Unlocking molecular mechanisms and identifying druggable targets in matched-paired brain metastasis of breast and lung cancers
IntroductionThe 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....
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-12-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1305644/full |
| _version_ | 1797393384835383296 |
|---|---|
| author | Shiva Najjary Willem de Koning Johan M. Kros Dana A. M. Mustafa |
| author_facet | Shiva Najjary Willem de Koning Johan M. Kros Dana A. M. Mustafa |
| author_sort | Shiva Najjary |
| collection | DOAJ |
| description | IntroductionThe 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.MethodsTo 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.ResultsOur 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.ConclusionIn conclusion, the findings highlight the significance of using matched-paired samples to identify cancer lineage-specific therapies that may improve brain metastasis patients outcomes. |
| first_indexed | 2024-03-09T00:01:41Z |
| format | Article |
| id | doaj.art-270604d075a549e693cb32fb468421f8 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-09T00:01:41Z |
| publishDate | 2023-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-270604d075a549e693cb32fb468421f82023-12-12T16:13:31ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-12-011410.3389/fimmu.2023.13056441305644Unlocking molecular mechanisms and identifying druggable targets in matched-paired brain metastasis of breast and lung cancersShiva NajjaryWillem de KoningJohan M. KrosDana A. M. MustafaIntroductionThe 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.MethodsTo 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.ResultsOur 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.ConclusionIn conclusion, the findings highlight the significance of using matched-paired samples to identify cancer lineage-specific therapies that may improve brain metastasis patients outcomes.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1305644/fullmolecular mechanismsbrain metastasisbreast cancerlung adenocarcinomagene expression |
| spellingShingle | Shiva Najjary Willem de Koning Johan M. Kros Dana A. M. Mustafa Unlocking molecular mechanisms and identifying druggable targets in matched-paired brain metastasis of breast and lung cancers Frontiers in Immunology molecular mechanisms brain metastasis breast cancer lung adenocarcinoma gene expression |
| title | Unlocking molecular mechanisms and identifying druggable targets in matched-paired brain metastasis of breast and lung cancers |
| title_full | Unlocking molecular mechanisms and identifying druggable targets in matched-paired brain metastasis of breast and lung cancers |
| title_fullStr | Unlocking molecular mechanisms and identifying druggable targets in matched-paired brain metastasis of breast and lung cancers |
| title_full_unstemmed | Unlocking molecular mechanisms and identifying druggable targets in matched-paired brain metastasis of breast and lung cancers |
| title_short | Unlocking molecular mechanisms and identifying druggable targets in matched-paired brain metastasis of breast and lung cancers |
| title_sort | unlocking molecular mechanisms and identifying druggable targets in matched paired brain metastasis of breast and lung cancers |
| topic | molecular mechanisms brain metastasis breast cancer lung adenocarcinoma gene expression |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1305644/full |
| work_keys_str_mv | AT shivanajjary unlockingmolecularmechanismsandidentifyingdruggabletargetsinmatchedpairedbrainmetastasisofbreastandlungcancers AT willemdekoning unlockingmolecularmechanismsandidentifyingdruggabletargetsinmatchedpairedbrainmetastasisofbreastandlungcancers AT johanmkros unlockingmolecularmechanismsandidentifyingdruggabletargetsinmatchedpairedbrainmetastasisofbreastandlungcancers AT danaammustafa unlockingmolecularmechanismsandidentifyingdruggabletargetsinmatchedpairedbrainmetastasisofbreastandlungcancers |