Cancer-induced immune responses affect tumor progression and therapeutic response. In multiple murine models and clinical datasets, we identified large variations of neutrophils and macrophages, which define “immune subtypes” of triple negative breast cancer (TNBC) including neutrophil-enriched (NES) and macrophage-enriched subtypes (MES). Different tumor-intrinsic pathways and mutual regulation between macrophages/monocytes and neutrophils contribute to the development of dichotomous myeloid compartment. MES contains predominantly macrophages that are CCR2-dependent and exhibit variable responses to immune checkpoint blockade (ICB). NES exhibits systemic and local accumulation of immunosuppressive neutrophils (or granulocytic myeloid-derived suppressor cells (gMDSCs), is resistant to ICB, and contains a minority of macrophages that appear to be unaffected by CCR2 knockout. A MES-to-NES conversion mediated acquired ICB resistance of initially sensitive MES models. Our results demonstrate diverse myeloid cell frequencies, functionality, and potential roles in immunotherapies, and highlight the need to better understand the inter-patient heterogeneity of the myeloid compartment.

Metastasis is the most devastating stage of cancer progression and causes the majority of cancer-related deaths. Clinical observations suggest that most cancers metastasize to specific organs, a process known as ''organotropism.'' Elucidating the underlying mechanisms may help identify targets and treatment strategies to benefit patients. This review summarizes recent findings on tumor-intrinsic properties and their interaction with unique features of host organs, which together determine organ-specific metastatic behaviors. Emerging insights related to the roles of metabolic changes, the immune landscapes of target organs, and variation in epithelial-mesenchymal transitions open avenues for future studies of metastasis organotropism. Mechanisms Underlying Organ-Tropism of Metastasis Classic ''Seed and Soil'' MechanismsStephen Paget stipulated that both cancer cell-intrinsic properties (''seed'') and the congenial ME (''soil'') are essential for metastasis formation (Paget, 1889). Research in the past few decades has greatly enhanced our understanding of the molecular and cellular nature of both ''seed'' and ''soil''. In this section, we will review some mechanisms of organ-specific metastasis focusing on the organ-specific ME. Bone TropismCancers disseminate to bone with different frequencies (Table 1). Breast and prostate cancers are the principal cancers that metastasize to bone (Budczies et al., 2015; DiSibio and French, 2008). Bone and bone marrow comprise unique cell types including osteoblasts, osteocytes, and osteoclasts. Osteoclasts

SUMMARY The fate of disseminated tumor cells is largely determined by microenvironment (ME) niche. The osteogenic niche promotes cancer cell proliferation and bone metastasis progression. We investigated the underlying mechanisms using pre-clinical models and analyses of clinical data. We discovered that the osteogenic niche serves as a calcium (Ca) reservoir for cancer cells through gap junction (GJs). Cancer cells cannot efficiently absorb Ca from ME, but depend on osteogenic cells to increase intracellular Ca concentration. The Ca signaling, together with previously identified mTOR signaling, promotes bone metastasis progression. Interestingly, effective inhibition of these pathways can be achieved by danusertib, or combination of everolimus and arsenic trioxide, which provide possibilities of eliminating bone micrometastases (BMM) using clinically established drugs.

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Most (80%) of the triple-negative breast cancers (TNBCs) express mutant p53 proteins that acquire oncogenic activities including promoting metastasis. We previously showed that wild-type ERβ (ERβ1) impedes epithelial to mesenchymal transition (EMT) and decreases the invasiveness of TNBC cells. In the present study we searched for signaling pathways that ERβ1 uses to inhibit EMT and invasion in TNBC cells. We show that ERβ1 binds to and opposes the transcriptional activity of mutant p53 at the promoters of genes that regulate metastasis. p63 that transcriptionally cooperates with mutant p53 also binds to ERβ1. Downregulation of p63 represses the epithelial phenotype of ERβ1-expressing cells and alters the expression of mutant p53 target genes. These results describe a novel mechanism through which ERβ1 can disturb oncogenic signals to inhibit aggressiveness in TNBCs.

Unfolded protein response (UPR) is an adaptive reaction that allows cancer cells to survive endoplasmic reticulum (EnR) stress that is often induced in the tumor microenvironment because of inadequate vascularization. Previous studies report an association between activation of the UPR and reduced sensitivity to antiestrogens and chemotherapeutics in estrogen receptor α (ERα)-positive and triple-negative breast cancers, respectively. ERα has been shown to regulate the expression of a key mediator of the EnR stress response, the X-box-binding protein-1 (XBP-1). Although network prediction models have associated ERβ with the EnR stress response, its role as regulator of the UPR has not been experimentally tested. Here, upregulation of wild-type ERβ (ERβ1) or treatment with ERβ agonists enhanced apoptosis in breast cancer cells in the presence of pharmacological inducers of EnR stress. Targeting the BCL-2 to the EnR of the ERβ1-expressing cells prevented the apoptosis induced by EnR stress but not by non-EnR stress apoptotic stimuli indicating that ERβ1 promotes EnR stress-regulated apoptosis. Downregulation of inositol-requiring kinase 1α (IRE1α) and decreased splicing of XBP-1 were associated with the decreased survival of the EnR-stressed ERβ1-expressing cells. ERβ1 was found to repress the IRE1 pathway of the UPR by inducing degradation of IRE1α. These results suggest that the ability of ERβ1 to target the UPR may offer alternative treatment strategies for breast cancer.

Metastasis to bones is determined by both intrinsic traits of metastatic tumor cells as well as properties appertaining to the bone microenvironment. Bone marrow niches are critical for all major steps of metastasis, including the seeding of disseminated tumor cells (DTCs) to bone, the survival of microscopic metastases under dormancy and the eventual outgrowth of overt metastases. In this review, we discuss the role of bone marrow niches in bone colonization. The emphasis is on complicated and dynamic nature of cancer cells-niche interaction, which may underpin the long-standing mystery of metastasis dormancy, and represent a therapeutic target for elimination of minimal residue diseases and prevention of life-taking, overt metastases.

Bone metastasis is a prominent cause of morbidity and mortality in cancer. High rates of bone colonization in breast cancer, especially in the subtype expressing estrogen receptors (ERs), suggests tissue-specific proclivities for metastatic tumor formation. The mechanisms behind this subtype-specific organ-tropism remains largely elusive. Interestingly, as the major driver of ER+ breast cancer, ERs also play important roles in bone development and homeostasis. Thus, any agents targeting ER will also inevitably affect the microenvironment, i.e., the osteoblasts and osteoclasts. Yet, how such microenvironmental effects are integrated with direct therapeutic responses of cancer cells remain poorly understood. Recent findings on ER mutations, especially their enrichment in bone metastasis, raised even more provocative questions on the role of ER in cancer-bone interaction. In this review, we evaluate the importance of estrogen receptors (ERs) in bone metastasis and discuss new avenues of investigation for bone metastasis treatment based on current knowledge.