Differential bone morphology and hypoxia activity in skeletal metastases of ER and ER breast cancer.

Bone metastases occur in the majority of advanced breast cancer patients, and the most common complications are osteolytic bone metastases. However, due to the limitations of models and methodologies for bone metastasis studies, the intricacies of bone metastasis have not been fully acknowledged and revealed in prior work. Our earlier study indicated that certain breast cancer cells undergo a pre-osteolytic stage before the establishment of overt metastatic lesions.

The bone microenvironment increases phenotypic plasticity of ER breast cancer cells.

Estrogen receptor-positive (ER) breast cancer exhibits a strong bone tropism in metastasis. How the bone microenvironment (BME) impacts ER signaling and endocrine therapy remains poorly understood. Here, we discover that the osteogenic niche transiently and reversibly reduces ER expression and activities specifically in bone micrometastases (BMMs), leading to endocrine resistance.

The bone microenvironment invigorates metastatic seeds for further dissemination.

Metastasis has been considered as the terminal step of tumor progression. However, recent genomic studies suggest that many metastases are initiated by further spread of other metastases. Nevertheless, the corresponding pre-clinical models are lacking, and underlying mechanisms are elusive.

Hormonal modulation of ESR1 mutant metastasis.

Estrogen receptor alpha gene (ESR1) mutations occur frequently in ER-positive metastatic breast cancer, and confer clinical resistance to aromatase inhibitors. Expression of the ESR1 Y537S mutation induced an epithelial-mesenchymal transition (EMT) with cells exhibiting enhanced migration and invasion potential in vitro. When small subpopulations of Y537S ESR1 mutant cells were injected along with WT parental cells, tumor growth was enhanced with mutant cells becoming the predominant population in distant metastases.

Resistance to natural killer cell immunosurveillance confers a selective advantage to polyclonal metastasis.

Polyclonal metastases frequently arise from clusters of circulating tumor cells (CTCs). CTC clusters metastasize better than single CTCs, but the underlying molecular mechanisms are poorly understood. Here, we show that polyclonal metastatic seeds exhibit higher resistance to natural killer (NK) cell killing.

Immuno-subtyping of breast cancer reveals distinct myeloid cell profiles and immunotherapy resistance mechanisms.

Cancer-induced immune responses affect tumour progression and therapeutic response. In multiple murine models and clinical datasets, we identified large variations of neutrophils and macrophages that define 'immune subtypes' of triple-negative breast cancer (TNBC), including neutrophil-enriched (NES) and macrophage-enriched subtypes (MES). Different tumour-intrinsic pathways and mutual regulation between macrophages (or monocytes) and neutrophils contribute to the development of a dichotomous myeloid compartment.

Bone Metastasis: Find Your Niche and Fit in.

Metastasis to bones is determined by both intrinsic traits of metastatic tumor cells and 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 DTCs and 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.

EMT in Metastasis: Finding the Right Balance.

The epithelial-to-mesenchymal transition (EMT) is a key driver of cancer metastasis. In this issue of Developmental Cell, Aiello et al. (2018) demonstrate that an EMT mechanism involving protein internalization impacts cell migration, while Reichert et al.

Perspective on Circulating Tumor Cell Clusters: Why It Takes a Village to Metastasize.

Circulating tumor cell (CTC) clusters may represent one of the key mechanisms initiating the metastasis process. However, the series of pathophysiologic events by which CTC clusters originate, enter the circulation, and reach the distant sites remain to be identified. The cellular and molecular mechanisms that provide survival advantage for CTC clusters during the transit in the blood stream are also still largely unknown.

Mapping bone marrow niches of disseminated tumor cells.

Breast cancer cells may disseminate early, before tumor diagnosis. Disseminated tumor cells, or DTCs, reside in the bone marrow, and may persist for years or even decades. Some of these cells may be re-activated to resume aggressive growth, and eventually become overt bone metastases.

Bone-in-culture array as a platform to model early-stage bone metastases and discover anti-metastasis therapies.

The majority of breast cancer models for drug discovery are based on orthotopic or subcutaneous tumours. Therapeutic responses of metastases, especially microscopic metastases, are likely to differ from these tumours due to distinct cancer-microenvironment crosstalk in distant organs. Here, to recapitulate such differences, we established an ex vivo bone metastasis model, termed bone-in-culture array or BICA, by fragmenting mouse bones preloaded with breast cancer cells via intra-iliac artery injection.

Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming.

Blockade of angiogenesis can retard tumour growth, but may also paradoxically increase metastasis. This paradox may be resolved by vessel normalization, which involves increased pericyte coverage, improved tumour vessel perfusion, reduced vascular permeability, and consequently mitigated hypoxia. Although these processes alter tumour progression, their regulation is poorly understood.