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SUMMARY:EPFL BioE Talks SERIES  "Oncogenic Activation of Dihydroceramide D
 esaturase (DEGS1) Promotes Anchorage-Independent Survival in Breast Cancer
 "
DTSTART:20201005T160000
DTEND:20201005T163000
DTSTAMP:20260429T101545Z
UID:5e9200f966859bc1b978774749b2dc33a910480031308d36bad873d1
CATEGORIES:Conferences - Seminars
DESCRIPTION:Prof. Christopher J. Clarke\, Stony Brook University\, Stony B
 rook\, NY (USA)\nWEEKLY EPFL BIOE TALKS SERIES\n\n(note that this talk is 
 number one of a double-feature seminar - see details of the second talk he
 re) \n\nAbstract:\nSurvival rates for metastatic breast cancer (BC) remain
  poor and there is a critical need to identify novel druggable targets for
  treatment of metastatic disease. Resistance to anoikis – cell death fol
 lowing detachment from the extracellular matrix (ECM) – is central to me
 tastasis and has recently emerged as a target biology of interest. Sphingo
 lipids (SL) are well-established mediators of cell death and SL metabolism
  is dysregulated in BC. However\, connections between oncogenic signaling\
 , deregulation of SL metabolism\, and the acquisition of anoikis resistanc
 e have not been explored. Culture of non-transformed MCF10A breast epithel
 ial cells in ECM-detached conditions resulted in initiation of cell death 
 pathways and accumulation of ceramide (Cer)\, dihydroceramide (dhCer) and 
 sphingosine (Sph) but not in anoikis-resistant HER2+ BC cells. Overexpress
 ion of oncogenic HER2 (NeuT) and PI3K in MCF10A cells – two commonly mut
 ated pathways in BC –promoted cell survival in ECM-detached conditions. 
 Surprisingly\, this was associated with suppression of dhCer but not Cer o
 r Sph suggesting increased dhCer metabolism is linked with anoikis resista
 nce. Consistent with this\, activity of DEGS1\, the major dhCer metabolizi
 ng enzyme – was decreased in ECM-detached MCF10A cells but was maintaine
 d in HER2+ BC cells in a HER2 and PI3K-dependent manner. Moreover\, oncoge
 nic NeuT and PI3K expression was sufficient to promote DESGS1 activity in 
 ECM-detached MCF10A cells. Functionally\, loss of DEGS1 activity through p
 harmacological inhibitors\, siRNA\, or by Crispr-mediated knockout results
  in dhCer accumulation\, decreased cell viability in ECM-detached conditio
 ns\, and decreased colony formation in HER2+ BC cells. Conversely\, overex
 pression of DEGS1 but not DEGS2 was able to promote anchorage-independent 
 survival in MCF10A cells and enhance colony formation in HER2+ BC cells. F
 inally\, analysis of public datasets linked high levels of DEGS1 to worse 
 relapse-free survival and distant metastasis free survival in HER2+ BC. Ta
 ken together\, these results demonstrate the oncogenic reprogramming of SL
  metabolism through DEGS1 activation is important for promoting anchorage-
 independent survival – a key biology for BC metastasis – and suggest t
 hat this could be exploited as a novel therapy for metastatic tumors.\n\nC
 o-authorship in this research: Ryan W. Linzer\, Gabrielle Khalife\, Jonath
 an Aminov\, Justin M. Snider\, A. Burak Buyukbayraktar\, Pule Wang\, Chun-
 Hao Pan\, Prajna Shanbhogue\, Jihui Ren\, Janet J. Allopenna\, and Christo
 pher J. Clarke\n\n\nZoom link (with registration) for attending remotely: 
 https://go.epfl.ch/EPFLBioETalks\n\n\nIMPORTANT NOTICE: due to restriction
 s resulting from the ongoing Covid-19 situation\, this seminar can be foll
 owed via Zoom web-streaming only\, following prior one-time registration t
 hrough the link above.
LOCATION:via Zoom web-streaming only\, due to Covid-19 situation https://g
 o.epfl.ch/EPFLBioETalks
STATUS:CONFIRMED
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