Department of Pathology and Clinical Bioinformatics, The Tumor Immuno-Pathology Laboratory, Erasmus University Medical Center, Rotterdam, Netherlands.
Front Immunol. 2023 Dec 12;14:1305644. doi: 10.3389/fimmu.2023.1305644. eCollection 2023.
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.
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.
Our results revealed the significant upregulation of cancer-related genes in primary tumors compared to their matched-paired brain metastases (adj. ≤ 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.
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.
癌症患者的脑转移发生率正在增加，其中肺癌和乳腺癌是最常见的来源。尽管靶向治疗取得了进展，但预后仍然较差，这凸显了研究脑转移潜在机制的重要性。本研究旨在探讨乳腺癌和肺癌脑转移中涉及的分子机制的差异。此外，我们旨在确定脑转移中癌症谱系特异性的可用药靶。
为此，收集了 44 份 FFPE 组织样本，包括 22 例乳腺癌和 22 例肺腺癌（LUAD）及其配对的脑转移。使用 NanoString 技术的 nCounter PanCancer IO 360 面板比较原发性肿瘤的靶向基因表达谱与其配对的脑转移样本。使用基因集分析（GSA）和基因集富集分析（GSEA）进行通路分析。通过免疫组织化学（IHC）验证来验证免疫检查点抑制剂的表达。
我们的结果显示，与配对的脑转移相比，原发性肿瘤中癌症相关基因显著上调（adj. ≤ 0.05）。我们发现，乳腺癌脑转移（BM-BC）和肺腺癌脑转移（BM-LUAD）中上调的差异表达基因与代谢应激途径有关，特别是与糖酵解有关。此外，我们发现 BM-BC 和 BM-LUAD 中上调的基因在免疫反应调节、肿瘤生长和增殖中发挥作用。重要的是，我们发现免疫检查点 VTCN1 在 BM-BC 中高表达，而 VISTA、IDO1、NT5E 和 HDAC3 在 BM-LUAD 中高表达。免疫组织化学验证进一步支持了这些发现。
总之，这些发现强调了使用配对样本来确定癌症谱系特异性治疗方法的重要性，这可能会改善脑转移患者的预后。
