Eldad Zacksenhaus

Eldad Zacksenhaus, PhD

Breast Cancer (BC)
In North America, the life-long incidence of BC is ~10%. The disease is heterogeneous and can be subdivided into three subtypes: ER+, HER2/NEU+ and triple negative tumors (TNT), the latter of which does not express hormone receptors or HER2/NEU. Specific treatments exist for ER+ and HER2+ but not TNTs; metastatic disease is virtually untreatable. To identify novel therapeutic targets we are using a mouse model for HER2/NEU+ BC (MMTV-Neu; Muller) and two models of TNTs, which we have developed based on inactivation of the tumour suppressors Rb or Pten in the mammary epithelium. In particular, we are interested in identifying and targeting tumour-initiating cells and early dissemination cancer cells, which are thought to drive tumour growth and spread.

a. We have identified tumour-initiating cells (TICs) in HER2/NEU mammary tumours and we are currently developing a specific TIC signature as well as screening for therapeutic targets using shRNA and small chemical libraries.

The Retinoblastoma Protein (Rb)
Rb plays a crucial role in regulating cell proliferation and survival and possibly terminal differentiation, and is mutated or functionally inactivated in virtually all human malignancies. Using loss- and gain-of-function approaches we are investigating the effects of Rb on embryonic development, homeostasis and cancer, as well as the mechanisms by which it exerts these diverse biological functions.

a. Previously, we showed that mouse embryos lacking Rb develop severe muscle defects including ectopic proliferation, cell death and abortive differentiation and degeneration. We have recently shown that the myogenic differentiation defect and degeneration could be rescued in vitro by survival factors, autophagy inhibitors or hypoxia. We have also determined the effect of combined mutations in all Rb protein family on myogenesis. Alternative roles for Rb in development and differentiation as well as its role in hypoxia and cell metabolism are currently being investigated.

b. Rb is primarily regulated by phosphorylation via cyclin-dependent kinases. pRb is hypo-phosphorylated and active in G0/G1 and then sequentially phosphorylated and inactivated by D and E type cyclins. We previously showed that expression of constitutively active phospho-mutant pRb transgenes inhibits cell proliferation but paradoxically induces tumours. To investigate the effect of blocking endogenous phosphorylation of Rb, we use a knockin approach to mutate key phosphorylation sites in Rb and test their impact in vitro and in vivo.
 
Trends Cancer. 2017 Nov;3(11):768-779
Zacksenhaus E, Shrestha M, Liu JC, Vorobieva I, Chung PED, Ju Y, Nir U, Jiang Z
Oncogene. 2017 Sep 18;:
Xia L, Xiao X, Liu WL, Song Y, Liu TJJ, Li YJ, Zacksenhaus E, Hao XJ, Ben-David Y
JCI Insight. 2017 Aug 03;2(15):
Wang S, Liu JC, Ju Y, Pellecchia G, Voisin V, Wang DY, Leha L R, Ben-David Y, Bader GD, Zacksenhaus E
Adv Protein Chem Struct Biol. 2017;107:223-273
Zacksenhaus E, Liu JC, Jiang Z, Yao Y, Xia L, Shrestha M, Ben-David Y
Oncotarget. 2016 Dec 30;:
Liu T, Yao Y, Zhang G, Wang Y, Deng B, Song J, Li X, Han F, Xiao X, Yang J, Xia L, Li YJ, Plachynta M, Zhang M, Yan C, Mu S, Luo H, Zacksenhaus E, Hao X, Ben-David Y
Cell Death Dis. 2016 Dec 22;7(12):e2560
Ren Z, Aerts JL, Vandenplas H, Wang JA, Gorbenko O, Chen JP, Giron P, Heirman C, Goyvaerts C, Zacksenhaus E, Minden MD, Stambolic V, Breckpot K, De Grève J
J Clin Invest. 2016 Aug 29;
Jones RA, Robinson TJ, Liu JC, Shrestha M, Voisin V, Ju Y, Chung PE, Pellecchia G, Fell VL, Bae S, Muthuswamy L, Datti A, Egan SE, Jiang Z, Leone G, Bader GD, Schimmer A, Zacksenhaus E

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Professor, Departments of Medicine, Laboratory Medicine & Pathobiology and Medical Biophysics, University of Toronto