The MexTAg collaborative cross: host genetics affects asbestos related disease latency, but has little influence once tumours develop
Objectives: This study combines two innovative mouse models in a major gene discovery project to assess the influence of host genetics on asbestos related disease (ARD). Conventional genetics studies provided evidence that some susceptibility to mesothelioma is genetic. However, the identification o...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-04-01
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| Series: | Frontiers in Toxicology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/ftox.2024.1373003/full |
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| author | Scott A. Fisher Scott A. Fisher Scott A. Fisher Kimberley Patrick Kimberley Patrick Kimberley Patrick Tracy Hoang Tracy Hoang Elly Marcq Elly Marcq Elly Marcq Kiarash Behrouzfar Kiarash Behrouzfar Kiarash Behrouzfar Sylvia Young Timothy J. Miller Bruce W. S. Robinson Bruce W. S. Robinson Bruce W. S. Robinson Raphael Bueno Anna K. Nowak Anna K. Nowak Anna K. Nowak W. Joost Lesterhuis Grant Morahan Richard A. Lake Richard A. Lake |
| author_facet | Scott A. Fisher Scott A. Fisher Scott A. Fisher Kimberley Patrick Kimberley Patrick Kimberley Patrick Tracy Hoang Tracy Hoang Elly Marcq Elly Marcq Elly Marcq Kiarash Behrouzfar Kiarash Behrouzfar Kiarash Behrouzfar Sylvia Young Timothy J. Miller Bruce W. S. Robinson Bruce W. S. Robinson Bruce W. S. Robinson Raphael Bueno Anna K. Nowak Anna K. Nowak Anna K. Nowak W. Joost Lesterhuis Grant Morahan Richard A. Lake Richard A. Lake |
| author_sort | Scott A. Fisher |
| collection | DOAJ |
| description | Objectives: This study combines two innovative mouse models in a major gene discovery project to assess the influence of host genetics on asbestos related disease (ARD). Conventional genetics studies provided evidence that some susceptibility to mesothelioma is genetic. However, the identification of host modifier genes, the roles they may play, and whether they contribute to disease susceptibility remain unknown. Here we report a study designed to rapidly identify genes associated with mesothelioma susceptibility by combining the Collaborative Cross (CC) resource with the well-characterised MexTAg mesothelioma mouse model.Methods: The CC is a powerful mouse resource that harnesses over 90% of common genetic variation in the mouse species, allowing rapid identification of genes mediating complex traits. MexTAg mice rapidly, uniformly, and predictably develop mesothelioma, but only after asbestos exposure. To assess the influence of host genetics on ARD, we crossed 72 genetically distinct CC mouse strains with MexTAg mice and exposed the resulting CC-MexTAg (CCMT) progeny to asbestos and monitored them for traits including overall survival, the time to ARD onset (latency), the time between ARD onset and euthanasia (disease progression) and ascites volume. We identified phenotype-specific modifier genes associated with these traits and we validated the role of human orthologues in asbestos-induced carcinogenesis using human mesothelioma datasets.Results: We generated 72 genetically distinct CCMT strains and exposed their progeny (2,562 in total) to asbestos. Reflecting the genetic diversity of the CC, there was considerable variation in overall survival and disease latency. Surprisingly, however, there was no variation in disease progression, demonstrating that host genetic factors do have a significant influence during disease latency but have a limited role once disease is established. Quantitative trait loci (QTL) affecting ARD survival/latency were identified on chromosomes 6, 12 and X. Of the 97-protein coding candidate modifier genes that spanned these QTL, eight genes (CPED1, ORS1, NDUFA1, HS1BP3, IL13RA1, LSM8, TES and TSPAN12) were found to significantly affect outcome in both CCMT and human mesothelioma datasets.Conclusion: Host genetic factors affect susceptibility to development of asbestos associated disease. However, following mesothelioma establishment, genetic variation in molecular or immunological mechanisms did not affect disease progression. Identification of multiple candidate modifier genes and their human homologues with known associations in other advanced stage or metastatic cancers highlights the complexity of ARD and may provide a pathway to identify novel therapeutic targets. |
| first_indexed | 2024-04-24T08:13:45Z |
| format | Article |
| id | doaj.art-3d44dba5e34544bab7bb7980e494ea5c |
| institution | Directory Open Access Journal |
| issn | 2673-3080 |
| language | English |
| last_indexed | 2024-04-24T08:13:45Z |
| publishDate | 2024-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Toxicology |
| spelling | doaj.art-3d44dba5e34544bab7bb7980e494ea5c2024-04-17T04:41:43ZengFrontiers Media S.A.Frontiers in Toxicology2673-30802024-04-01610.3389/ftox.2024.13730031373003The MexTAg collaborative cross: host genetics affects asbestos related disease latency, but has little influence once tumours developScott A. Fisher0Scott A. Fisher1Scott A. Fisher2Kimberley Patrick3Kimberley Patrick4Kimberley Patrick5Tracy Hoang6Tracy Hoang7Elly Marcq8Elly Marcq9Elly Marcq10Kiarash Behrouzfar11Kiarash Behrouzfar12Kiarash Behrouzfar13Sylvia Young14Timothy J. Miller15Bruce W. S. Robinson16Bruce W. S. Robinson17Bruce W. S. Robinson18Raphael Bueno19Anna K. Nowak20Anna K. Nowak21Anna K. Nowak22W. Joost Lesterhuis23Grant Morahan24Richard A. Lake25Richard A. Lake26National Centre for Asbestos Related Diseases (NCARD), Perth, WA, AustraliaSchool of Biomedical Sciences, The University of Western Australia, Perth, WA, AustraliaInstitute for Respiratory Health, University of Western Australia, Perth, WA, AustraliaNational Centre for Asbestos Related Diseases (NCARD), Perth, WA, AustraliaSchool of Biomedical Sciences, The University of Western Australia, Perth, WA, AustraliaInstitute for Respiratory Health, University of Western Australia, Perth, WA, AustraliaNational Centre for Asbestos Related Diseases (NCARD), Perth, WA, AustraliaInstitute for Respiratory Health, University of Western Australia, Perth, WA, AustraliaCenter for Oncological Research (CORE), University of Antwerp, Antwerp, BelgiumLab of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, BelgiumBrussels Center for Immunology, Vrije Universiteit Brussel, Brussels, BelgiumNational Centre for Asbestos Related Diseases (NCARD), Perth, WA, AustraliaSchool of Biomedical Sciences, The University of Western Australia, Perth, WA, AustraliaInstitute for Respiratory Health, University of Western Australia, Perth, WA, AustraliaCentre for Diabetes Research, Harry Perkins Institute of Medical Research, Perth, WA, AustraliaMedical School, The University of Western Australia, Perth, WA, AustraliaNational Centre for Asbestos Related Diseases (NCARD), Perth, WA, AustraliaInstitute for Respiratory Health, University of Western Australia, Perth, WA, AustraliaMedical School, The University of Western Australia, Perth, WA, AustraliaDivision of Thoracic Surgery, The Lung Center and the International Mesothelioma Program, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United StatesNational Centre for Asbestos Related Diseases (NCARD), Perth, WA, AustraliaInstitute for Respiratory Health, University of Western Australia, Perth, WA, AustraliaMedical School, The University of Western Australia, Perth, WA, AustraliaNational Centre for Asbestos Related Diseases (NCARD), Perth, WA, AustraliaCentre for Diabetes Research, Harry Perkins Institute of Medical Research, Perth, WA, AustraliaNational Centre for Asbestos Related Diseases (NCARD), Perth, WA, AustraliaInstitute for Respiratory Health, University of Western Australia, Perth, WA, AustraliaObjectives: This study combines two innovative mouse models in a major gene discovery project to assess the influence of host genetics on asbestos related disease (ARD). Conventional genetics studies provided evidence that some susceptibility to mesothelioma is genetic. However, the identification of host modifier genes, the roles they may play, and whether they contribute to disease susceptibility remain unknown. Here we report a study designed to rapidly identify genes associated with mesothelioma susceptibility by combining the Collaborative Cross (CC) resource with the well-characterised MexTAg mesothelioma mouse model.Methods: The CC is a powerful mouse resource that harnesses over 90% of common genetic variation in the mouse species, allowing rapid identification of genes mediating complex traits. MexTAg mice rapidly, uniformly, and predictably develop mesothelioma, but only after asbestos exposure. To assess the influence of host genetics on ARD, we crossed 72 genetically distinct CC mouse strains with MexTAg mice and exposed the resulting CC-MexTAg (CCMT) progeny to asbestos and monitored them for traits including overall survival, the time to ARD onset (latency), the time between ARD onset and euthanasia (disease progression) and ascites volume. We identified phenotype-specific modifier genes associated with these traits and we validated the role of human orthologues in asbestos-induced carcinogenesis using human mesothelioma datasets.Results: We generated 72 genetically distinct CCMT strains and exposed their progeny (2,562 in total) to asbestos. Reflecting the genetic diversity of the CC, there was considerable variation in overall survival and disease latency. Surprisingly, however, there was no variation in disease progression, demonstrating that host genetic factors do have a significant influence during disease latency but have a limited role once disease is established. Quantitative trait loci (QTL) affecting ARD survival/latency were identified on chromosomes 6, 12 and X. Of the 97-protein coding candidate modifier genes that spanned these QTL, eight genes (CPED1, ORS1, NDUFA1, HS1BP3, IL13RA1, LSM8, TES and TSPAN12) were found to significantly affect outcome in both CCMT and human mesothelioma datasets.Conclusion: Host genetic factors affect susceptibility to development of asbestos associated disease. However, following mesothelioma establishment, genetic variation in molecular or immunological mechanisms did not affect disease progression. Identification of multiple candidate modifier genes and their human homologues with known associations in other advanced stage or metastatic cancers highlights the complexity of ARD and may provide a pathway to identify novel therapeutic targets.https://www.frontiersin.org/articles/10.3389/ftox.2024.1373003/fullmesotheliomacollaborative crossMexTAgasbestos related diseasehost geneticsmouse model |
| spellingShingle | Scott A. Fisher Scott A. Fisher Scott A. Fisher Kimberley Patrick Kimberley Patrick Kimberley Patrick Tracy Hoang Tracy Hoang Elly Marcq Elly Marcq Elly Marcq Kiarash Behrouzfar Kiarash Behrouzfar Kiarash Behrouzfar Sylvia Young Timothy J. Miller Bruce W. S. Robinson Bruce W. S. Robinson Bruce W. S. Robinson Raphael Bueno Anna K. Nowak Anna K. Nowak Anna K. Nowak W. Joost Lesterhuis Grant Morahan Richard A. Lake Richard A. Lake The MexTAg collaborative cross: host genetics affects asbestos related disease latency, but has little influence once tumours develop Frontiers in Toxicology mesothelioma collaborative cross MexTAg asbestos related disease host genetics mouse model |
| title | The MexTAg collaborative cross: host genetics affects asbestos related disease latency, but has little influence once tumours develop |
| title_full | The MexTAg collaborative cross: host genetics affects asbestos related disease latency, but has little influence once tumours develop |
| title_fullStr | The MexTAg collaborative cross: host genetics affects asbestos related disease latency, but has little influence once tumours develop |
| title_full_unstemmed | The MexTAg collaborative cross: host genetics affects asbestos related disease latency, but has little influence once tumours develop |
| title_short | The MexTAg collaborative cross: host genetics affects asbestos related disease latency, but has little influence once tumours develop |
| title_sort | mextag collaborative cross host genetics affects asbestos related disease latency but has little influence once tumours develop |
| topic | mesothelioma collaborative cross MexTAg asbestos related disease host genetics mouse model |
| url | https://www.frontiersin.org/articles/10.3389/ftox.2024.1373003/full |
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