Maastro lab offer research rotations at the BSc and MSc level for biomedical and medical students.
If you are interested in a project please select the project below add the topic in the subject line and send an email using the form below and we will get back to you.
I. Targeting NOTCH to induce chemosensitivity in tumors
Background: Overexpression of Notch pathway is common in many cancers. Drugs that target Notch (GSI), cause mechanism based toxicity in normal tissues limiting their clinical application (i.e gut). Notch is a master regulator of cell fate/differentiation and proliferation and impinges on many signaling pathways. For example Notch suppresses EGFR/ErbB2 signaling. Suppression of Notch in cancers can induce sensitivity to targeted agents such as herceptin. Other examples include crosstalk with ER/PR pathway. Vice versa mutation in some pathways (e.g PI-3K/PTEN) block sensitivity to GSI. Temporal modulation of these pathways would transiently increases sensitivity to GSI through activation of the Notch pathway (for which no resistance has been established). Alternatively Notch signaling in tumors may activate signaling pathways that protect cells from chemotherapy. Inhibiting Notch in these tumors may sensitise to chemotherapy. The mechanism proposed maybe may be EMT, stem cells, DNA repair direct regulation of drug efflux pumps suppression of cell death and others. Hypothesis: Inhibition of Notch in cancer cells may trigger synergistic chemo-sensitivity or overcome acquired chemo-resistance. This maybe achieved at doses where Notch signaling in normal tissues is less affected. Objective 1- To establish a screening system to uncover synthetic lethality between Notch and pathways that promote chemo-resistance. 2- To test chemotherapeutics and targeted agents used in the clinic in combination with Notch inhibitors.
II. The response of normal lung to cancer treatments
Treatment induced damage to the normal lung tissue is one of the most importants factors limiting the maximum effective dose which can be used to treat lung cancer. In this project you will be responsible for conducting basic research studying the effects of combined cancer treatments (radiation + chemotherapy and targeted drugs) on normal lung tissue response in vitro. The focus of your project will be to study how radiation therapy and hypoxia impact on lung proliferation and differentiation using patient derived lung epithelial cells in a multilayer system. You will use inhibitors of the NOTCH signalling pathway to study how they modify this response.
You will use IHC on sections from cultured human bronchial epithelial cells (PBEC) against lung specific proteins as well proteins in the NOTCH and DNA damage response pathway. You will quantitate these results using image analysis.
IV. Novel regulators of Notch Receptor Signaling
The highly conserved Notch receptors receive short-range signals that operate in regulating cell fate selection, differentiation and proliferation during many developmental processes and in self-renewing tissues in vertebrates. Mutation or overexpression of the Notch signaling pathway frequently occurs in human cancers. Notch proteins are transmembrane receptors that are activated by extracellular cleavage after ligand binding from adjacent cells. This cleavage removes the Notch extracellular domain, which is followed by another cleavage in the membrane that releases the Notch cytoplasmic domain that translocates to the nucleus where it acts as a transcription factor. We have identified ADAM10 as the metalloprotease that is involved in extracellular Notch1 cleavage (Van Tetering et al., JBC 2009).There are four receptors in human cells which can interact with 5 ligands which can all induce cleavage by Adam10 (Groot et al., MCB 2014 ). Whether other metalloproteases can also cleave NOTCH1-4 receptors is not known. We have conducted a high throughput barcode loss of function screen to identify novel regulators of NOTCh signalling.
You will work on a novel gene and study how these regulate Notch in biochemical and cel differentiation assays (neurogenic differentiation myogenic differentiaton , T-ALL leukemic cells). You wil use gain and loss of function approaches to study their casualty in Notch regulation.