WNT-mediated signaling relay in stem cells and oncogenesis - from basic biology to applications

Targeting non-canonical WNT/PCP pathway receptors in chronic lymphocytic leukemia

Early stage researcher 5 (ESR5) project

Supervision: Vitezslav Bryja

Lab webpage:  http://www.sci.muni.cz/ofiz/index_en.php?page=groups&sub=bryja

Aim:
To develop reagents that can interfere with the chronic lymphocytic leukemia (CLL)-specific composition of WNT/PCP receptor complexes and their downstream signalling.

Methodology:
ESR5 will screen peptide and small inhibitor libraries for their ability to block migration of CLL cells in a chemokine gradient (private sector secondment: Isogenica), to determine suitability for preclinical testing. ESR5 will also determine key intracellular residues required for the interaction of FZD3 and FZD7 with Dishevelled (international secondment: Maurice and collaboration Schulte). The interaction interface will be characterized biochemically and biophysically. Blocking peptides will be designed using rational design (collaboration Friedler). ESR5 will inhibit activity of the PCP receptors CELSR1 and ROR1 that are uniquely expressed in CLL by monoclonal antibodies against essential extracellular epitopes (collaboration Pepscan).

Collaborators:
Schulte, Friedler, Maurice, Pepscan, Isogenica

Project goals:
ESR5 will identify reagents capable of interfering with WNT/PCP-controlled migration of CLL cells and describe the molecular mechanism of action.

Risk assessment and contingency plans:
A high-throughput screening system for CLL migration is established. Screening approaches are high-risk, high gain, while characterization of the FZD3/7 binding site with Dvl is rather straightforward. Pilot experiments will determine the most promising route for development of a potent blocking reagent.

Key publications:

1. Soldano A, Okray Z, Janovska P, Tmejová K, Reynaud E, Claeys A, Yan J, Atak ZK, De Strooper B, Dura JM, Bryja V, Hassan BA (2013): The Drosophila Homologue of the Amyloid Precursor Protein Is a Conserved Modulator of Wnt PCP Signaling. PLoS Biol. 11(5):e1001562.

2. M. Kaucká, K. Plevová, Š. Pavlová, J. Verner, J. Procházková, P. Janovská, P. Krejčí, J. Kotašková, P. Ovesná, B. Tichý, Y. Brychtová, M. Doubek, A. Kozubík, J. Mayer, Š. Pospíšilová and V. Bryja: The planar cell polarity pathway drives pathogenesis of chronic lymphocytic leukemia by the regulation of B-lymphocyte migration. Cancer Res. 73(5):1491-501.

3. Chaki M, Airik R, Ghosh AK, Giles RH, Chen R, Slaats GG, Wang H, Hurd TW, Zhou W, Cluckey A, Gee HY, Ramaswami G, Hong CJ, Hamilton BA, Cervenka I, Ganji RS, Bryja V, Arts HH, van Reeuwijk J, Oud MM, Letteboer SJ, Roepman R, Husson H, Ibraghimov-Beskrovnaya O, Yasunaga T, Walz G, Eley L, Sayer JA, Schermer B, Liebau MC, Benzing T, Le Corre S, Drummond I, Janssen S, Allen SJ, Natarajan S, O'Toole JF, Attanasio M, Saunier S, Antignac C, Koenekoop RK, Ren H, Lopez I, Nayir A, Stoetzel C, Dollfus H, Massoudi R, Gleeson JG, Andreoli SP, Doherty DG, Lindstrad A, Golzio C, Katsanis N, Pape L, Abboud EB, Al-Rajhi AA, Lewis RA, Omran H, Lee EY, Wang S, Sekiguchi JM, Saunders R, Johnson CA, Garner E, Vanselow K, Andersen JS, Shlomai J, Nurnberg G, Nurnberg P, Levy S, Smogorzewska A, Otto EA, Hildebrandt F. (2012): Exome Capture Reveals ZNF423 and CEP164 Mutations, Linking Renal Ciliopathies to DNA Damage Response Signaling. Cell. 150(3): 533-48.