Project description:Treatment of PC3 and MDA-MB-231 cell lines with sublethal doses of docetaxel or cisplatin in vitro resulted in induction of polyploid cancer cells. Single cell copy number profiling was conducted to understand resistance of polyploid cancer cells to chemotherapy.
Project description:Treatment of PC3 and MDA-MB-231 cell lines with sublethal doses of docetaxel or cisplatin in vitro resulted in induction of polyploid cancer cells. Single cell copy RNA-sequencing was conducted to understand resistance of polyploid cancer cells to chemotherapy.
Project description:To elucidate the mechanisms underlying relapse from chemotherapy in multiple myeloma we performed a longitudinal study of 33 patients entered into Total Therapy protocols investigating them using gene expression profiling, high resolution copy number arrays and whole exome sequencing. The study illustrates the mechanistic importance of acquired mutations in known myeloma driver genes and the critical nature of bi-allelic inactivation events affecting tumor suppressor genes, especially TP53. The end result being resistance to apoptosis and increased proliferation rates, which drive relapse by Darwinian type clonal evolution. The number of copy number aberration changes and bi-allelic inactivation of tumor suppressor genes was increased in GEP70 high risk, consistent with genomic instability being a key feature of high risk. In conclusion, the study highlights the impact of acquired genetic events, which enhance the evolutionary fitness level of myeloma propagating cells to survive multi-agent chemotherapy and to result in relapse.
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: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:Wilms tumor (WT), the commonest renal tumor of the childhood, is originated from pluripotent metanephric blastemal cells resulting in tumors with triphasic histology, composed by blastemal, epithelial, and stromal cells. Histological subtype and tumor stage have long been recognized as important prognostic factors and used for the current therapeutic approach with blastema considered as the component with the highest clinical impact. Current clinical and molecular research is directed toward identifying prognostic factors for both purposes, definition of the minimal or intense required therapy for successful treatment of children with low or high risk of relapse, respectively. In this study, to identify molecular prognostic markers predictive of tumor relapse, samples from 26 advanced (Stage III or IV) blastemal WT, whose patients presented (13 samples) or did not present (13 samples) relapse, were interrogated by 4,608 human genes immobilized in a customized cDNA platform. This analysis revealed a set of 69 differentially expressed genes, where the nine top genes were evaluated by qRT-PCR in the initial WT samples. TSPAN3, NCOA6, CDO1, MPP2 and MCM2 were technically confirmed showing down-regulation in relapse WT. TSPAN3 and NCOA6 were validated in an independent sample group. Gene trios containing these two genes combined with one of the remaining three reported a reasonable capability of discriminating relapse and no-relapse WT. Negative protein expression of MCM2 and NCOA6 was observed in around 62% and 72% of 34 independent stage III and IV WT patients, respectively without association with relapse. However, a significant association between MCM2 negative staining and chemotherapy as first treatment was observed suggesting that MCM2 protein expression is implicated anyhow with chemotherapy treatment in WT.
Project description:Genome-wide analysis of adult and pediatric acute myeloid leukemias (AMLs) revealed distinct mutational profiles characterized by a higher incidence of RAS mutations in young patients. Here we show that the BET inhibitor PLX51107 potently suppresses the growth and promotes apoptosis of NRAS-mutant monocytic AML cell lines, and that these activities are enhanced by co-treatment with the MEK inhibitor PD0325901. Controlled preclinical trials in primary mouse Nras-mutant monocytic AMLs revealed single agent efficacy of PLX51107 that was enhanced by PD0325901. Leukemias that relapsed during treatment developed intrinsic drug resistance characterized by transition to a more primitive state, up-regulation of Myc target genes, and down-regulation of Ras-associated transcriptional programs. AMLs that relapsed after frontline chemotherapy showed similar transcriptional remodeling. These studies demonstrate transcriptional plasticity in primary AMLs that relapse following in vivo treatment with either targeted agents or chemotherapy, and support evaluating BET inhibition in leukemias with monocytic differentiation and RAS mutations.