Project description:The purpose of this study is the investigation of new host-microbiome interactions promoting adenoma formation and adenocarcinoma progression. For that purpose, the investigators will collect saliva, stool and colon biopsy specimens from patients referred to colonoscopy or surgical resection of colorectal tumor. Besides, a questionnaire about diet, lifestyle and medical history will be collected. Sample analysis will involve simultaneous characterization of host and microbiota genomic and transcriptomic components.
Project description:Hypomethylating agents (HMAs) are frontline therapies effective at altering the natural course of Myelodysplastic Neoplasms (MDS). However, acquired resistance and treatment failure are hallmarks of HMA therapy. Developing effective and rational HMA-focused combinatorial therapies is challenging as the underlying mechanisms driving HMA efficacy are complex. To address this clinical need, we performed a genome-wide CRISPR-Cas9 screen in a human MDS-derived cell line, MDS-L, and characterized TOPORS as a highly ranked target that synergizes with HMAs to reduce leukemic burden and improve survival in xenograft models. We demonstrated that the depletion of TOPORS mediates sensitivity to HMAs by predisposing leukemic blasts to an impaired DNA damage response (DDR) accompanied by an accumulation of SUMOylated DNMT1 in HMA-treated TOPORS-depleted cells. Importantly, the combination of HMAs with targeting of TOPORS did not functionally impair healthy hematopoiesis. While inhibitors of TOPORS are currently unavailable, we show that inhibition of SUMOylation (upstream of TOPORS functions) with TAK-981 partially phenocopies HMA-sensitivity and DDR impairment. Overall, our data suggest that the combination of HMAs with the inhibition of SUMOylation demonstrates a favourable therapeutic index and represents a rational framework towards the treatment of High-Risk MDS (HR-MDS) or Acute Myeloid Leukemia (AML).
Project description:In this study, we assessed lower airway microbiome from a cohort of patients to determine whether specific microbiome taxa correlate with with specific metabolic activities. In a subset of 12 patients, transcriptomic expression were analyzed to compare host mucosa immune response We collected peripheral airway brushings from the 12 subjects whose lung microbiome were analyzed; Total RNA were obtained from the peripheral airway epithelium.
