Mechanisms of Carcinogenesis and Tumor progression

  • Stamenkovic, Ivan (PI)

Project Details

Description

Despite a great deal of knowledge gained regarding mechanisms that underlie transformation and subsequent tumor formation and progression, management of the majority of solid malignancies still faces major obstacles. Many of the cancer cell properties that have been detected or proposed decades ago, including their heterogeneity despite clonal origin and their capacity to subvert the host tissue stroma, have yet to be fully understood and metastasis, the main cause of cancer-related death, remains virtually unscathed by the therapeutic arsenal currently at hand. To complicate issues further, it is becoming increasingly clear that epigenetic changes may play a key role in tumor progression and resistance to therapy and even override the influence of genetic mutations themselves. The long term goal of this project is to acquire a better understanding of the mechanisms that underlie cancer initiation, development and progression with the hope that such understanding will help identify new therapeutic targets and lead to rationally designed, effective therapeutic strategies. We have chosen to work on sarcomas, which include some of the most aggressive tumors, often arising in children and young adults and associated with a somber prognosis despite multimodal therapy. Because these malignancies have not been investigated as intensely as the more common carcinomas, they are still poorly understood from a biological standpoint. The short term goal is to determine the nature of tumor cell heterogeneity in sarcomas, the properties that distinguish sarcoma stem/initiator cells (CSC/CIC) from the bulk of tumor cells, including their chromatin modifications and bioenergetics, the possibilities to distinctly target CSC/CIC therapeutically and the mechanisms that render mesenchymal stem/progenitor cells (MSC/MPC) permissive for specific oncogene expression and action and thereby elucidate how sarcomas are generated. These issues will be addressed using Ewing sarcoma family tumors (ESFT) as a model, but other sarcoma types, and possibly other malignancies will be investigated as the project unfolds. The specific aims are as follows:Specific Aim 1: Assessment of the effect of targeted therapy, alone or in combination with standard of care treatment, on ESFT CSC/CIC and tumor growth. This section will include:1.1. Analysis of the effect of fluoroquinolones alone on primary ESFT growth in vivo ; 1.2. Analysis of the effect of combined standard of care and fluoroquinolone treatment on primary ESFT growth in vivo;1.3. Assessment of the properties of residual tumors following single and combined therapy in terms of tumor initiation, clonogenicity and resistance to therapy ;1.4. Assessment of the broader applicability of fluoroquinolones in CSC targeting: investigation of their effect alone or in combination with conventional therapy in glioblastomas;Specific Aim 2: Determination of epigenetic mechanisms that regulate ESFT CSC properties. This section will include:2.1. Determination of chromatin modification in spherogenic versus adherent cells;2.2. Determination of chromatin modification in CD133+ versus CD133- cells;2.3 RNA-seq analysis of CD133+ versus CD133- cells and assessment of 3’UTR length;Specific Aim 3: Assessment of the epigenetic changes in MSC grown under different culture conditions. This section will include:3.1. Assessment of chromatin modifications in MSC grown in KO versus normal medium;3.2. Assessment of chromatin modifications of MSC grown as spheres versus adherent cells;3.3. Assessment of chromatin modifications of MSC expressing EWS-FLI1; Specific Aim 4: Assessment of ESFT CSC bioenergetics as viewed through the function of Imp2 and the requirement or not for oxidative phosphorylation. This section will include:4.1. Assessment of mRNA binding by Imp2 in ESFT CSC versus bulk cells;4.2. Assessment of Imp2 phosphorylation in ESFT CSC versus bulk cells;

StatusFinished
Effective start/end date1/04/0530/11/16

Funding

  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung: $810,228.00

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