Current lack of insight into mechanisms governing breast cancer metastasis has precluded development of curative therapies. Previous reports, including our own, have demonstrated that metastatic success is due to tumor cell intrinsic properties as well as microenvironmental and systemic factors (Castano, et al., Cancer Discovery, 2013). The goal of our current study was to determine whether metastasis initiating cells (MIC), i.e., cells enriched for metastatic capacity, also rely on systemic cues. Using a preclinical model of the early phases of breast cancer metastasis, when cells are disseminated in the presence of the primary tumor (McAllister, et al., Cell 2008), we were surprised to find that certain primary tumors inhibit progression of disseminated MICs into overt tumors. In the presence of the primary tumor, MICs were maintained in a Zeb1hi/CDH1lo state and were less proliferative and poorly differentiated relative to those that formed in the absence of the primary tumor. We established that the primary tumor induces mobilization of IL1beta-expressing innate immune cells that are recruited to sites where MICs reside. At those sites, signaling via the IL1 receptor maintains MICs in the Zeb1hi/CDH1lo state, thus promoting disease indolence. Confirming our xenograft results, we established that expression of IL1beta in patient tumors is associated with metastasis free survival. Collectively, these data highlight the profound impact a primary tumor can exert on metastasizing cells - in this case, by altering the systemic environment to the detriment of secondary tumor growth-. Moreover, our data highlight a central role for IL1 pathway in modulating tumor cell plasticity and suggest it may provide a novel avenue for targeting recurrent disease.

Citation Format: Zafira Castano. Innate immune response to primary breast cancer prevents metastasis-initiating cell colonization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1098.