Cellular architecture of human brain metastases.

Brain metastasis (BrM) is the most common form of brain cancer, characterized by neurologic disability and an abysmal prognosis. Unfortunately, our understanding of the biology underlying human BrMs remains rudimentary. Here, we present an integrative analysis of >100,000 malignant and non-malignant cells from 15 human parenchymal BrMs, generated by single-cell transcriptomics, mass cytometry, and complemented with mouse model- and in silico approaches. We interrogated the composition of BrM niches, molecularly defined the blood-tumor interface, and revealed stromal immunosuppressive states enriched with infiltrated T cells and macrophages. Specific single-cell interrogation of metastatic tumor cells provides a framework of 8 functional cell programs that coexist or anticorrelate. Collectively, these programs delineate two functional BrM archetypes, one proliferative and the other inflammatory, that are evidently shaped through tumor-immune interactions. Our resource provides a foundation to understand the molecular basis of BrM in patients with tumor cell-intrinsic and host environmental traits.

Negative feedback of NF-κB signaling by long noncoding RNA MALAT1 controls lipopolysaccharide-induced inflammation injury in human lung fibroblasts WI-38.

The study was designed to elucidate the regulatory mechanism of long noncoding RNA human metastasis associated lung adenocarcinoma transcript 1 (MALAT1) in lipopolysaccharides (LPS)-caused inflammation injury in human lung fibroblasts WI-38. WI-38 cells were stimulated with LPS to construct acute pneumonia cell model. MALAT1 in LPS-stimulated WI-38 cells was examined. LPS-induced inflammation injury was estimated using viability, apoptosis, and cytokine secretion including interleukin-1ß (IL-1ß) and IL-6. Furthermore, the modulatory relations of MALAT1 and nuclear factor-kappa B (NF-κB) signaling were explored. We found that the sensitivity of WI-38 cells to apoptosis was enhanced by LPS-caused inflammation. Moreover, LPS promoted MALAT1 expression which was found to alleviate LPS-caused damages. Besides, NF-κB p65 overexpression resulted in an increased expression of MALAT1, and MALAT1 was identified as a target gene of p65. Furthermore, overexpression of MALAT1 reduced NF-κB activation. Pulldown assay showed that MALAT1 could directly interact with p65. Taken together, our findings revealed that MALAT1 was upregulated in LPS-stimulated WI-38 cells. Through directly interacting with p65, MALAT1 blocked LPS-caused activation of NF-κB and repressed LPS-induced inflammation injury. MALAT1 may serve as a potential diagnostic indicator or therapeutic target for pneumonia.