EPFL BioE Talks SERIES "Mechanisms of Androgen Deprivation Therapy Induced Lineage Plasticity in Prostate Cancer"


Event details

Date 04.04.2022
Hour 16:0017:00
Speaker Prof. Wouter Karthaus, ISREC, School of Life Sciences, EPFL, Lausanne (CH)
Location Online
Category Conferences - Seminars
Event Language English

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.

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
  1. send D. Reinhard a note before noon on seminar day, informing that you plan to attend the talk online, and
  2. be signed in on Zoom with a recognizable user name (not a pseudonym making it difficult or impossible to be identified).
Students attending the seminar in-person should collect a confirmation signature after the talk - please print your own signature sheet beforehand (71 kB pdf available for download here).

Practical information

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