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Neutrophil oxidative stress mediates obesity-associated vascular inflammation and metastatic transmigration (Neutrophils_RNA-seq)

ABSTRACT: Obesity is linked to greater cancer incidence and mortality across multiple tumor types. In breast cancer, metastasis is the leading cause of cancer-related deaths, and epidemiological studies have shown that obesity is associated with increased breast cancer metastasis to lung and liver. Using both diet-induced and genetic preclinical models of obesity, it was previously shown that obese adipose tissue systemically induces lung neutrophilia, which is associated with enhanced breast cancer metastasis to this site. Here we performed RNAseq on neutrophils isolated on the lungs from lf vs hf mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE165442 | GEO | 2021/01/25

REPOSITORIES: GEO

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Project description:Gene Expression Profiling of Breast Cancer Patients with Brain Metastases Brain metastases confer the worst prognosis of breast cancer as no therapy exists that prevents or eliminates the cancer from spreading to the brain. We developed a new computational modeling method to derive specific downstream signaling pathways that reveal unknown target-disease connections and new mechanisms for specific cancer subtypes. The model enables us to reposition drugs based on available gene expression data of patients. We applied this model to repurpose known or shelved drugs for brain, lung, and bone metastases of breast cancer with the hypothesis that cancer subtypes have their own specific signaling mechanisms. To test the hypothesis, we addressed the specific CSBs for each metastasis that satisfy that (1) CSB proteins are activated by the maximal number of enriched signaling pathways specific to this metastasis, and (2) CSB proteins involve in the most differential expressed coding-genes specific to the specific breast cancer metastasis. The identified signaling networks for the three types of metastases contain 31, 15, and 18 proteins, respectively, and are used to reposition 15, 9, and 2 drug candidates for the brain, lung, and bone metastases of breast cancer. We performed in vitro and in vivo preclinical experiments as well as analysis on patient tumor specimens to evaluate the targets and repositioned drugs. Two known drugs, Sunitinib (FDA approved for renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumor) and Dasatinib (FDA approved for chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia), were shown to prohibit the metastatic colonization in brain. The TMH-52 cohort includes 11 patients who were examined with brain metastasis at the time of breast cancer diagnosis. The other 41 patients were examined with other organ metastasis at the time of breast cancer diagnosis.

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Neutrophil oxidative stress mediates obesity-associated vascular inflammation and metastatic transmigration (Neutrophils_RNA-seq)

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