Abstract 2512: The metastatic breast cancer microenvironment in bone exhibits unique BMP signaling
Authors: Ihle Claire Louise , Straign Desiree , Owens Philip 
Published: June 2022

Abstract
In 2021, an estimated 281,550 women will be diagnosed with breast cancer (BC) in the U.S., and 43,600 BC patients will succumb to the disease. BC patient prognosis has improved for localized BC, yet metastatic BC continues to cause high mortality with a 5 year survival rate of only 27%. Approximately 70% of BC metastases occur in the bone, with a tumor microenvironment (TME) composed primarily of BC cells, immune cells, and bone cells. In these cellular compartments, bone morphogenetic protein (BMP) signaling exhibits unique TME dependent tumor promoter and suppressor effects. Previous studies in our lab have found BMPs promote myeloid progenitors, polarization of M2 macrophages, and tumor progression in a BMPR1a LysMCre conditional knockout mouse model. Yet to establish BMPs as a viable target for the treatment of metastatic bone, the mechanisms behind BMPs promoting BC bone metastases must be investigated. To further investigate BMP dependent myeloid heterogeneity in cancer, we have utilized a cohort of non-treatment naïve BC patient bone biopsies to unveil the distinct myeloid populations in the TME of BC bone metastases. Differential gene expression analysis revealed a subset of patient samples with a high myeloid gene signature, corresponding with increased chemokine, cytokine and JAK/STAT signaling gene pathways in addition to enhanced BMP signaling. Digital Spatial Profiling via the NanoString GeoMx platform and multiplexed immunohistochemistry staining via the AKOYA Vectra Polaris platform were used to analyze the spatial context of the TME in our cohort of patient bone. We found enhanced myeloid cell infiltration, myeloid heterogeneity and M2 macrophage polarization in the TME of high myeloid gene signature patient samples. This precision oncology analysis into the unique landscape of the metastatic bone TME revealed BMP driven phenotypes in distinct TME cellular components. To then determine if the TME features observed in the metastatic bone samples was reflective of altered innate trained immunity regulated by BMPs, we investigated the requirement for BMP signaling in myeloid inflammatory responses both in vitro and in a mouse model of BC bone metastasis. We found BMPs alter the ability for macrophages to undergo innate trained immunity functions and BC bone metastases alter myeloid inflammatory responses in mice. Investigating the heterogeneity and functions of myeloid cells in the TME of bone metastatic BC will help advance therapeutic target development for BC patients with bone lesions. Expanding therapeutic options for metastatic BC patients will improve patient quality of life and reduce deaths caused by metastasis.
Citation Format: Claire Louise Ihle, Desiree Straign, Philip Owens. The metastatic breast cancer microenvironment in bone exhibits unique BMP signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2512.