Compelling evidences have manifested that breast cancer cells prefer to metastasize to certain distant organs, including brain, lung, bone and liver. According to the canonical “seed and soil” theory, this prominent biological behavior, termed as metastatic organotropism, involves intricate interactions between breast cancer cells (the “seeds”) and specific residents in the tumor microenvironment (the “soil”), initiating from pre-metastatic niche formation to metastatic outgrowth. Recently, multifaceted heterogeneity of tissue-specific macrophages (TSMs) and their roles played in organotropic metastases of breast cancer are incrementally unveiled. Herein, we decipher multiple diversities of TSMs, including evolvement, profiles, functions and metabolic characteristics under different polarization states. Further, we elaborate on bidirectional effects of TSMs on metastatic organotropism of breast cancer (both to the “seeds” and “soil”), and unearth underlying signaling pathways based on updated mechanistic researches. Lastly, we compile a series of clinical trials, hoping to illuminate promising TSM-targeting therapies against breast cancer organotropic metastases.

Breast cancer is one of the most common cancers worldwide, 30-50 % of patients with advanced breast cancer develop brain metastasis, causing severe damage to their life quality. Due to the existence of the blood-brain barrier (BBB), brain lesions were recognized to be a unique microenvironment with limited infiltration of circulating immune cells and drugs. However, emerging studies reported the immunology of the brain tumor microenvironment (TME) and indicated the potential of immunotherapy against brain metastases. Therefore, it is of great value to comprehensively investigate the TME and identify the pro-tumoral mechanisms facilitating brain metastases and the crucial molecules involved in this process. In this research, we re-analyzed public data on three brain surgical specimens of breast cancer metastases and identified the immunosuppressive roles of macrophages in the metastatic TME. Then, we conducted the first single-cell RNA sequencing on a murine model of breast cancer brain metastasis. In the brain TME, immune cells showed prominent heterogeneity, especially the mononuclear phagocyte system (MPS). We identified the alteration of macrophage subclusters in the central nerve system (CNS) after breast cancer invasion and found that metastatic cancer cells re-shaped the TME cellular interactions for immune evasion and nutrition supply. Finally, this research could serve as a reference for further analysis of new therapies against brain metastatic lesions.

To investigate the roles of CARM1 and its regulatory effect on YIPF2 in breast cancer progression. Breast cancer cells were transfected with CARM1 siRNA to knock down CARM1 expression. Cell proliferation, apoptosis, migration, and invasion were assessed using EdU, CCK-8, Annexin V/PI flow cytometry, wound-healing, and transwell assays, respectively. Co-expression of CARM1 and YIPF2 was evaluated using the GEPIA database and validated by qRT-PCR. Co-immunoprecipitation (Co-IP) was performed to assess the association between CARM1 and YIPF2, and asymmetric dimethylarginine (ADMA) signals in YIPF2 immunoprecipitates were assessed. Rescue experiments were performed following YIPF2 overexpression. In vivo studies were conducted to examine the anti-tumor effects of CARM1 inhibition. We found that CARM1 was upregulated in breast cancer patients and cell lines. Higher CARM1 expression was associated with poorer survival. CARM1 knockdown inhibited proliferation, colony formation, migration, and invasion of breast cancer cells, and induced apoptosis. The correlation analysis indicated that CARM1 and YIPF2 were positively co-expressed. Co-IP experiments supported an association between CARM1 and YIPF2. CARM1 knockdown reduced the ADMA signal in YIPF2 immunoprecipitates, consistent with CARM1-dependent YIPF2 methylation. In addition, elevated YIPF2 predicted worse survival outcomes in breast cancer patients. Overexpression of YIPF2 partially rescued the suppression of tumor progression induced by CARM1 knockdown. Finally, tumors derived from sh-CARM1 cells were markedly smaller than those from control cells. Collectively, our findings support a role for CARM1 in breast cancer progression and provide evidence of its association with YIPF2 and CARM1-dependent YIPF2 methylation, offering insights into the CARM1-YIPF2 regulatory axis and potential therapeutic strategies.