Dataset Information

Proteomic study in a preclinical lung-derived brain metastasis

ABSTRACT: To study the features of tumor microenvironment (TME) of BM brain metastasis, a proteomic approach has been performed in a preclinical BM model with the human lung adenocarcinoma-derived H2030-BrM3 cells implanted into the cortex and striatum of nude rats. Proteomic analyzes were performed 24 days after tumor cell inoculation. Here, we provided protein expression changes in BM compared to healthy brain tissue with rat analyzes. In total, 8420 proteins were quantified from the 8 samples analyzed.

ORGANISM(S): Rattus Norvegicus

SUBMITTER: Bernaudin Myriam

PROVIDER: PXD040905 | iProX | Wed Mar 15 00:00:00 GMT 2023

REPOSITORIES: iProX

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Publications

Assessment of hypoxia and oxidative-related changes in a lung-derived brain metastasis model by [<sup>64</sup>Cu][Cu(ATSM)] PET and proteomic studies.

Fantin Jade J Toutain Jérôme J Pérès Elodie A EA Bernay Benoit B Mehani Sarina Maya SM Helaine Charly C Bourgeois Mickael M Brunaud Carole C Chazalviel Laurent L Pontin Julien J Corroyer-Dulmont Aurélien A Valable Samuel S Cherel Michel M Bernaudin Myriam M

EJNMMI research 20231125 1

<h4>Background</h4>Brain metastases (BM) are the most frequent malignant brain tumors. The aim of this study was to characterize the tumor microenvironment (TME) of BM and particularly hypoxia and redox state, known to play a role in tumor growth and treatment resistance with multimodal PET and MRI imaging, immunohistochemical and proteomic approaches in a human lung cancer (H2030-BrM3)-derived BM model in rats.<h4>Results</h4>First, in vitro studies confirmed that H2030-BrM3 cells respond to hy ...[more]

PMID: 38006431

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Project description:Metastases in the brain are the most severe and devastating complication of cancer. The incidence of brain metastasis is increasing. Therefore, the need of finding specific druggable targets for brain metastasis is demanding. The aim of this study was to compare the brain (immune) response to brain metastases of the most common tumor lineages, viz., lung adenocarcinoma and breast cancer. Targeted gene expression profiles of 11 brain metastasis of lung adenocarcinoma (BM-LUAD) were compared to 11 brain metastasis of breast cancer (BCBM) using NanoString nCounter PanCancer IO 360™ Panel. The most promising results were validated spatially using the novel GeoMx™ Digital Spatial Profiler (DSP) Technology. Additionally, Immune cell profiles and expression of drug targets were validated by multiplex immunohistochemistry. We found more active immune response in BM-LUAD as compared to BCBM. In the BM-LUAD, 138 genes were upregulated as compared to BCBM (adj. p ≤ 0.05). Conversely, in BCBM 28 genes were upregulated (adj. p ≤ 0.05). Additionally, genes related to CD45+ cells, T cells and cytotoxic T cells showed to be expressed higher in BM-LUAD compared to BCBM (adj. p = 0.01, adj. p = 0.023, adj. p = 0.023, respectively). The spatial quantification of the immune cells using the GeoMx DSP technique revealed the significantly higher quantification of CD14 and CD163 in tumor regions of BM-LUAD as compared to BCBM. Importantly, the immune checkpoint VISTA and IDO1 were identified as highly expressed in the BM-LUAD. Multiplex immunohistochemistry confirmed the finding and showed that VISTA is expressed mainly in BM-LUAD tumor cells, CD3+ cells, and to less levels in some microglial cells in BM-LUAD. This is the first report on differences in the brain immune response between metastatic tumor of different lineages. We found a far more extensive infiltration of immune cells in BM-LUAD as compared to BCBM. In addition, we found higher expression of VISTA and IDO1 in BM-LUAD. Taken together, targeted immune therapy should be considered to treat patients with BM-LUAD.

Project description:Introduction: The incidence of brain metastases in cancer patients is increasing, with lung and breast cancer being the most common sources. Despite advancements in targeted therapies, the prognosis remains poor, highlighting the importance to investigate the underlying mechanisms in brain metastases. The aim of this study was to investigate the differences in the molecular mechanisms involved in brain metastasis of breast and lung cancers. In addition, we aimed to identify cancer lineage-specific druggable targets in the brain metastasis. Methods: To that aim, a cohort of 44 FFPE tissue samples, including 22 breast cancer and 22 lung adenocarcinoma (LUAD) and their matched-paired brain metastases were collected. Targeted gene expression profiles of primary tumors were compared to their matched-paired brain metastases samples using nCounter PanCancer IO 360™ Panel of NanoString technologies. Pathway analysis was performed using gene set analysis (GSA) and gene set enrichment analysis (GSEA). The validation was performed by using Immunohistochemistry (IHC) to confirm the expression of immune checkpoint inhibitors. Results: Our results revealed the significant upregulation of cancer-related genes in primary tumors compared to their matched-paired brain metastases (adj. p ≤ 0.05). We found that upregulated differentially expressed genes in breast cancer brain metastasis (BM-BC) and brain metastasis from lung adenocarcinoma (BM-LUAD) were associated with the metabolic stress pathway, particularly related to the glycolysis. Additionally, we found that the upregulated genes in BM-BC and BM-LUAD played roles in immune response regulation, tumor growth, and proliferation. Importantly, we identified high expression of the immune checkpoint VTCN1 in BM-BC, and VISTA, IDO1, NT5E, and HDAC3 in BM-LUAD. Validation using immunohistochemistry further supported these findings. Conclusion: In conclusion, the findings highlight the significance of using matched-paired samples to identify cancer lineage-specific therapies that may improve brain metastasis patients outcomes.

Dataset Information

Proteomic study in a preclinical lung-derived brain metastasis

Publications

Assessment of hypoxia and oxidative-related changes in a lung-derived brain metastasis model by [<sup>64</sup>Cu][Cu(ATSM)] PET and proteomic studies.

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