The role of placental gene PEG10 during transdifferenciation into neuroendocrine prostate cancer
Final Report Abstract
The project initially termed “The Role Of Placental Gene PEG10 During Transdifferentiation Into Neuroendocrine Prostate Cancer” was modified before the start of my research fellowship, because of the development of the project between the time of my application and the time of the start of the research fellowship. The resulting project was termed “Characterization of stress-induced tunneling nanotubes and their support of treatment adaptation in prostate cancer”. Here, we define roles of tunneling nanotubes (TNTs), a newly identified stress-induced structure for intercellular communication, in stress adaptation and treatment resistance in prostate cancer (PCa). Androgen receptor (AR) blockade and metabolic stress induce TNTs in PCa, but not in normal prostatic epithelial and osteoblast cells. Co-culture assays reveal enhanced TNT formation between stressed and unstressed PCa cells as well as from stressed PCa to osteoblasts. Stress chaperones clusterin (CLU), YB-1 and Hsp27 localize within TNTs, and CLU-containing particles are transported bi-directionally via TNTs. TNT formation was attenuated by PI3K inhibition and also by silencing CLU or YB-1. AR splice variant V7, which is induced by AR antagonism and help mediate resistance to AR pathway inhibition, enhances TNT formation and rescues loss of CLU- or YB-1-repressed TNT formation. Disruption of TNT sensitizes PCa to AR blockade- or metabolic stress-induced cell death. These data identify induction of TNT formation by PCa cells for intercellular communication of stress-associated material to confer survival.
Publications
- (2019) Stress-induced tunneling nanotubes support treatment adaptation in prostate cancer. Scientific reports 9 (1) 7826
Kretschmer, Alexander; Zhang, Fan; Somasekharan, Syam Prakash; Tse, Charan; Leachman, Lauren; Gleave, Anna; Li, Brian; Asmaro, Ivan; Huang, Teresa; Kotula, Leszek; Sorensen, Poul H.; Gleave, Martin E.
(See online at https://doi.org/10.1038/s41598-019-44346-5) - Characterizing androgen receptor blockade- and metabolic stress-induced tunneling nanotube formation supporting stress adaptivity in prostate cancer. 2017. European Urology Supplements 16(3):e254
Alexander Kretschmer, Fan Zhang, Syam Prakash Somasekharan, Charan Tse, Lauren Leachman, Anna Gleave, Brian Li, Ivan Asmaro, Poul H. Sorensen, Martin E. Gleave
(See online at https://dx.doi.org/10.1016/S1569-9056(17)30218-X) - (2020): Paternally Expressed Gene 10 (PEG10) Promotes Growth, Invasion, and Survival of Bladder Cancer. In: Molecular cancer therapeutics 19 (10), S. 2210–2220
Yoshihisa Kawai, Kenjiro Imada, Shusuke Akamatsu, Fan Zhang, Tetsutaro Hayashi, Jeffrey Leong, Eliana Beraldi, Neetu Saxena, Alexander Kretschmer, Htoo Oo, Masatoshi Eto, Hideyasu Matsuyama, Ladan Fazli, Colin C Collins, Alexander W. Wyatt, Peter C Black,
(See online at https://doi.org/10.1158/1535-7163.MCT-19-1031)
