Distinct tumor architectures and microenvironments for the initiation of breast cancer metastasis in the brain

Cancer Cell, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 1, 2024

Language: Английский

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Harnessing immunotherapy for brain metastases: insights into tumor–brain microenvironment interactions and emerging treatment modalities

Journal of Hematology & Oncology, Journal Year: 2023, Volume and Issue: 16(1)

Published: Dec. 16, 2023

Abstract Brain metastases signify a deleterious milestone in the progression of several advanced cancers, predominantly originating from lung, breast and melanoma malignancies, with median survival timeframe nearing six months. Existing therapeutic regimens yield suboptimal outcomes; however, burgeoning insights into tumor microenvironment, particularly immunosuppressive milieu engendered by tumor–brain interplay, posit immunotherapy as promising avenue for ameliorating brain metastases. In this review, we meticulously delineate research advancements concerning microenvironment metastases, striving to elucidate panorama their onset evolution. We encapsulate three emergent immunotherapeutic strategies, namely immune checkpoint inhibition, chimeric antigen receptor (CAR) T cell transplantation glial cell-targeted immunoenhancement. underscore imperative aligning development in-depth understanding engendering innovative delivery platforms. Moreover, integration established or avant-garde physical methodologies localized applications warrants consideration prevailing schema.

Language: Английский

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Utilizing human cerebral organoids to model breast cancer brain metastasis in culture

Breast Cancer Research, Journal Year: 2024, Volume and Issue: 26(1)

Published: July 1, 2024

Abstract Background Metastasis, the spread, and growth of malignant cells at secondary sites within a patient’s body, accounts for over 90% cancer-related mortality. Breast cancer is most common tumor type diagnosed leading cause lethality in women United States. It estimated that 10–16% breast patients will have brain metastasis. Current therapies to treat with metastasis (BCBM) remain palliative. This largely due our limited understanding fundamental molecular cellular mechanisms through which BCBM progresses, represents critical barrier development efficient affected patients. Methods Previous research relied on co-culture assays rodent neural or slice ex vivo. Given need overcome obstacle human-relevant host study cell-cell communication BCBM, we generated human embryonic stem cell-derived cerebral organoids cell lines. We used MDA-MB-231 its metastatic derivate Br-EGFP, other lines MCF-7, HCC-1806, SUM159PT. leveraged this novel 3D platform investigate crosstalk organoid. Results found SUM159PT formed colonies organoids. Moreover, Br-EGFP showed increased capacity invade expand Conclusions Our model has demonstrated remarkable discern ability The generation BCBM-like structures organoid facilitate microenvironment culture.

Language: Английский

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The Immune Landscape in Brain Metastasis

Neuro-Oncology, Journal Year: 2024, Volume and Issue: 27(1), P. 50 - 62

Published: Oct. 14, 2024

Abstract The prognosis for patients with brain metastasis remains dismal despite intensive therapy including surgical resection, radiotherapy, chemo-, targeted, and immunotherapy. Thus, there is a high medical need new therapeutic options. Recent advances employing high-throughput spatially resolved single-cell analyses have provided unprecedented insights into the composition phenotypes of diverse immune cells in metastatic brain, revealing unique landscape starkly different from that primary tumors or other sites. This review summarizes current evidence on most prominent niche, along their dynamic interactions tumor each other. As abundant cell types this we explore detail phenotypic heterogeneity functional plasticity tumor-associated macrophages, both resident microglia monocyte-derived as well T-cell compartment. We also preclinical clinical trials evaluating potential targeting microenvironment metastasis. Given substantial highlighting significant role microenvironmental niche pathogenesis, comprehensive understanding key molecular cellular factors within holds great promise developing novel approaches innovative combinatory treatment strategies

Language: Английский

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Unsupervised clustering reveals noncanonical myeloid cell subsets in the brain tumor microenvironment

Cancer Immunology Immunotherapy, Journal Year: 2025, Volume and Issue: 74(2)

Published: Jan. 3, 2025

Abstract The tumor immune microenvironment (TiME) of human central nervous system (CNS) tumors remains to be comprehensively deciphered. Here, we employed flow cytometry and RNA sequencing analysis for a deep data-driven dissection diverse TiME uncover noncanonical cell types in CNS by using seven from five patients. Myeloid subsets comprised classical microglia, monocyte-derived macrophages, neutrophils, two myeloid subsets: CD3 + myeloids CD19 myeloids. T lymphocyte included double-negative (CD4 − CD8 ) cells (DNTs). Noncanonical DNTs were explored on independent datasets, suggesting that our DNT phenotype represents γδ cells. validated orthogonal methods across 73 patients three datasets. While the proportions agreed with reported malignancy type-associated TiMEs, unexpectedly high frequencies detected gliosarcoma, which also showed unique expression pattern immune-related genes. Our findings highlight potential approaches resolving reveal mosaic constituting TiME, warranting need future studies nonclassical subsets.

Language: Английский

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Habitat‐based MRI radiomics to predict the origin of brain metastasis

Medical Physics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 6, 2025

Abstract Background This study aims to explore the value of habitat‐based magnetic resonance imaging (MRI) radiomics for predicting origin brain metastasis (BM). Purpose To investigate whether can identify metastatic tumor type BM and an imaging‐based model that integrates volume peritumoral edema (VPE) enhance predictive performance. Methods A primary cohort was developed with 384 patients from two centers, which comprises 734 lesions. An independent 28 a third center, 70 All underwent T1‐weighted contrast‐enhanced (T1CE) T2‐weighted (T2W) MRI scans before treatment. Radiomics features were extracted active area (TAA) (PEA) selected using least absolute shrinkage selection operator (LASSO) construct signatures (Rads). The Rads further integrated VPE build combined models BM. Performance assessed through receiver operating characteristic (ROC) curve analysis. Results derived TAA PEA both showed power identifying generated best performance in training (AUCs, lung cancer [LC]/non‐lung [NLC] vs. small cell [SCLC]/non‐small [NSCLC] breast [BC]/gastrointestinal [GIC], 0.870 0.946 0.886), internal validation (area under curves [AUCs], LC/NLC SCLC/NSCLC BC/GIC, 0.786 0.863 0.836) external LC /NLC 0.805 0.877 0.774) cohort. Conclusions effectively may be considered as potential preoperative basis timely treatment planning.

Language: Английский

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Genomic and Immune Landscape of Non–Small Cell Lung Cancer Brain Metastases

JCO Precision Oncology, Journal Year: 2025, Volume and Issue: 9

Published: Jan. 1, 2025

PURPOSE Metastatic spread of non–small cell lung cancer (NSCLC) to the brain is a commonly occurring and challenging clinical problem, often resulting in patient mortality. Systemic therapies including immunotherapy have modest efficacy treating metastases. Moreover, local immune environment metastases remains poorly described. This study aims understand genomic landscape NSCLC METHODS A total 3,060 patients with sequenced Strata Select assay on Oncology Platform were analyzed. Genomic alterations, tumor mutation burden (TMB), PD-L1 expression, gene expression compared across different tissue sites histologies within RESULTS significant increase TMB was observed metastasis samples nonbrain samples. Mutations TP53 , KRAS CDKNA2A more prevalent cohort other locations. In addition, significantly decreased sites. The overall largely reduced primary However, an immune-enriched identified higher expressions immune-related genes. CONCLUSION increased associated markedly diminished landscape. identification subgroup suggests potential heterogeneity cohort, which might implications for development targeted therapies.

Language: Английский

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Practice Variation in Perioperative Dexamethasone Use and Outcomes in Brain Metastasis Resection

JAMA Network Open, Journal Year: 2025, Volume and Issue: 8(4), P. e254689 - e254689

Published: April 11, 2025

Importance Variations in perioperative dexamethasone dosing are common brain metastasis resection, but their impact on patient outcomes remains unclear. Objective To evaluate the association between and outcomes, focusing overall survival (OS) progression-free (PFS). Design, Setting, Participants This retrospective multicenter comparative effectiveness study used data collected from January 2010 to December 2023. Patients with symptomatic metastases undergoing primary surgical resection at 7 neurological centers Germany 1 Austria who had complete records of were included. Propensity score matching (PSM) was control for confounders. Analysis conducted March June 2024. Exposures Cumulative administration over 27 days, dichotomized 122 mg using maximally selected rank statistics. Main Outcomes Measures The outcome OS. Secondary included extracranial PFS (ecPFS) intracranial (icPFS) as well incidence wound revision surgery after resection. Hazard ratios (HRs) calculated Cox proportional hazards models. Results A total 1064 patients analysis. median (IQR) age 64 (56-72) years, 489 female (49%) 541 male (51%). Non–small cell lung cancer (NSCLC) most tumor entity (564 [53%]), followed by breast (146 [14%]) melanoma (138 [13%]). After PSM, receiving cumulative doses less than a OS 19.1 (95% CI, 15.2-22.4) months compared 12.0 9.1-14.7) those or more ( P = .002). Multivariable analysis showed an independent higher reduced (HR, 1.40; 95% 1.18-1.66; < .001). analyses demonstrated consistent findings icPFS ecPFS dose-response hazard death. Conclusions Relevance In this study, associated OS, icPFS, These suggest that stricter protocols could improve outcomes. Prospective trials warranted confirm these associations guide evidence-based practice.

Language: Английский

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Harnessing human iPSC-microglia for CNS-wide delivery of disease-modifying proteins

Cell stem cell, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Widespread delivery of therapeutic proteins to the brain remains challenging. To determine whether human induced pluripotent stem cell (iPSC)-microglia (iMG) could enable brain-wide and pathology-responsive cargo, we utilized CRISPR gene editing engineer iMG express Aβ-degrading enzyme neprilysin under control plaque-responsive promoter, CD9. further increased engraftment enhances efficacy, a CSF1R-inhibitor resistance approach. Interestingly, both localized in Alzheimer's disease (AD) mice reduced multiple biochemical measures pathology. However, within plaque-dense subiculum, reductions plaque load, dystrophic neurites, astrogliosis preservation neuronal density were only achieved following widespread microglial engraftment. Lastly, examined chimeric models breast cancer metastases demyelination, demonstrating that adopt diverse transcriptional responses differing neuropathologies, which be harnessed therapeutics CNS.

Language: Английский

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Integrated analysis of molecular and clinical features associated with overall survival in melanoma patients with brain metastasis

Acta Neuropathologica Communications, Journal Year: 2025, Volume and Issue: 13(1)

Published: April 14, 2025

Language: Английский

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