Transcriptional and Microenvironmental Landscape of Macrophage Transition in Cancer: A Boolean Analysis
The balance between pro- and anti-inflammatory immune system responses is crucial to face and counteract complex diseases such as cancer. Macrophages are an essential population that contributes to this balance in collusion with the local tumor microenvironment. Cancer cells evade the attack of macr...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-06-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.642842/full |
| _version_ | 1818740994209742848 |
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| author | Ugo Avila-Ponce de León Ugo Avila-Ponce de León Aarón Vázquez-Jiménez Meztli Matadamas-Guzman Meztli Matadamas-Guzman Rosana Pelayo Osbaldo Resendis-Antonio Osbaldo Resendis-Antonio |
| author_facet | Ugo Avila-Ponce de León Ugo Avila-Ponce de León Aarón Vázquez-Jiménez Meztli Matadamas-Guzman Meztli Matadamas-Guzman Rosana Pelayo Osbaldo Resendis-Antonio Osbaldo Resendis-Antonio |
| author_sort | Ugo Avila-Ponce de León |
| collection | DOAJ |
| description | The balance between pro- and anti-inflammatory immune system responses is crucial to face and counteract complex diseases such as cancer. Macrophages are an essential population that contributes to this balance in collusion with the local tumor microenvironment. Cancer cells evade the attack of macrophages by liberating cytokines and enhancing the transition to the M2 phenotype with pro-tumoral functions. Despite this pernicious effect on immune systems, the M1 phenotype still exists in the environment and can eliminate tumor cells by liberating cytokines that recruit and activate the cytotoxic actions of TH1 effector cells. Here, we used a Boolean modeling approach to understand how the tumor microenvironment shapes macrophage behavior to enhance pro-tumoral functions. Our network reconstruction integrates experimental data and public information that let us study the polarization from monocytes to M1, M2a, M2b, M2c, and M2d subphenotypes. To analyze the dynamics of our model, we modeled macrophage polarization in different conditions and perturbations. Notably, our study identified new hybrid cell populations, undescribed before. Based on the in vivo macrophage behavior, we explained the hybrid macrophages’ role in the tumor microenvironment. The in silico model allowed us to postulate transcriptional factors that maintain the balance between macrophages with anti- and pro-tumoral functions. In our pursuit to maintain the balance of macrophage phenotypes to eliminate malignant tumor cells, we emulated a theoretical genetically modified macrophage by modifying the activation of NFκB and a loss of function in HIF1-α and discussed their phenotype implications. Overall, our theoretical approach is as a guide to design new experiments for unraveling the principles of the dual host-protective or -harmful antagonistic roles of transitional macrophages in tumor immunoediting and cancer cell fate decisions. |
| first_indexed | 2024-12-18T01:49:34Z |
| format | Article |
| id | doaj.art-b265aa20b93b40ed9a554b14f41547e6 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-18T01:49:34Z |
| publishDate | 2021-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-b265aa20b93b40ed9a554b14f41547e62022-12-21T21:25:05ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-06-011210.3389/fimmu.2021.642842642842Transcriptional and Microenvironmental Landscape of Macrophage Transition in Cancer: A Boolean AnalysisUgo Avila-Ponce de León0Ugo Avila-Ponce de León1Aarón Vázquez-Jiménez2Meztli Matadamas-Guzman3Meztli Matadamas-Guzman4Rosana Pelayo5Osbaldo Resendis-Antonio6Osbaldo Resendis-Antonio7Programa de Doctorado en Ciencias Biológicas, Universidad Nacional Autónoma de México, Ciudad de México, MexicoHuman Systems Biology Laboratory, Instituto Nacional de Medicina Genómica (INMEGEN), Ciudad de México, MexicoHuman Systems Biology Laboratory, Instituto Nacional de Medicina Genómica (INMEGEN), Ciudad de México, MexicoHuman Systems Biology Laboratory, Instituto Nacional de Medicina Genómica (INMEGEN), Ciudad de México, MexicoDoctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, MexicoOncoimmunology Laboratory, Centro de Investigación Biomédica de Oriente, Instituto Mexicano del Seguro Social, Puebla, MexicoHuman Systems Biology Laboratory, Instituto Nacional de Medicina Genómica (INMEGEN), Ciudad de México, MexicoCoordinación de la Investigación Científica - Red de Apoyo a la Investigación, UNAM, Ciudad de México, MexicoThe balance between pro- and anti-inflammatory immune system responses is crucial to face and counteract complex diseases such as cancer. Macrophages are an essential population that contributes to this balance in collusion with the local tumor microenvironment. Cancer cells evade the attack of macrophages by liberating cytokines and enhancing the transition to the M2 phenotype with pro-tumoral functions. Despite this pernicious effect on immune systems, the M1 phenotype still exists in the environment and can eliminate tumor cells by liberating cytokines that recruit and activate the cytotoxic actions of TH1 effector cells. Here, we used a Boolean modeling approach to understand how the tumor microenvironment shapes macrophage behavior to enhance pro-tumoral functions. Our network reconstruction integrates experimental data and public information that let us study the polarization from monocytes to M1, M2a, M2b, M2c, and M2d subphenotypes. To analyze the dynamics of our model, we modeled macrophage polarization in different conditions and perturbations. Notably, our study identified new hybrid cell populations, undescribed before. Based on the in vivo macrophage behavior, we explained the hybrid macrophages’ role in the tumor microenvironment. The in silico model allowed us to postulate transcriptional factors that maintain the balance between macrophages with anti- and pro-tumoral functions. In our pursuit to maintain the balance of macrophage phenotypes to eliminate malignant tumor cells, we emulated a theoretical genetically modified macrophage by modifying the activation of NFκB and a loss of function in HIF1-α and discussed their phenotype implications. Overall, our theoretical approach is as a guide to design new experiments for unraveling the principles of the dual host-protective or -harmful antagonistic roles of transitional macrophages in tumor immunoediting and cancer cell fate decisions.https://www.frontiersin.org/articles/10.3389/fimmu.2021.642842/fullmacrophagephenotypeboolean modelssystems immunologygene regulatory networkcancer immunology |
| spellingShingle | Ugo Avila-Ponce de León Ugo Avila-Ponce de León Aarón Vázquez-Jiménez Meztli Matadamas-Guzman Meztli Matadamas-Guzman Rosana Pelayo Osbaldo Resendis-Antonio Osbaldo Resendis-Antonio Transcriptional and Microenvironmental Landscape of Macrophage Transition in Cancer: A Boolean Analysis Frontiers in Immunology macrophage phenotype boolean models systems immunology gene regulatory network cancer immunology |
| title | Transcriptional and Microenvironmental Landscape of Macrophage Transition in Cancer: A Boolean Analysis |
| title_full | Transcriptional and Microenvironmental Landscape of Macrophage Transition in Cancer: A Boolean Analysis |
| title_fullStr | Transcriptional and Microenvironmental Landscape of Macrophage Transition in Cancer: A Boolean Analysis |
| title_full_unstemmed | Transcriptional and Microenvironmental Landscape of Macrophage Transition in Cancer: A Boolean Analysis |
| title_short | Transcriptional and Microenvironmental Landscape of Macrophage Transition in Cancer: A Boolean Analysis |
| title_sort | transcriptional and microenvironmental landscape of macrophage transition in cancer a boolean analysis |
| topic | macrophage phenotype boolean models systems immunology gene regulatory network cancer immunology |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.642842/full |
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