Spatially resolved, high-dimensional transcriptomics sorts out the evolution of biphasic malignant pleural mesothelioma: new paradigms for immunotherapy
Abstract Background Malignant Pleural Mesothelioma (MPM) is a dreadful disease escaping the classical genetic model of cancer evolution and characterized by wide heterogeneity and transcriptional plasticity. Clinical evolution of MPM is marked by a progressive transdifferentiation that converts well...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-07-01
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| Series: | Molecular Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12943-023-01816-9 |
| _version_ | 1797774357695561728 |
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| author | F Torricelli B Donati F Reggiani V Manicardi S Piana R Valli F Lococo Alessia Ciarrocchi |
| author_facet | F Torricelli B Donati F Reggiani V Manicardi S Piana R Valli F Lococo Alessia Ciarrocchi |
| author_sort | F Torricelli |
| collection | DOAJ |
| description | Abstract Background Malignant Pleural Mesothelioma (MPM) is a dreadful disease escaping the classical genetic model of cancer evolution and characterized by wide heterogeneity and transcriptional plasticity. Clinical evolution of MPM is marked by a progressive transdifferentiation that converts well differentiated epithelioid (E) cells into undifferentiated and pleomorphic sarcomatoid (S) phenotypes. Catching the way this transition takes place is necessary to understand how MPM develops and progresses and it is mandatory to improve patients’ management and life expectancy. Bulk transcriptomic approaches, while providing a significant overview, failed to resolve the timing of this evolution and to identify the hierarchy of molecular events through which this transition takes place. Methods We applied a spatially resolved, high-dimensional transcriptomic approach to study MPM morphological evolution. 139 regions across 8 biphasic MPMs (B-MPMs) were profiled using the GeoMx™Digital Spatial Profiler to reconstruct the positional context of transcriptional activities and the spatial topology of MPM cells interactions. Validation was conducted on an independent large cohort of 84 MPMs by targeted digital barcoding analysis. Results Our results demonstrated the existence of a complex circular ecosystem in which, within a strong asbestos-driven inflammatory environment, MPM and immune cells affect each other to support S-transdifferentiation. We also showed that TGFB1 polarized M2-Tumor Associated Macrophages foster immune evasion and that TGFB1 expression correlates with reduced survival probability. Conclusions Besides providing crucial insights into the multidimensional interactions governing MPM clinical evolution, these results open new perspectives to improve the use of immunotherapy in this disease. |
| first_indexed | 2024-03-12T22:19:50Z |
| format | Article |
| id | doaj.art-71f3b5ed1c8a49c19f1b0b0ec4911f32 |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-03-12T22:19:50Z |
| publishDate | 2023-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-71f3b5ed1c8a49c19f1b0b0ec4911f322023-07-23T11:08:22ZengBMCMolecular Cancer1476-45982023-07-0122111510.1186/s12943-023-01816-9Spatially resolved, high-dimensional transcriptomics sorts out the evolution of biphasic malignant pleural mesothelioma: new paradigms for immunotherapyF Torricelli0B Donati1F Reggiani2V Manicardi3S Piana4R Valli5F Lococo6Alessia Ciarrocchi7Laboratory of Translational Research, Azienda Unità Sanitaria Locale-IRCCS di Reggio EmiliaLaboratory of Translational Research, Azienda Unità Sanitaria Locale-IRCCS di Reggio EmiliaLaboratory of Translational Research, Azienda Unità Sanitaria Locale-IRCCS di Reggio EmiliaLaboratory of Translational Research, Azienda Unità Sanitaria Locale-IRCCS di Reggio EmiliaPathology Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio EmiliaPathology Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio EmiliaThoracic Surgery Unit, IRCCS-Fondazione Policlinico GemelliLaboratory of Translational Research, Azienda Unità Sanitaria Locale-IRCCS di Reggio EmiliaAbstract Background Malignant Pleural Mesothelioma (MPM) is a dreadful disease escaping the classical genetic model of cancer evolution and characterized by wide heterogeneity and transcriptional plasticity. Clinical evolution of MPM is marked by a progressive transdifferentiation that converts well differentiated epithelioid (E) cells into undifferentiated and pleomorphic sarcomatoid (S) phenotypes. Catching the way this transition takes place is necessary to understand how MPM develops and progresses and it is mandatory to improve patients’ management and life expectancy. Bulk transcriptomic approaches, while providing a significant overview, failed to resolve the timing of this evolution and to identify the hierarchy of molecular events through which this transition takes place. Methods We applied a spatially resolved, high-dimensional transcriptomic approach to study MPM morphological evolution. 139 regions across 8 biphasic MPMs (B-MPMs) were profiled using the GeoMx™Digital Spatial Profiler to reconstruct the positional context of transcriptional activities and the spatial topology of MPM cells interactions. Validation was conducted on an independent large cohort of 84 MPMs by targeted digital barcoding analysis. Results Our results demonstrated the existence of a complex circular ecosystem in which, within a strong asbestos-driven inflammatory environment, MPM and immune cells affect each other to support S-transdifferentiation. We also showed that TGFB1 polarized M2-Tumor Associated Macrophages foster immune evasion and that TGFB1 expression correlates with reduced survival probability. Conclusions Besides providing crucial insights into the multidimensional interactions governing MPM clinical evolution, these results open new perspectives to improve the use of immunotherapy in this disease.https://doi.org/10.1186/s12943-023-01816-9Malignant pleural mesotheliomaCancer heterogeneityTumor microenvironmentInflammationEpithelial mesenchymal transitionTumor associated Macrophages |
| spellingShingle | F Torricelli B Donati F Reggiani V Manicardi S Piana R Valli F Lococo Alessia Ciarrocchi Spatially resolved, high-dimensional transcriptomics sorts out the evolution of biphasic malignant pleural mesothelioma: new paradigms for immunotherapy Molecular Cancer Malignant pleural mesothelioma Cancer heterogeneity Tumor microenvironment Inflammation Epithelial mesenchymal transition Tumor associated Macrophages |
| title | Spatially resolved, high-dimensional transcriptomics sorts out the evolution of biphasic malignant pleural mesothelioma: new paradigms for immunotherapy |
| title_full | Spatially resolved, high-dimensional transcriptomics sorts out the evolution of biphasic malignant pleural mesothelioma: new paradigms for immunotherapy |
| title_fullStr | Spatially resolved, high-dimensional transcriptomics sorts out the evolution of biphasic malignant pleural mesothelioma: new paradigms for immunotherapy |
| title_full_unstemmed | Spatially resolved, high-dimensional transcriptomics sorts out the evolution of biphasic malignant pleural mesothelioma: new paradigms for immunotherapy |
| title_short | Spatially resolved, high-dimensional transcriptomics sorts out the evolution of biphasic malignant pleural mesothelioma: new paradigms for immunotherapy |
| title_sort | spatially resolved high dimensional transcriptomics sorts out the evolution of biphasic malignant pleural mesothelioma new paradigms for immunotherapy |
| topic | Malignant pleural mesothelioma Cancer heterogeneity Tumor microenvironment Inflammation Epithelial mesenchymal transition Tumor associated Macrophages |
| url | https://doi.org/10.1186/s12943-023-01816-9 |
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