

MeSH terms

  • Animals
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / genetics
  • Breast Neoplasms* / metabolism
  • Breast Neoplasms* / pathology
  • Cell Line, Tumor
  • Cell Proliferation*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Interleukin-4 / metabolism
  • Macrophages / metabolism
  • Mice
  • Neoplasm Recurrence, Local* / metabolism
  • Neoplasm Recurrence, Local* / prevention & control
  • Osteopontin* / genetics
  • Osteopontin* / metabolism
  • Prognosis

Substances

  • Osteopontin
  • SPP1 protein, human
  • Interleukin-4