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Transcriptional Signature Derived from Murine Tumor-Associated Macrophages Correlates with Poor Outcome in Breast Cancer Patients.

ABSTRACT: Tumor-associated macrophages (TAMs) are frequently the most abundant immune cells in cancers and are associated with poor survival. Here, we generated TAM molecular signatures from K14cre;Cdh1^flox/flox;Trp53^flox/flox (KEP) and MMTV-NeuT (NeuT) transgenic mice that resemble human invasive lobular carcinoma (ILC) and HER2⁺ tumors, respectively. Determination of TAM-specific signatures requires comparison with healthy mammary tissue macrophages to avoid overestimation of gene expression differences. TAMs from the two models feature a distinct transcriptomic profile, suggesting that the cancer subtype dictates their phenotype. The KEP-derived signature reliably correlates with poor overall survival in ILC but not in triple-negative breast cancer patients, indicating that translation of murine TAM signatures to patients is cancer subtype dependent. Collectively, we show that a transgenic mouse tumor model can yield a TAM signature relevant for human breast cancer outcome prognosis and provide a generalizable strategy for determining and applying immune cell signatures provided the murine model reflects the human disease.

SUBMITTER: Tuit S

PROVIDER: S-EPMC7057267 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Transcriptional signatures derived from murine tumor-associated macrophages predict outcome in breast cancer patients

Project description:Macrophages are frequently the most abundant immune cells in murine and human cancers. Studies in various transgenic mouse tumor models have revealed pro-tumor functions of tumor-associated macrophages (TAMs), but despite their association with poor clinical outcome in human patients, molecular signatures for the prediction of clinical outcome in humans are still missingbeen demonstrated. Here we generated molecular signatures from F4/80+CD11b+ TAMs from two transgenic breast cancer models: K14cre;Cdh1flox/flox;Trp53flox/flox (KEP), which resembles human invasive lobular carcinoma (ILC) and MMTV-NeuT (NeuT), which resembles HER2-overexpressing breast cancer. Determination of truly specific TAM transcriptome signatures in breast cancer required relationship analysis with healthy mammary gland tissue macrophages (MTMs), since comparison with macrophages from tissues overestimated TAM-specific gene expression. Furthermore, translation of the TAM signatures to outcome prediction in patients required consideration of the breast cancer subtype. TAM signatures derived from the KEP, but not the NeuT model reliably predicted outcome in ILC patients. Collectively, we show that a transgenic mouse tumor model can be utilized to derive a TAM-based signature for human breast cancer outcome prediction and provide a generalizable strategy for determining and applying specific molecular signatures of immune cells to, in principle, any cancer provided the murine model reflects the human disease.

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Transcriptional signatures derived from murine tumor-associated macrophages predict outcome in breast cancer patients

Project description:Transcriptional signatures derived from murine tumor-associated macrophages predict outcome in breast cancer patients

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An Eleven-microRNA Signature Related to Tumor-Associated Macrophages Predicts Prognosis of Breast Cancer.

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| S-EPMC8424990 | biostudies-literature

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