Induction of interferon signaling and allograft inflammatory factor 1 in macrophages in a mouse model of breast cancer metastases [version 2; peer review: 2 approved, 1 approved with reservations]
Background: Metastatic breast cancer cells recruit macrophages (metastasis-associated macrophages, or MAMs) to facilitate their seeding, survival and outgrowth. However, a comprehensive understanding of the gene expression program in MAMs and how this program contributes to metastasis remain elusive...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Wellcome
2021-06-01
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| Series: | Wellcome Open Research |
| Online Access: | https://wellcomeopenresearch.org/articles/6-52/v2 |
| _version_ | 1818643949189857280 |
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| author | Wei Zheng Dejian Zhao Hui Zhang Prameladevi Chinnasamy Nicholas Sibinga Jeffrey W. Pollard |
| author_facet | Wei Zheng Dejian Zhao Hui Zhang Prameladevi Chinnasamy Nicholas Sibinga Jeffrey W. Pollard |
| author_sort | Wei Zheng |
| collection | DOAJ |
| description | Background: Metastatic breast cancer cells recruit macrophages (metastasis-associated macrophages, or MAMs) to facilitate their seeding, survival and outgrowth. However, a comprehensive understanding of the gene expression program in MAMs and how this program contributes to metastasis remain elusive. Methods: We compared the transcriptomes of MAMs recruited to lung metastases and resident alveolar macrophages (RAMs) and identified a large variety of differentially expressed genes and their associated signaling pathways. Some of the changes were validated using qRT-PCR and immunofluorescence. To probe the functional relevance to metastatic growth, a gene-targeting mouse model of female mice in the C57BL6/J background was used to study allograft inflammatory factor 1 (AIF1, also known as ionized calcium-binding adapter molecule 1 or IBA1). Results: Interferon signaling is one of the most activated pathways in MAMs, with strong upregulation of multiple components of the pathway and a significant enrichment for the gene signatures of interferon-alpha-treated human macrophages. Aif1, an interferon-responsive gene that regulates multiple macrophage activities, was robustly induced in MAMs. Aif1 deficiency in MAMs, however, did not affect development of lung metastases, suggesting that AIF1 indicates MAM activation but is dispensable for regulating metastasis. Conclusions: The drastically different gene expression profile of MAMs as compared to RAMs suggests an important role in promoting metastatic growth. Dissection of the underlying mechanisms and functional validation of potential targets in the profile may provide novel therapeutic strategies for the treatment of metastatic diseases. |
| first_indexed | 2024-12-17T00:07:05Z |
| format | Article |
| id | doaj.art-83a6b7fec207418181a2ef9007ecd23b |
| institution | Directory Open Access Journal |
| issn | 2398-502X |
| language | English |
| last_indexed | 2024-12-17T00:07:05Z |
| publishDate | 2021-06-01 |
| publisher | Wellcome |
| record_format | Article |
| series | Wellcome Open Research |
| spelling | doaj.art-83a6b7fec207418181a2ef9007ecd23b2022-12-21T22:10:55ZengWellcomeWellcome Open Research2398-502X2021-06-01610.12688/wellcomeopenres.16569.218757Induction of interferon signaling and allograft inflammatory factor 1 in macrophages in a mouse model of breast cancer metastases [version 2; peer review: 2 approved, 1 approved with reservations]Wei Zheng0Dejian Zhao1Hui Zhang2Prameladevi Chinnasamy3Nicholas Sibinga4Jeffrey W. Pollard5Department of Developmental and Molecular Biology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, 10461, USAYale Center for Genome Analysis, Yale University, New Haven, Connecticut, 06510, USADepartment of Developmental and Molecular Biology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, 10461, USADepartment of Developmental and Molecular Biology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, 10461, USADepartment of Developmental and Molecular Biology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, 10461, USAMRC Centre for Reproductive Health, Queen’s Medical Research Institute, The University of Edinburgh, Edinburgh, EH16 4TJ, UKBackground: Metastatic breast cancer cells recruit macrophages (metastasis-associated macrophages, or MAMs) to facilitate their seeding, survival and outgrowth. However, a comprehensive understanding of the gene expression program in MAMs and how this program contributes to metastasis remain elusive. Methods: We compared the transcriptomes of MAMs recruited to lung metastases and resident alveolar macrophages (RAMs) and identified a large variety of differentially expressed genes and their associated signaling pathways. Some of the changes were validated using qRT-PCR and immunofluorescence. To probe the functional relevance to metastatic growth, a gene-targeting mouse model of female mice in the C57BL6/J background was used to study allograft inflammatory factor 1 (AIF1, also known as ionized calcium-binding adapter molecule 1 or IBA1). Results: Interferon signaling is one of the most activated pathways in MAMs, with strong upregulation of multiple components of the pathway and a significant enrichment for the gene signatures of interferon-alpha-treated human macrophages. Aif1, an interferon-responsive gene that regulates multiple macrophage activities, was robustly induced in MAMs. Aif1 deficiency in MAMs, however, did not affect development of lung metastases, suggesting that AIF1 indicates MAM activation but is dispensable for regulating metastasis. Conclusions: The drastically different gene expression profile of MAMs as compared to RAMs suggests an important role in promoting metastatic growth. Dissection of the underlying mechanisms and functional validation of potential targets in the profile may provide novel therapeutic strategies for the treatment of metastatic diseases.https://wellcomeopenresearch.org/articles/6-52/v2 |
| spellingShingle | Wei Zheng Dejian Zhao Hui Zhang Prameladevi Chinnasamy Nicholas Sibinga Jeffrey W. Pollard Induction of interferon signaling and allograft inflammatory factor 1 in macrophages in a mouse model of breast cancer metastases [version 2; peer review: 2 approved, 1 approved with reservations] Wellcome Open Research |
| title | Induction of interferon signaling and allograft inflammatory factor 1 in macrophages in a mouse model of breast cancer metastases [version 2; peer review: 2 approved, 1 approved with reservations] |
| title_full | Induction of interferon signaling and allograft inflammatory factor 1 in macrophages in a mouse model of breast cancer metastases [version 2; peer review: 2 approved, 1 approved with reservations] |
| title_fullStr | Induction of interferon signaling and allograft inflammatory factor 1 in macrophages in a mouse model of breast cancer metastases [version 2; peer review: 2 approved, 1 approved with reservations] |
| title_full_unstemmed | Induction of interferon signaling and allograft inflammatory factor 1 in macrophages in a mouse model of breast cancer metastases [version 2; peer review: 2 approved, 1 approved with reservations] |
| title_short | Induction of interferon signaling and allograft inflammatory factor 1 in macrophages in a mouse model of breast cancer metastases [version 2; peer review: 2 approved, 1 approved with reservations] |
| title_sort | induction of interferon signaling and allograft inflammatory factor 1 in macrophages in a mouse model of breast cancer metastases version 2 peer review 2 approved 1 approved with reservations |
| url | https://wellcomeopenresearch.org/articles/6-52/v2 |
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