EPFL BioE Talks SERIES "Mechanisms of Androgen Deprivation Therapy Induced Lineage Plasticity in Prostate Cancer"
Event details
| Date | 04.04.2022 |
| Hour | 16:00 › 17:00 |
| Speaker | Prof. Wouter Karthaus, ISREC, School of Life Sciences, EPFL, Lausanne (CH) |
| Location | Online |
| Category | Conferences - Seminars |
| Event Language | English |
WEEKLY EPFL BIOE TALKS SERIES
Abstract:
The inherent plasticity of tumor cells provides a mechanism of resistance to many molecularly targeted therapies, exemplified by adeno-to-neuroendocrine lineage transitions seen in prostate and lung cancer. Here we investigate the root cause of this lineage plasticity in a primary murine prostate organoid model that mirrors the lineage transition seen in patients. These cells lose luminal identity within weeks following deletion of Trp53 and Rb1, ultimately acquiring an Ar-negative, Syp+ phenotype after orthotopic in vivo transplantation. Single-cell transcriptomic analysis revealed progressive mixing of luminal-basal lineage features after tumor suppressor gene deletion, accompanied by activation of Jak/Stat and Fgfr pathway signaling and interferon-a and -g gene expression programs prior to any morphologic changes. Genetic or pharmacologic inhibition of Jak1/2 in combination with FGFR blockade restored luminal differentiation and sensitivity to antiandrogen therapy in models with residual AR expression. Collectively, we show lineage plasticity initiates quickly as a largely cell-autonomous process and, through newly developed computational approaches, identify a pharmacological strategy that restores lineage identity using clinical grade inhibitors.
Bio:
2007 BSc Rijksuniversiteit, Groningen (NL)
2008 MSc Rijksuniversiteit, Groningen (NL)
2013 PhD Hans Clevers group, Molecular Genetics Dept., Hubrecht Institute, Utrecht, The Netherlands
2014-2022 Research Associate, Memorial Sloan Kettering Cancer Center, New York City, NY (USA)
From April 1, 2022 Assistant Professor (Tenure Track), ISREC, EPFL, Lausanne (CH)
Zoom link (with one-time registration for the whole series) for attending remotely: https://go.epfl.ch/EPFLBioETalks
Instructions for 1st-year Ph.D. students who are under EDBB’s mandatory seminar attendance rule:
IF you are not attending in-person in the room, please make sure to
Abstract:
The inherent plasticity of tumor cells provides a mechanism of resistance to many molecularly targeted therapies, exemplified by adeno-to-neuroendocrine lineage transitions seen in prostate and lung cancer. Here we investigate the root cause of this lineage plasticity in a primary murine prostate organoid model that mirrors the lineage transition seen in patients. These cells lose luminal identity within weeks following deletion of Trp53 and Rb1, ultimately acquiring an Ar-negative, Syp+ phenotype after orthotopic in vivo transplantation. Single-cell transcriptomic analysis revealed progressive mixing of luminal-basal lineage features after tumor suppressor gene deletion, accompanied by activation of Jak/Stat and Fgfr pathway signaling and interferon-a and -g gene expression programs prior to any morphologic changes. Genetic or pharmacologic inhibition of Jak1/2 in combination with FGFR blockade restored luminal differentiation and sensitivity to antiandrogen therapy in models with residual AR expression. Collectively, we show lineage plasticity initiates quickly as a largely cell-autonomous process and, through newly developed computational approaches, identify a pharmacological strategy that restores lineage identity using clinical grade inhibitors.
Bio:
2007 BSc Rijksuniversiteit, Groningen (NL)
2008 MSc Rijksuniversiteit, Groningen (NL)
2013 PhD Hans Clevers group, Molecular Genetics Dept., Hubrecht Institute, Utrecht, The Netherlands
2014-2022 Research Associate, Memorial Sloan Kettering Cancer Center, New York City, NY (USA)
From April 1, 2022 Assistant Professor (Tenure Track), ISREC, EPFL, Lausanne (CH)
Zoom link (with one-time registration for the whole series) for attending remotely: https://go.epfl.ch/EPFLBioETalks
Instructions for 1st-year Ph.D. students who are under EDBB’s mandatory seminar attendance rule:
IF you are not attending in-person in the room, please make sure to
- send D. Reinhard a note before noon on seminar day, informing that you plan to attend the talk online, and
- be signed in on Zoom with a recognizable user name (not a pseudonym making it difficult or impossible to be identified).
Practical information
- Informed public
- Registration required
Organizer
- Prof. Giovanni D'Angelo, EPFL
Contact
- Institute of Bioengineering (IBI), Dietrich REINHARD