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Dysregulation of core neurodevelopmental pathways: a common feature of cancers with perineural invasion
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).ORCID iD: 0000-0002-9793-1631
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).ORCID iD: 0000-0002-5847-2778
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).ORCID iD: 0000-0003-3664-8178
2023 (English)In: Frontiers in Genetics, E-ISSN 1664-8021, Vol. 14, article id 1181775Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2023. Vol. 14, article id 1181775
Keywords [en]
bioinformatics, biomarker, cancer, head and neck squamous cell carcinoma, neurodevelopment, pancreatic ductal adenocarcinoma, perineural invasion, stomach adenocarcinoma
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:umu:diva-214621DOI: 10.3389/fgene.2023.1181775Scopus ID: 2-s2.0-85170839267OAI: oai:DiVA.org:umu-214621DiVA, id: diva2:1800402
Funder
Umeå University, FS 2.1.6-1119-19Knut and Alice Wallenberg Foundation, MMW 2020.0189Marianne and Marcus Wallenberg Foundation, MMW 2020.0189Available from: 2023-09-26 Created: 2023-09-26 Last updated: 2023-11-20Bibliographically approved
In thesis
1. Molecular mechanisms of nerve-tumor interactions: the intersection of cancer and neurodevelopment
Open this publication in new window or tab >>Molecular mechanisms of nerve-tumor interactions: the intersection of cancer and neurodevelopment
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Molekylära mekanismer för interaktioner mellan nerver och tumörer : kopplingar mellan cancer och neuroutveckling
Abstract [en]

A wide range of cancers throughout the body are characterized by high nerve density and invasion of cancer cells within the nerves, a process called perineural invasion (PNI). Work in the field has shown that blocking nerves in organs with tumors leads to improved disease outcomes suggesting that finding ways to block tumor nerves could lead to new treatment approaches. Despite the importance of this, little is known about the molecular mechanisms underlying nerve-tumor interactions. An increasing number of studies have revealed that the genes associated with PNI are classical neurodevelopmental genes associated with neurodevelopmental processes. Therefore, the central hypothesis of this thesis was that nerve-tumor interactions result in part from an abnormal reactivation of the molecular pathways underlying the embryonic development of the nervous system. To test this hypothesis, public datasets from different types of cancer with high incidence of PNI were analyzed to identify molecular pathways common between these cancers. This analysis revealed that neurodevelopmental pathways accounted for 12 - 16% of the differentially expressed genes (DEGs), with axon guidance genes being markedly dysregulated. Overall, 17 different axon guidance gene families, including ephrin-Eph, semaphorin-neuropilin/plexin and slit-robo pathways were dysregulated. Further disruption of these pathways was a common feature across a number of cancers analyzed and their dysregulation had a significant impact on disease survival. Overall, this suggested that neurodevelopmental molecular pathways may contribute to tumor axonogenesis and PNI. 

These findings suggested a significant role of neurodevelopmental pathways in cancer dysregulation. Thus, a comprehensive understanding of the pathways during the nervous system development is imperative. Therefore, in my thesis, the embryo was used as a tool to study the mechanisms by which these molecular pathways influence axonogenesis more broadly. First, the role of the axon guidance genes Slit/Robo was examined during mouse neurodevelopment. Our results showed that Robo2 enrichment influences the migration and axonal projections of spinal ipsilateral neurons. In parallel, we investigated the role of alternative splicing of transcription factors as a mechanism of increase neuronal diversity. In particular we examined the expression dynamics of Lhx9, a transcription factor that controls the expression of the axon guidance gene Robo3. Lhx9 splice variants showed a differential expression at key developmental points in the spinal cord, suggesting Lhx9 splice dynamics plays an important role in neural guidance choices. 

In the third part of the thesis, I investigated the role of gap junctions, in nerve-tumor interactions, using pancreatic ductal adenocarcinoma (PDAC) cancer cells in vitro models. The connexin GJB2 emerged as the most overexpressed gap junction component in PDAC tumors. In vitro analysis, involving blocking gap junctions or connexin overexpression, revealed that gap junctions influenced PDAC cancer cell behaviors and properties. Further we developed a novel nerve-tumor assay and used it to examine the role of gap junction genes in PDAC cells neuronal growth. 

Overall, this thesis postulated that several key molecular pathways crucial for normal nervous system embryonic development, could underly nerve- tumor interactions during cancer development and progression.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2023. p. 81
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2272
Keywords
Perineural invasion, cancer, PDAC, axonogenesis, neurodevelopment, spinal cord, axon guidance, bioinformatics.
National Category
Cell and Molecular Biology Cancer and Oncology Neurosciences Developmental Biology
Research subject
biomedical laboratory science
Identifiers
urn:nbn:se:umu:diva-216925 (URN)978-91-8070-221-8 (ISBN)978-91-8070-222-5 (ISBN)
Public defence
2023-12-13, NAT.D.360, Naturvetarhuset, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2023-11-22 Created: 2023-11-20 Last updated: 2023-11-21Bibliographically approved

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Gonzalez-Castrillon, Luz MariaWurmser, MaudÖhlund, DanielWilson, Sara I

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