Dysregulation of core neurodevelopmental pathways—a common feature of cancers with perineural invasion
Background: High nerve density in tumors and metastasis via nerves (perineural invasion—PNI) have been reported extensively in solid tumors throughout the body including pancreatic, head and neck, gastric, prostate, breast, and colorectal cancers. Ablation of tumor nerves results in improved disease...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-08-01
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| Series: | Frontiers in Genetics |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2023.1181775/full |
| _version_ | 1797730776068915200 |
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| author | Luz María González-Castrillón Maud Wurmser Daniel Öhlund Sara Ivy Wilson |
| author_facet | Luz María González-Castrillón Maud Wurmser Daniel Öhlund Sara Ivy Wilson |
| author_sort | Luz María González-Castrillón |
| collection | DOAJ |
| description | Background: High nerve density in tumors and metastasis via nerves (perineural invasion—PNI) have been reported extensively in solid tumors throughout the body including pancreatic, head and neck, gastric, prostate, breast, and colorectal cancers. Ablation of tumor nerves results in improved disease outcomes, suggesting that blocking nerve–tumor communication could be a novel treatment strategy. However, the molecular mechanisms underlying this remain poorly understood. Thus, the aim here was to identify molecular pathways underlying nerve–tumor crosstalk and to determine common molecular features between PNI-associated cancers.Results: Analysis of head and neck (HNSCC), pancreatic, and gastric (STAD) cancer Gene Expression Omnibus datasets was used to identify differentially expressed genes (DEGs). This revealed extracellular matrix components as highly dysregulated. To enrich for pathways associated with PNI, genes previously correlated with PNI in STAD and in 2 HNSCC studies where tumor samples were segregated by PNI status were analyzed. Neurodevelopmental genes were found to be enriched with PNI. In datasets where tumor samples were not segregated by PNI, neurodevelopmental pathways accounted for 12%–16% of the DEGs. Further dysregulation of axon guidance genes was common to all cancers analyzed. By examining paralog genes, a clear pattern emerged where at least one family member from several axon guidance pathways was affected in all cancers examined. Overall 17 different axon guidance gene families were disrupted, including the ephrin–Eph, semaphorin–neuropilin/plexin, and slit–robo pathways. These findings were validated using The Cancer Genome Atlas and cross-referenced to other cancers with a high incidence of PNI including colon, cholangiocarcinoma, prostate, and breast cancers. Survival analysis revealed that the expression levels of neurodevelopmental gene families impacted disease survival.Conclusion: These data highlight the importance of the tumor as a source of signals for neural tropism and neural plasticity as a common feature of cancer. The analysis supports the hypothesis that dysregulation of neurodevelopmental programs is a common feature associated with PNI. Furthermore, the data suggested that different cancers may have evolved to employ alternative genetic strategies to disrupt the same pathways. Overall, these findings provide potential druggable targets for novel therapies of cancer management and provide multi-cancer molecular biomarkers. |
| first_indexed | 2024-03-12T11:49:11Z |
| format | Article |
| id | doaj.art-f9c0ab485afe4b73b7362dda1f88a4e4 |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-03-12T11:49:11Z |
| publishDate | 2023-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-f9c0ab485afe4b73b7362dda1f88a4e42023-08-31T12:19:15ZengFrontiers Media S.A.Frontiers in Genetics1664-80212023-08-011410.3389/fgene.2023.11817751181775Dysregulation of core neurodevelopmental pathways—a common feature of cancers with perineural invasionLuz María González-Castrillón0Maud Wurmser1Daniel Öhlund2Sara Ivy Wilson3Department of Integrative Medical Biology, Umeå University, Umeå, SwedenDepartment of Integrative Medical Biology, Umeå University, Umeå, SwedenWallenberg Centre for Molecular Medicine, Department of Radiation Sciences, Umeå University, Umeå, SwedenDepartment of Integrative Medical Biology, Umeå University, Umeå, SwedenBackground: High nerve density in tumors and metastasis via nerves (perineural invasion—PNI) have been reported extensively in solid tumors throughout the body including pancreatic, head and neck, gastric, prostate, breast, and colorectal cancers. Ablation of tumor nerves results in improved disease outcomes, suggesting that blocking nerve–tumor communication could be a novel treatment strategy. However, the molecular mechanisms underlying this remain poorly understood. Thus, the aim here was to identify molecular pathways underlying nerve–tumor crosstalk and to determine common molecular features between PNI-associated cancers.Results: Analysis of head and neck (HNSCC), pancreatic, and gastric (STAD) cancer Gene Expression Omnibus datasets was used to identify differentially expressed genes (DEGs). This revealed extracellular matrix components as highly dysregulated. To enrich for pathways associated with PNI, genes previously correlated with PNI in STAD and in 2 HNSCC studies where tumor samples were segregated by PNI status were analyzed. Neurodevelopmental genes were found to be enriched with PNI. In datasets where tumor samples were not segregated by PNI, neurodevelopmental pathways accounted for 12%–16% of the DEGs. Further dysregulation of axon guidance genes was common to all cancers analyzed. By examining paralog genes, a clear pattern emerged where at least one family member from several axon guidance pathways was affected in all cancers examined. Overall 17 different axon guidance gene families were disrupted, including the ephrin–Eph, semaphorin–neuropilin/plexin, and slit–robo pathways. These findings were validated using The Cancer Genome Atlas and cross-referenced to other cancers with a high incidence of PNI including colon, cholangiocarcinoma, prostate, and breast cancers. Survival analysis revealed that the expression levels of neurodevelopmental gene families impacted disease survival.Conclusion: These data highlight the importance of the tumor as a source of signals for neural tropism and neural plasticity as a common feature of cancer. The analysis supports the hypothesis that dysregulation of neurodevelopmental programs is a common feature associated with PNI. Furthermore, the data suggested that different cancers may have evolved to employ alternative genetic strategies to disrupt the same pathways. Overall, these findings provide potential druggable targets for novel therapies of cancer management and provide multi-cancer molecular biomarkers.https://www.frontiersin.org/articles/10.3389/fgene.2023.1181775/fullperineural invasioncancerneurodevelopmentbioinformaticsbiomarkerhead and neck squamous cell carcinoma |
| spellingShingle | Luz María González-Castrillón Maud Wurmser Daniel Öhlund Sara Ivy Wilson Dysregulation of core neurodevelopmental pathways—a common feature of cancers with perineural invasion Frontiers in Genetics perineural invasion cancer neurodevelopment bioinformatics biomarker head and neck squamous cell carcinoma |
| title | Dysregulation of core neurodevelopmental pathways—a common feature of cancers with perineural invasion |
| title_full | Dysregulation of core neurodevelopmental pathways—a common feature of cancers with perineural invasion |
| title_fullStr | Dysregulation of core neurodevelopmental pathways—a common feature of cancers with perineural invasion |
| title_full_unstemmed | Dysregulation of core neurodevelopmental pathways—a common feature of cancers with perineural invasion |
| title_short | Dysregulation of core neurodevelopmental pathways—a common feature of cancers with perineural invasion |
| title_sort | dysregulation of core neurodevelopmental pathways a common feature of cancers with perineural invasion |
| topic | perineural invasion cancer neurodevelopment bioinformatics biomarker head and neck squamous cell carcinoma |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2023.1181775/full |
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