Unlocking molecular mechanisms and identifying druggable targets in matched-paired brain metastasis of breast and lung cancers

Shiva Najjary; Willem de Koning; Johan M Kros; Dana A M Mustafa

doi:10.3389/fimmu.2023.1305644

Unlocking molecular mechanisms and identifying druggable targets in matched-paired brain metastasis of breast and lung cancers

Front Immunol. 2023 Dec 12:14:1305644. doi: 10.3389/fimmu.2023.1305644. eCollection 2023.

Authors

Shiva Najjary¹, Willem de Koning¹, Johan M Kros¹, Dana A M Mustafa¹

Affiliation

¹ Department of Pathology and Clinical Bioinformatics, The Tumor Immuno-Pathology Laboratory, Erasmus University Medical Center, Rotterdam, Netherlands.

Abstract

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.

Keywords: brain metastasis; breast cancer; gene expression; lung adenocarcinoma; molecular mechanisms.

MeSH terms

Adenocarcinoma of Lung* / drug therapy
Adenocarcinoma of Lung* / genetics
Adenocarcinoma of Lung* / pathology
Brain Neoplasms* / pathology
Breast Neoplasms* / drug therapy
Breast Neoplasms* / genetics
Breast Neoplasms* / pathology
Female
Humans
Lung Neoplasms* / drug therapy
Lung Neoplasms* / genetics
Lung Neoplasms* / pathology
Prognosis

Grants and funding

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.