EPFL BioE Talks SERIES "Oncogenic Activation of Dihydroceramide Desaturase (DEGS1) Promotes Anchorage-Independent Survival in Breast Cancer"
Event details
| Date | 05.10.2020 |
| Hour | 16:00 › 16:30 |
| Speaker | Prof. Christopher J. Clarke, Stony Brook University, Stony Brook, NY (USA) |
| Location | |
| Category | Conferences - Seminars |
WEEKLY EPFL BIOE TALKS SERIES
(note that this talk is number one of a double-feature seminar - see details of the second talk here)
Abstract:
Survival 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 following detachment from the extracellular matrix (ECM) – is central to metastasis and has recently emerged as a target biology of interest. Sphingolipids (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 resistance have not been explored. Culture of non-transformed MCF10A breast epithelial 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. Overexpression of oncogenic HER2 (NeuT) and PI3K in MCF10A cells – two commonly mutated pathways in BC –promoted cell survival in ECM-detached conditions. Surprisingly, this was associated with suppression of dhCer but not Cer or Sph suggesting increased dhCer metabolism is linked with anoikis resistance. Consistent with this, activity of DEGS1, the major dhCer metabolizing enzyme – was decreased in ECM-detached MCF10A cells but was maintained in HER2+ BC cells in a HER2 and PI3K-dependent manner. Moreover, oncogenic NeuT and PI3K expression was sufficient to promote DESGS1 activity in ECM-detached MCF10A cells. Functionally, loss of DEGS1 activity through pharmacological inhibitors, siRNA, or by Crispr-mediated knockout results in dhCer accumulation, decreased cell viability in ECM-detached conditions, and decreased colony formation in HER2+ BC cells. Conversely, overexpression of DEGS1 but not DEGS2 was able to promote anchorage-independent survival in MCF10A cells and enhance colony formation in HER2+ BC cells. Finally, analysis of public datasets linked high levels of DEGS1 to worse relapse-free survival and distant metastasis free survival in HER2+ BC. Taken 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 that this could be exploited as a novel therapy for metastatic tumors.
Co-authorship in this research: Ryan W. Linzer, Gabrielle Khalife, Jonathan Aminov, Justin M. Snider, A. Burak Buyukbayraktar, Pule Wang, Chun-Hao Pan, Prajna Shanbhogue, Jihui Ren, Janet J. Allopenna, and Christopher J. Clarke
Zoom link (with registration) for attending remotely: https://go.epfl.ch/EPFLBioETalks
IMPORTANT NOTICE: due to restrictions resulting from the ongoing Covid-19 situation, this seminar can be followed via Zoom web-streaming only, following prior one-time registration through the link above.
(note that this talk is number one of a double-feature seminar - see details of the second talk here)
Abstract:
Survival 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 following detachment from the extracellular matrix (ECM) – is central to metastasis and has recently emerged as a target biology of interest. Sphingolipids (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 resistance have not been explored. Culture of non-transformed MCF10A breast epithelial 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. Overexpression of oncogenic HER2 (NeuT) and PI3K in MCF10A cells – two commonly mutated pathways in BC –promoted cell survival in ECM-detached conditions. Surprisingly, this was associated with suppression of dhCer but not Cer or Sph suggesting increased dhCer metabolism is linked with anoikis resistance. Consistent with this, activity of DEGS1, the major dhCer metabolizing enzyme – was decreased in ECM-detached MCF10A cells but was maintained in HER2+ BC cells in a HER2 and PI3K-dependent manner. Moreover, oncogenic NeuT and PI3K expression was sufficient to promote DESGS1 activity in ECM-detached MCF10A cells. Functionally, loss of DEGS1 activity through pharmacological inhibitors, siRNA, or by Crispr-mediated knockout results in dhCer accumulation, decreased cell viability in ECM-detached conditions, and decreased colony formation in HER2+ BC cells. Conversely, overexpression of DEGS1 but not DEGS2 was able to promote anchorage-independent survival in MCF10A cells and enhance colony formation in HER2+ BC cells. Finally, analysis of public datasets linked high levels of DEGS1 to worse relapse-free survival and distant metastasis free survival in HER2+ BC. Taken 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 that this could be exploited as a novel therapy for metastatic tumors.
Co-authorship in this research: Ryan W. Linzer, Gabrielle Khalife, Jonathan Aminov, Justin M. Snider, A. Burak Buyukbayraktar, Pule Wang, Chun-Hao Pan, Prajna Shanbhogue, Jihui Ren, Janet J. Allopenna, and Christopher J. Clarke
Zoom link (with registration) for attending remotely: https://go.epfl.ch/EPFLBioETalks
IMPORTANT NOTICE: due to restrictions resulting from the ongoing Covid-19 situation, this seminar can be followed via Zoom web-streaming only, following prior one-time registration through the link above.
Practical information
- Informed public
- Registration required
Organizer
Contact
- Institute of Bioengineering (IBI), Dietrich REINHARD