Brain metastases (BrMs) are a common occurrence in lung cancer with a dismal outcome. To understand the mechanism of metastasis to inform prognosis and treatment, here we analyze primary and metastasized tumor specimens from 44 non-small cell lung cancer patients by spatial RNA sequencing, affording a whole transcriptome map of metastasis resolved with morphological markers for the tumor core, tumor immune microenvironment (TIME), and tumor brain microenvironment (TBME). Our data indicate that the tumor microenvironment (TME) in the brain, including the TIME and TBME, undergoes extensive remodeling to create an immunosuppressive and fibrogenic niche for the BrMs. Specifically, the brain TME is characterized with reduced antigen presentation and B/T cell function, increased neutrophils and M2-type macrophages, immature microglia, and reactive astrocytes. Differential gene expression and network analysis identify fibrosis and immune regulation as the major functional modules disrupted in both the lung and brain TME. Besides providing systems-level insights into the mechanism of lung cancer brain metastasis, our study uncovers potential prognostic biomarkers and suggests that therapeutic strategies should be tailored to the immune and fibrosis status of the BrMs.

Epilepsy affects approximately 50 million people worldwide, with 60% of adult epilepsies presenting an onset of focal origin. The most common focal epilepsy is temporal lobe epilepsy (TLE). The role of astrocytes in the presentation and development of TLE has been increasingly studied and discussed within the literature. The most common histopathological diagnosis of TLE is hippocampal sclerosis. Hippocampal sclerosis is characterized by neuronal cell loss within the Cornu ammonis and reactive astrogliosis. In some cases, mossy fiber sprouting may be observed. Mossy fiber sprouting has been controversial in its contribution to epileptogenesis in TLE patients, and the mechanisms surrounding the phenomenon have yet to be elucidated. Several studies have reported that mossy fiber sprouting has an almost certain co-existence with reactive astrogliosis within the hippocampus under epileptic conditions. Astrocytes are known to play an important role in the survival and axonal outgrowth of central and peripheral nervous system neurons, pointing to a potential role of astrocytes in TLE and associated cellular alterations. Herein, we review the recent developments surrounding the role of astrocytes in the pathogenic process of TLE and mossy fiber sprouting, with a focus on proposed signaling pathways and cellular mechanisms, histological observations, and clinical correlations in human patients.

Background Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and the human papillomavirus (HPV+)-driven subtype is the fastest rising cancer in North America. Although most cases of HPV+ HNSCC respond favorably to the treatment via surgery followed by radiochemotherapy, up to 20% recur with a poor prognosis. The molecular and cellular mechanisms of recurrence are not fully understood. Methods To gain insights into the mechanisms of recurrence and to inform patient stratification and personalized treatment, we compared the proteome and phosphoproteome of recurrent and non-recurrent tumors by quantitative mass spectrometry. Results We observe significant differences between the recurrent and non-recurrent tumors in cellular composition, function, and signaling. The recurrent tumors are characterized by a pro-fibrotic and immunosuppressive tumor microenvironment (TME) featuring markedly more abundant cancer-associated fibroblasts, extracellular matrix (ECM), neutrophils, and suppressive myeloid cells. Defective T cell function and increased epithelial-mesenchymal transition potential are also associated with recurrence. These cellular changes in the TME are accompanied by reprogramming of the kinome and the signaling networks that regulate the ECM, cytoskeletal reorganization, cell adhesion, neutrophil function, and coagulation. Conclusions In addition to providing systems-level insights into the molecular basis of recurrence, our work identifies numerous mechanism-based, candidate biomarkers and therapeutic targets that may aid future endeavors to develop prognostic biomarkers and precision-targeted treatment for recurrent HPV+ HNSCC.

Brain metastases (BM) are responsible for the majority of cancer mortality. Breast cancer is one of the most common primary sites for brain metastasis. Metastatic cancer cells are known to diverge genetically and phenotypically from their primary counterpart. Together with the unique tumor brain microenvironment (TBME), this poses additional challenges in the treatment of BM. METHODS: We identified 30 cases of patient-paired, surgically resected brain metastasis with breast origin. Six cases of non-tumoral brain control were also included. Two tissue microarray (TMA) blocks were constructed to include all cases. Spatial RNAseq was performed while PanCK, CD45, and GFAP were used as morphology markers to annotate the regions of interest (ROIs). For each patient, five ROIs were analyzed: primary breast cancer (BC), primary breast cancer microenvironment (BCME), metastatic tumor cells (MTC), immediate TBME (iTBME), and distant TBME (dTBME). RESULTS: 1) Triple-negative breast cancers (TNBC) demonstrated distinct gene signatures in both primary and metastatic sites. 2) There were 9 BC shifted their genetic profiles and were reclassified into different molecular subtypes at their matched brain metastatic site. Functional enrichment analysis revealed enriched EMT, ECM-receptor interaction, and the complement system in these profile shifting-BC cases. In contrast, the BC cases that preserved their original profiles (non-shifting BC) shared upregulated pathways of ribosome biogenesis and cell cycle. 3) TBME underwent cellular and molecular plasticity characterized by elevated neutrophils, reactive astrocytes, and activated microglia. In the TBME homing TNBC, cancer-associated fibroblasts (CAF) represented a hub in the cellular interaction between MTCs and TBME.

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