Grant: CIHR Fellowship

In aggressive cancers, chemotherapy often results in an initial but unsustained remission followed by a fatal relapse with cancer cells that are no longer responsive to available treatments. One explanation for this is the postulated existence of intrinsically therapy-resistant tumor-initiating cells (TICs) that can regenerate a cancer population. Because these cells are often rare, standard genomics and proteomics technologies may be unable to detect them in analyses of unseparated samples taken directly from patients either at diagnosis or remission. In addition, TIC signatures change across disease subtypes and patients. It is therefore critical to have the appropriate technologies to characterize these TICs to obtain a detailed understanding of the molecular systems that allow their expansion. In this project, I hypothesize that proliferation and expansion of TICs is controlled by epigenetic deregulation of critical signaling pathways and that mapping these signals will facilitate their isolation and eradication. Mass cytometry is a transformative new proteomics technology that enables characterization of signaling pathways for a wide range of (rare) cell types. This project makes specific use of several technologies based on this platform, and state-of-the-art bioinformatics analysis, to systematically identify and disrupt the epigenetic events that contribute to tumor-initiation at a single-cell-level. Strategic collaborations with leading Canadian laboratories are already in place to complement the expertise of the host laboratory and ensure the impact of this work on the Canadian research community. Based on our promising preliminary results, we believe that this work not only can lead to stronger prognostic markers for risk stratification, but also can guide the design of risk-adapted and synergistic "personalized" therapies to improve the poor outcome associated with aggressive and therapy-resistant tumor