Osteopontin is a therapeutic target that drives breast cancer recurrence
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.
Authors
- Michel L. Tremblay (ORCID: https://orcid.org/0000-0002-0281-541X)
- Virginie Sanguin‐Gendreau (ORCID: https://orcid.org/0009-0005-1236-8800)
- Melissa E. Hughes (ORCID: https://orcid.org/0000-0001-6190-9101)
- Lewis A. Chodosh (ORCID: https://orcid.org/0000-0003-1027-8674)
- Tung Bui
- William J. Muller (ORCID: https://orcid.org/0000-0002-7293-4166)
- Tien-Chi Pan (ORCID: https://orcid.org/0000-0002-5380-0867)
- Sherif Samer Attalla (ORCID: https://orcid.org/0000-0003-4193-6393)
- Nancy U. Lin (ORCID: https://orcid.org/0000-0003-2263-5413)
- Rinath M. Jeselsohn (ORCID: https://orcid.org/0000-0001-7996-7529)
- Tarek Taifour (ORCID: https://orcid.org/0000-0002-1390-3597)
- Vasilios Papavasiliou (ORCID: https://orcid.org/0009-0006-6805-8235)
- Alain Pacis (ORCID: https://orcid.org/0000-0003-4883-6176)
- Kalie Smith (ORCID: https://orcid.org/0000-0003-0461-8118)
- Anne-Marie Fortier (ORCID: https://orcid.org/0000-0002-0428-3066)
- Alexandre Poirier (ORCID: https://orcid.org/0000-0002-6754-6003)
- Morag Park (ORCID: https://orcid.org/0000-0001-5400-606X)
- Yu Gu (ORCID: https://orcid.org/0009-0006-3002-307X)
- Dongmei Zuo (ORCID: https://orcid.org/0000-0002-5061-3310)
Institutions
- McGill University Health Centre (CA)
- Dana-Farber Cancer Institute (US)
- McGill Genome Centre (CA)
- McGill University (CA)
- University of Pennsylvania (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-10-24
- DOI
- https://doi.org/10.1038/s41467-024-53023-9
- Citations
- 26
- Primary Topic
- Bone and Dental Protein Studies
- Type
- article
- Field-Weighted Citation Impact
- 12.22
Funders
- McGill University
- Canadian Institutes of Health Research
- Canadian Cancer Society Research Institute