ABSTRACT
Estrogen receptor (ER)-positive luminal breast cancer is a subtype with generally lower risk of metastasis to most distant organs. However, bone recurrence occurs preferentially in luminal breast cancer. The mechanisms of this subtype-specific organotropism remain elusive. Here we show that an ER-regulated secretory protein SCUBE2 contributes to bone tropism of luminal breast cancer. Single-cell RNA sequencing analysis reveals osteoblastic enrichment by SCUBE2 in early bone-metastatic niches. SCUBE2 facilitates release of tumor membrane-anchored SHH to activate Hedgehog signaling in mesenchymal stem cells, thus promoting osteoblast differentiation. Osteoblasts deposit collagens to suppress NK cells via the inhibitory LAIR1 signaling and promote tumor colonization. SCUBE2 expression and secretion are associated with osteoblast differentiation and bone metastasis in human tumors. Targeting Hedgehog signaling with Sonidegib and targeting SCUBE2 with a neutralizing antibody both effectively suppress bone metastasis in multiple metastasis models. Overall, our findings provide a mechanistic explanation for bone preference in luminal breast cancer metastasis and new approaches for metastasis treatment.
Subject(s)
Breast Neoplasms , Humans , Female , Hedgehog Proteins/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Calcium-Binding Proteins , Signal Transduction , Cell Line, TumorABSTRACT
Bone is a common site of metastasis in lung cancer, but the regulatory mechanism remains incompletely understood. Osteoclasts are known to play crucial roles in osteolytic bone metastasis by digesting bone matrix and indirectly enhancing tumor colonization. In this study, we found that IL receptor 20 subunit ß (IL-20RB) mediated a direct tumoral response to osteoclasts. Tumoral expression of IL-20RB was associated with bone metastasis of lung cancer, and functionally, IL-20RB promoted metastatic growth of lung cancer cells in bone. Mechanistically, tumor cells induced osteoclasts to secrete the IL-20RB ligand IL-19, and IL-19 stimulated IL-20RB-expressing tumor cells to activate downstream JAK1/STAT3 signaling, leading to enhanced proliferation of tumor cells in bone. Importantly, blocking IL-20RB with a neutralizing antibody significantly suppressed bone metastasis of lung cancer. Overall, our data revealed a direct protumor role of osteoclastic niche in bone metastasis and supported IL-20RB-targeting approaches for metastasis treatment.
Subject(s)
Bone Neoplasms , Lung Neoplasms , Antibodies, Neutralizing , Bone Neoplasms/pathology , Cell Line, Tumor , Humans , Ligands , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Neoplasm Metastasis/pathology , Osteoclasts/metabolismABSTRACT
Giant cell tumor of bone (GCTB) is an aggressive osteolytic bone tumor characterized by the within-tumor presence of osteoclast-like multinucleated giant cells (MGCs), which are induced by the neoplastic stromal cells and lead to extensive bone destruction. However, the underlying mechanism of the pathological process of osteoclastogenesis in GCTB is poorly understood. Here we show that the proteoglycan Serglycin (SRGN) secreted by neoplastic stromal cells plays a crucial role in the formation of MGCs and tumorigenesis in GCTB. Upregulated SRGN expression and secretion are observed in GCTB tumor cells and patients. Stromal-derived SRGN promotes osteoclast differentiation from monocytes. SRGN knockdown in stromal cells inhibits tumor growth and bone destruction in a patient-derived orthotopic xenograft model of mice. Mechanistically SRGN interacts with CD44 on the cell surface of monocytes and thus activates focal adhesion kinase (FAK), leading to osteoclast differentiation. Importantly, blocking CD44 with a neutralizing antibody reduces the number of MGCs and suppresses tumorigenesis in vivo. Overall, our data reveal a mechanism of MGC induction in GCTB and support CD44-targeting approaches for GCTB treatment.
Subject(s)
Giant Cell Tumor of Bone/metabolism , Giant Cell Tumor of Bone/pathology , Osteogenesis , Proteoglycans/metabolism , Vesicular Transport Proteins/metabolism , Animals , Antibodies, Neutralizing/pharmacology , Carcinogenesis/drug effects , Carcinogenesis/genetics , Carcinogenesis/pathology , Cell Differentiation/drug effects , Cell Differentiation/genetics , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/genetics , Enzyme Activation/drug effects , Focal Adhesion Protein-Tyrosine Kinases/metabolism , Gene Expression Regulation, Neoplastic/drug effects , Giant Cell Tumor of Bone/genetics , Giant Cells/drug effects , Giant Cells/metabolism , Giant Cells/pathology , Humans , Hyaluronan Receptors/metabolism , Male , Mice , Mice, Inbred NOD , Mice, SCID , Osteogenesis/drug effects , Osteogenesis/genetics , Osteosarcoma/genetics , Osteosarcoma/pathology , Proteoglycans/genetics , RAW 264.7 Cells , Up-Regulation/drug effects , Up-Regulation/genetics , Vesicular Transport Proteins/geneticsABSTRACT
Lung metastasis is the major cause of breast cancer-related mortality. The neutrophil-associated inflammatory microenvironment aids tumor cells in metastatic colonization in lungs. Here, we show that tumor-secreted protease cathepsin C (CTSC) promotes breast-to-lung metastasis by regulating recruitment of neutrophils and formation of neutrophil extracellular traps (NETs). CTSC enzymatically activates neutrophil membrane-bound proteinase 3 (PR3) to facilitate interleukin-1ß (IL-1ß) processing and nuclear factor κB activation, thus upregulating IL-6 and CCL3 for neutrophil recruitment. In addition, the CTSC-PR3-IL-1ß axis induces neutrophil reactive oxygen species production and formation of NETs, which degrade thrombospondin-1 and support metastatic growth of cancer cells in the lungs. CTSC expression and secretion are associated with NET formation and lung metastasis in human breast tumors. Importantly, targeting CTSC with compound AZD7986 effectively suppresses lung metastasis of breast cancer in a mouse model. Overall, our findings reveal a mechanism of how tumor cells regulate neutrophils in metastatic niches and support CTSC-targeting approaches for cancer treatment.
Subject(s)
Breast Neoplasms/metabolism , Cathepsin C/metabolism , Extracellular Traps/metabolism , Lung Neoplasms/metabolism , Neutrophil Infiltration/physiology , Neutrophils/metabolism , Animals , Breast Neoplasms/pathology , Cell Line, Tumor , Female , Humans , Interleukin-1beta/metabolism , Interleukin-6/metabolism , Lung Neoplasms/pathology , Mice , Mice, Inbred BALB C , Mice, Nude , Neutrophils/pathology , Reactive Oxygen Species/metabolism , Tumor Microenvironment/physiologyABSTRACT
In order to explore the factors affecting coal spontaneous combustion, the fractal characteristics of coal samples are tested, and a pore-scale model for oxygen adsorption in coal porous media is developed based on self-similar fractal model. The liquid nitrogen adsorption experiments show that the coal samples indicate evident fractal scaling laws at both low-pressure and high-pressure sections, and the fractal dimensions, respectively, represent surface morphology and pore structure of coal rock. The pore-scale model has been validated by comparing with available experimental data and numerical simulation. The present numerical results indicate that the oxygen adsorption depends on both the pore structures and temperature of coal rock. The oxygen adsorption increases with increased porosity, fractal dimension and ratio of minimum to maximum pore sizes. The edge effect can be clearly seen near the cavity/pore, where the oxygen concentration is low. The correlation between the oxygen adsorption and temperature is found to obey Langmuir adsorption theory, and a new formula for oxygen adsorption and porosity is proposed. This study may help understanding the mechanisms of oxygen adsorption and accordingly provide guidelines to lower the risk of spontaneous combustion of coal.
