Project description:Mortality from breast cancer is almost exclusively a result of tumor metastasis and resistance to therapy and therefore understanding the underlying mechanisms is an urgent challenge. Chemotherapy, routinely used to treat breast cancer, induces extensive tissue damage, eliciting an inflammatory response that may hinder efficacy and promote metastatic relapse. Here we show that systemic treatment with chemotherapy following resection of a triple-negative breast tumor induced the expression of complement factors in lung fibroblasts and modulated an immunosuppressive metastatic niche that supported lung metastasis. CAF-derived complement signaling mediated the recruitment of myeloid-derived suppressor cells (MDSCs) to the metastatic niche, thus promoting T cell dysfunction. Functionally, we show that pharmacological targeting of complement signaling in combination with chemotherapy alleviated immune dysregulation and attenuated lung metastasis. Our findings suggest that combining cytotoxic treatment with blockade of complement signaling in triple-negative breast cancer patients may attenuate the adverse effects of chemotherapy, thus offering a promising approach for clinical use.
Project description:Mortality from breast cancer is almost exclusively a result of tumor metastasis and resistance to therapy and therefore understanding the underlying mechanisms is an urgent challenge. Chemotherapy, routinely used to treat breast cancer, induces extensive tissue damage, eliciting an inflammatory response that may hinder efficacy and promote metastatic relapse. Here we show that systemic treatment with doxorubicin, but not cisplatin, following resection of a triple-negative breast tumor induced the expression of complement factors in lung fibroblasts and modulated an immunosuppressive metastatic niche that supported lung metastasis. CAF-derived complement signaling mediated the recruitment of myeloid-derived suppressor cells (MDSCs) to the metastatic niche, thus promoting T cell dysfunction. Pharmacological targeting of complement signaling in combination with chemotherapy alleviated immune dysregulation and attenuated lung metastasis. Our findings suggest that combining cytotoxic treatment with blockade of complement signaling in triple-negative breast cancer patients may attenuate the adverse effects of chemotherapy, thus offering a promising approach for clinical use.
Project description:To identify lung metastasis associated microRNAs in triple negative breast cancer (TNBC), we have employed the commercially available Agilent Human miRNA V19.0 Microarray (Platform GPL19730) as a discovery platform. In comparison with LM-Normal, 11 microRNAs significantly altered in both LM-Met and LM-Tumor, and then three of them (hsa-miR-21-3p, hsa-miR-21-5p and hsa-miR-211-3p) were excluded, which were also up-regulated in RF-Tumor. Consequently, eight deregulated microRNAs were identified to be putatively involved in process of lung metastasis, especially miR-629-3p, which was most up-regulated in both LM-Met and LM-Tumor. To validate the microarray data, we utilized qRT-PCR to assess expression levels of the eight miRNAs in the same samples.
Project description:In this study, analysis of mRNA sequencing was used to identify potential biological signalling pathways involved in the inhibition of triple negative breast cancer metastasis by ITSN.
Project description:To define the molecular regulators of metastasis of triple-negative breast cancer, we conducted a rigorous characterization of four populations of MDA-MB-231 human triple-negative breast cancer cells that display a range of intrinsic spontaneous metastatic capacities in immuno-deficient mice, from non-metastatic to highly metastatic to lung, liver, spleen and spine. PAT-Seq gene expression profiling of primary tumor cells identified the fibroblast growth factor homologous factor, FGF13, as a candidate metastatic virulence gene highly upregulated in aggressively metastatic MDA-MB-231HM tumors.
