Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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An Ets2-specific transcriptional program in tumor-associated macrophages promotes metastasis

ABSTRACT: Macrophages have been implicated in breast cancer progression and metastasis, but relatively little is known about the genes and pathways that are involved. Using a conditional allele of Ets2 in the mouse, we have identified Ets2 as a critical gene in tumor associated macrophages (TAMs) that specifically promotes mammary tumor metastasis. Loss of Ets2 in TAMs decreased the frequency and size of lung metastases without impacting primary tumor burden. Expression profiling of isolated tumor macrophages established that Ets2 deficiency resulted in the de-repression of a defined set of anti-angiogenic genes. Activation of this transcriptional program correlated with decreased angiogenesis in metastatic tumors and decreased metastatic growth. Comparison of this Ets2-specific TAM expression profile with human breast cancer profiles revealed a macrophage gene expression signature that could predict overall survival of estrogen receptor negative patients. In summary, we have identified a critical factor, Ets2, in TAMs that represses a transcriptional program to promote the growth of mammary tumor metastases in the lung. Breast TAMs were isolated from early-stage PyMT-induced mammary tumors expressing Ets2 and also from the tumors with Ets2-deficient TAMs. Since macrophages have also been implicated in normal mammary gland remodeling, normal remeodeling macrophages were also purified from females expressing Ets2 and the ones where Ets2 is deleted in the macrophages. One RNA sample was extracted from each genetic group for gene-expression profiling.

ORGANISM(S): Mus musculus

SUBMITTER: Michael Ostrowski

PROVIDER: E-GEOD-12863 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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An ets2-driven transcriptional program in tumor-associated macrophages promotes tumor metastasis.

Zabuawala Tahera T Taffany David A DA Sharma Sudarshana M SM Merchant Anand A Adair Brett B Srinivasan Ruchika R Rosol Thomas J TJ Fernandez Soledad S Huang Kun K Leone Gustavo G Ostrowski Michael C MC

Cancer research 20100209 4

Tumor-associated macrophages (TAM) are implicated in breast cancer metastasis, but relatively little is known about the underlying genes and pathways that are involved. The transcription factor Ets2 is a direct target of signaling pathways involved in regulating macrophage functions during inflammation. We conditionally deleted Ets in TAMs to determine its function at this level on mouse mammary tumor growth and metastasis. Ets2 deletion in TAMs decreased the frequency and size of lung metastase ...[more]

PMID: 20145133

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Project description:Molecular mechanisms of the cancer cells-macrophages interactions growing in vitro conditions as a co-culture. The five canine mammary cancer cell lines were cultured with monocytes sorted from the canine blood for 72hrs. Then, the cancer cells and macrophages were sorted and the gene expression analysis was conducted. The control for each co-cultured cell line was the same cell line growing as a single culture, whereas the control for the macrophages growing in a co-culture conditions were macrophages growing as a single culture. Solid tumors are comprised of various cells, like cancer cells, resident stromal cells, migratory hemopoietic cells and so on. These cells regulate tumor growth and metastasis. Macrophages are probably the most important element of the interactions within the tumor microenvironment. However, the molecular mechanism how the tumor environment can educate tumor-associated macrophages (TAMs) toward a tumor-promoting phenotype still remains unknown. Moreover, there are no information how the presence of macrophages change the cancer cells phenotype. Exploring the underlying molecular mechanisms of these phenomena was the aim of this study. Solid tumors are comprised of various cells, like cancer cells, resident stromal cells, migratory hemopoietic cells and so on. These cells regulate tumor growth and metastasis. Macrophages are probably the most important element of the interactions within the tumor microenvironment. However, the molecular mechanism how the tumor environment can educate tumor-associated macrophages (TAMs) toward a tumor-promoting phenotype still remains unknown. Moreover, there are no information how the presence of macrophages change the cancer cells phenotype. Exploring the underlying molecular mechanisms of these phenomena was the aim of this study. Dye-swap experiment, each cell line growing in the co-culture conditions was compared to the same cell line growing as a single culture, macrophages growing in the co-culture conditions were compared to the macrophages growing as the single culture.

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An Ets2-specific transcriptional program in tumor-associated macrophages promotes metastasis

Publications

An ets2-driven transcriptional program in tumor-associated macrophages promotes tumor metastasis.

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