Abstract A102: Osteopontin produced by myeloid cells determines the outcome of breast cancer metastases

Abstract The matricellular protein osteopontin (OPN) combines regulatory and structural functions in the extracellular matrix and, when produced by tumor cells, concurs to progression, cell invasion and metastasis. Little is known about its activity when produced by host cells including that component of tumor stroma. Combining gene silencing in tumor cells and mice deficient for OPN we have dissected the role of tumor and host produced OPN in breast cancer metastasis using 4T1 and BJMC3879 spontaneously metastatic models. While tumor produced OPN favors lung metastasis promoting tumor cell survival in the blood stream, stromal OPN greatly affects the immusuppression at the metastatic site. Immunosuppression is often associated with the expansion of a heterogeneous myeloid population called myeloid derived suppressor cells (MDSC) comprising a granulocytic (Gr-1high) and a monocytic (Gr-1int/low) subset, the latter endowed with higher immune suppressive capacity and characterized by OPN expression. Analysis of MDSC showed that inhibition of lung metastases in OPN-deficient mice goes along with a skewing toward the Gr1high subset, whereas the Gr1int/low subset is more expanded in wild type mice. Moreover, the latter subset, in lungs of tumor-bearing OPN-deficient animals, is less suppressive than its wild type counterpart, and associated with a lower expression of arginase-1, IL-6 and phospho-STAT3. Our results find correlation with human tumors and underscore that different mechanisms characterize tumor- and host-produced OPN activities in breast cancer metastasis and reveal a new function for host-derived OPN as regulator of the local immune response in the metastatic lung niche. Citation Format: Mario P. Colombo, Claudia Chiodoni. Osteopontin produced by myeloid cells determines the outcome of breast cancer metastases. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A102.