Single-cell and spatial genomic landscape of non-small cell lung cancer brain metastases

Nature Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 27, 2025

Language: Английский

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Exploring the Impact of TREM2 in Tumor-Associated Macrophages

Vaccines, Journal Year: 2022, Volume and Issue: 10(6), P. 943 - 943

Published: June 14, 2022

Tumor-associated macrophages (TAMs) represent a key component of the tumor microenvironment and are generally associated with immunosuppression poor prognosis. TREM2 is transmembrane receptor immunoglobulin superfamily expressed in myeloid cells. has been extensively studied microglia neurodegenerative diseases recently emerged as marker pro-tumorigenic macrophages. The accumulation TREM2-expressing TAMs was reported across numerous cancer patients models. genetic blockade or targeting antibodies resulted improved control, enhanced response to anti-PD1, significant changes immune landscape. Preclinical studies paved way for an ongoing clinical trial depleting antibody inspired further exploration therapies. Here, we review current knowledge about impact cancer, emphasis on TREM2+ macrophage signature different types, contribution TAM phenotype function, promising effects modulation.

Language: Английский

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Multimodal single-cell and whole-genome sequencing of small, frozen clinical specimens

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(1), P. 19 - 25

Published: Jan. 1, 2023

Language: Английский

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Phenotypic diversity of T cells in human primary and metastatic brain tumors revealed by multiomic interrogation

Nature Cancer, Journal Year: 2023, Volume and Issue: 4(6), P. 908 - 924

Published: May 22, 2023

Abstract The immune-specialized environment of the healthy brain is tightly regulated to prevent excessive neuroinflammation. However, after cancer development, a tissue-specific conflict between brain-preserving immune suppression and tumor-directed activation may ensue. To interrogate potential roles T cells in this process, we profiled these from individuals with primary or metastatic cancers via integrated analyses on single-cell bulk population levels. Our analysis revealed similarities differences cell biology individuals, most pronounced observed subgroup metastasis, characterized by accumulation CXCL13 -expressing CD39 + potentially tumor-reactive (pTRT) cells. In subgroup, high pTRT abundance was comparable that lung cancer, whereas all other tumors had low levels, similar breast cancer. These findings indicate cell-mediated tumor reactivity can occur certain metastases inform stratification for treatment immunotherapy.

Language: Английский

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Immunogenomic analysis of human brain metastases reveals diverse immune landscapes across genetically distinct tumors

Cell Reports Medicine, Journal Year: 2023, Volume and Issue: 4(1), P. 100900 - 100900

Published: Jan. 1, 2023

Brain metastases (BrMs) are the most common form of brain tumors in adults and frequently originate from lung breast primary cancers. BrMs associated with high mortality, emphasizing need for more effective therapies. Genetic profiling is increasingly used as part effort to guide targeted therapies against BrMs, immune-based strategies treatment metastatic cancer gaining momentum. However, tumor immune microenvironment (TIME) BrM extremely heterogeneous, whether specific genetic profiles distinct states remains unknown. Here, we perform an extensive characterization immunogenomic landscape human by combining whole-exome/whole-genome sequencing, RNA sequencing cell populations, flow cytometry, immunofluorescence staining, tissue imaging analyses. This revealed unique TIME phenotypes genetically lung- breast-BrMs, thereby enabling development personalized immunotherapies tailored makeup tumors.

Language: Английский

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RARRES2 regulates lipid metabolic reprogramming to mediate the development of brain metastasis in triple negative breast cancer

Military Medical Research, Journal Year: 2023, Volume and Issue: 10(1)

Published: July 25, 2023

Triple negative breast cancer (TNBC), the most aggressive subtype of cancer, is characterized by a high incidence brain metastasis (BrM) and poor prognosis. As lethal form BrM remains major clinical challenge due to its rising lack effective treatment strategies. Recent evidence suggested potential role lipid metabolic reprogramming in (BCBrM), but underlying mechanisms are far from being fully elucidated.Through analysis BCBrM transcriptome data mice patients, immunohistochemical validation on patient tissues, we identified verified specific down-regulation retinoic acid receptor responder 2 (RARRES2), multifunctional adipokine chemokine, TNBC. We investigated effect aberrant RARRES2 expression both vitro vivo studies. Key signaling pathway components were evaluated using multi-omics approaches. Lipidomics performed elucidate regulation RARRES2.We found that specifically associated with BCBrM, deficiency promoted through reprogramming. Mechanistically, reduced metastatic TNBC cells resulted increased levels glycerophospholipid decreased triacylglycerols regulating phosphatase tensin homologue (PTEN)-mammalian target rapamycin (mTOR)-sterol regulatory element-binding protein 1 (SREBP1) facilitate survival unique microenvironment.Our work uncovers an essential linking development BrM. RARRES2-dependent functions may serve as biomarkers or therapeutic targets for BCBrM.

Language: Английский

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Type I interferon response in astrocytes promotes brain metastasis by enhancing monocytic myeloid cell recruitment

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: May 6, 2023

Cancer metastasis to the brain is a significant clinical problem. Metastasis consequence of favorable interactions between invaded cancer cells and microenvironment. Here, we demonstrate that cancer-activated astrocytes create sustained low-level activated type I interferon (IFN) microenvironment in metastatic lesions. We further confirm IFN response facilitates metastasis. Mechanistically, signaling activates C-C Motif Chemokine Ligand 2 (CCL2) production, which increases recruitment monocytic myeloid cells. The correlation CCL2 confirmed samples. Lastly, genetically or pharmacologically inhibiting Receptor (CCR2) reduces metastases. Our study clarifies pro-metastatic effect even though has been considered have anti-tumor effects. Moreover, this work expands our understandings on immune

Language: Английский

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Single-cell sequencing reveals the landscape of the human brain metastatic microenvironment

Communications Biology, Journal Year: 2023, Volume and Issue: 6(1)

Published: July 21, 2023

Abstract Brain metastases is the most common intracranial tumor and account for approximately 20% of all systematic cancer cases. It a leading cause death in advanced-stage cancer, resulting five-year overall survival rate below 10%. Therefore, there critical need to identify effective biomarkers that can support frequent surveillance promote efficient drug guidance brain metastasis. Recently, remarkable breakthroughs single-cell RNA-sequencing (scRNA-seq) technology have advanced our insights into microenvironment (TME) at resolution, which offers potential unravel metastasis-related cellular crosstalk provides improving therapeutic effects mediated by multifaceted interactions within TME. In this study, we applied scRNA-seq profiled 10,896 cells collected from five tissue samples originating breast lung cancers. Our analysis reveals presence various intratumoral components, including cells, fibroblasts, myeloid stromal expressing neural stem cell markers, as well minor populations oligodendrocytes T cells. Interestingly, distinct compositions are observed across different samples, indicating influence diverse on infiltration patterns Importantly, tumor-associated fibroblasts both in-house dataset external datasets. These exhibit high expression type I collagen genes, dominate cell-cell TME via signaling axis, facilitate remodeling collagen-I-rich extracellular matrix similar original primary sites. Additionally, observe M1 activation native microglial infiltrated macrophages, may contribute proinflammatory upregulation fibroblasts. Furthermore, cell-specific receptors significant association with patient metastasis glioblastoma Taken together, comprehensive analyses collagen-secreting key mediators metastatic tumors uncover potentially associated survival. discoveries provide targets intervention strategies.

Language: Английский

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TREM2: A new player in the tumor microenvironment

Seminars in Immunology, Journal Year: 2023, Volume and Issue: 67, P. 101739 - 101739

Published: March 28, 2023

Language: Английский

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Active Remodeling of Capillary Endothelium via Cancer Cell–Derived MMP9 Promotes Metastatic Brain Colonization

Cancer Research, Journal Year: 2023, Volume and Issue: 83(8), P. 1299 - 1314

Published: Jan. 18, 2023

Crossing the blood-brain barrier is a crucial, rate-limiting step of brain metastasis. Understanding mechanisms cancer cell extravasation from microcapillaries limited as underlying cellular and molecular processes cannot be adequately investigated using in vitro models endpoint vivo experiments. Using ultrastructural functional imaging, we demonstrate that dynamic changes activated promote mandatory first steps colonization. Successful arrested cells occurred when adjacent capillary endothelial (EC) entered into distinct remodeling process. After extravasation, loops were formed, which was characteristic aggressive metastatic growth. Upon arrest microcapillaries, matrix-metalloprotease 9 (MMP9) expressed. Inhibition MMP2/9 genetic perturbation MMP9 cells, but not host, reduced EC projections, metastasis outgrowth. These findings establish an active role ECs process facilitated by cross-talk between two types. This extends our understanding how host can contribute to formation prevent it.

Language: Английский

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