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Effect of CSF1R inhibition in tumor macrophages on gene expression in metastatic epithelial cells

ABSTRACT: Metastasis is the primary cause of mortality in breast cancer patients. Tumor associated macrophages (TAMs) are active collaborators in mediating several steps of the tumor metastatic cascade, but the molecular details governing this collaboration remain ill-defined. Colony Stimulating Factor 1 (CSF1), a factor critical for macrophage differentiation and survival, functions to recruit TAMs to the primary tumor site, and anti-CSF1 therapies are in clinical trials.In this study, we tested the effect of inhibiting CSF1 signaling in macrophages on gene expression in metastatic tumor cells in mouse models of breast cancer metastasis. Tumor cells were sorted from lung metastases from control and CSF1R inhibitor treated mice. Several pro-tumor processes were significantly affected by CSF1R inhibitor treatment, including angiogenesis and tumor cell proliferation. In addition, a 29 gene signature derived from this data could retrospectively predict survival in a cohort of luminal B breast cancer patients. Collectievly, our results highlight the utility of employing CSF1R inhibitors for the treatment of metastatic breast cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE55855 | GEO | 2014/03/13

SECONDARY ACCESSION(S): PRJNA241162

REPOSITORIES: GEO

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Effect of CSF1R inhibition in tumor macrophages on gene expression in metastatic epithelial cells

Project description:Metastasis is the primary cause of mortality in breast cancer patients. Tumor associated macrophages (TAMs) are active collaborators in mediating several steps of the tumor metastatic cascade, but the molecular details governing this collaboration remain ill-defined. Colony Stimulating Factor 1 (CSF1), a factor critical for macrophage differentiation and survival, functions to recruit TAMs to the primary tumor site, and anti-CSF1 therapies are in clinical trials.In this study, we tested the effect of inhibiting CSF1 signaling in macrophages on gene expression in metastatic tumor cells in mouse models of breast cancer metastasis. Tumor cells were sorted from lung metastases from control and CSF1R inhibitor treated mice. Several pro-tumor processes were significantly affected by CSF1R inhibitor treatment, including angiogenesis and tumor cell proliferation. In addition, a 29 gene signature derived from this data could retrospectively predict survival in a cohort of luminal B breast cancer patients. Collectievly, our results highlight the utility of employing CSF1R inhibitors for the treatment of metastatic breast cancer. GFP tagged MVT1 metastatic mammary tumor cells were injected intravenously into FVB/N mice. Mice were gavaged with the CSF1R inhibitor GW2580 or vehicle starting one week post injection. GFP tagged tumor cells were sorted from metastatic tumor bearing lungs 1 and 2 weeks post injection from 2 vehicle treated mice for each. These are denoted 1_week_WT and 2_week_WT respectively. GFP tagged tumor cells were simultaneously sorted from mice gavaged with GW2580. These samples are denoted 2_week_GW. RNA was extracted and gene expression profiling was performed using the Affymetrix Mouse Genome 430 2.0 Array platform.

2014-03-13 | E-GEOD-55855 | biostudies-arrayexpress

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

Project description: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.

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

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Expression analysis of tumor-associated macrophages from primary tumor and metastatic lung

Project description:In tumor microenvironment, tumor-associated macrophages (TAMs) have been characterized as M1-like or M2-like phenotype. In this study, we investigated the characteristics and functional roles of different TAMs on cancer metastasis. We isolated TAMs from primary tumor and metastatic lung and performed microarrays to identify the gene expression in distinct TAMs populations.

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Glioblastoma Genetic Drivers Dictate the Function of Tumor-Associated Macrophages/Microglia and Responses to CSF1R Inhibition

Project description:Tumor-associated macrophages/microglia (TAMs) are prominent microenvironment components in human glioblastoma (GBM) that are potential targets for anti-tumor therapy. However, TAM depletion by CSF1R inhibition showed mixed results in clinical trials. We hypothesized that GBM subtype-specific tumor microenvironment convey distinct sensitivities to TAM targeting.We generated syngeneic PDGFB-driven and RAS-driven GBM models that resemble proneural-like and mesenchymal-like gliomas, and determined the effect of TAM targeting by CSF1R inhibitor PLX3397 on glioma growth. We also investigated the co-targeting of TAMs and angiogenesis on PLX3397-resistant RAS-driven GBM. Using single-cell transcriptomic profiling, we further explored differences in tumor microenvironment cellular compositions and functions in PDGFB- and RAS-driven gliomas. We found that growth of PDGFB-driven tumors was markedly inhibited by PLX3397. In contrast, depletion of TAMs at the early phase accelerated RAS-driven tumor growth and had no effects on other proneural and mesenchymal GBM models. In addition, PLX3397-resistant RAS-driven tumors did not respond to PI3K signaling inhibition. Single-cell transcriptomic profiling revealed that PDGFB-driven gliomas induced expansion and activation of pro-tumor microglia, whereas TAMs in mesenchymal RAS-driven GBM were enriched in pro-inflammatory and angiogenic signaling. Co-targeting of TAMs and angiogenesis decreased cell proliferation and changed the morphology of RAS-driven gliomas.Our work identify functionally distinct TAM subpopulations in the growth of different glioma subtypes. Notably, we uncover a potential responsiveness of resistant mesenchymal-like gliomas to combined anti-angiogenic therapy and CSF1R inhibition. These data highlight the importance of characterization of the microenvironment landscape in order to optimally stratify patients for TAM-targeted therapy.

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Human Tumor-Associated Macrophage and Monocyte Transcriptional Landscapes Reveal Cancer-Specific Reprogramming, Biomarkers, and Therapeutic Targets

Project description:The roles of tumor-associated macrophages (TAMs) and circulating monocytes in human cancer are poorly understood. Here, we show that monocyte subpopulation distribution and transcriptomes are significantly altered by the presence of endometrial and breast cancer. Furthermore, TAMs from endometrial and breast cancers are transcriptionally distinct from monocytes and their respective tissue-resident macrophages. We identified a breast TAM signature that is highly enriched in aggressive breast cancer subtypes and associated with shorter disease-specific survival. We also identified an auto-regulatory loop between TAMs and cancer cells driven by tumor necrosis factor alpha involving SIGLEC1 and CCL8, which is self- reinforcing through the production of CSF1. Together these data provide direct evidence that monocyte and macrophage transcriptional landscapes are perturbed by cancer, reflecting patient outcomes.

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