TY - JOUR
T1 - Stem cell-associated heterogeneity in Glioblastoma results from intrinsic tumor plasticity shaped by the microenvironment
AU - Dirkse, Anne
AU - Golebiewska, Anna
AU - Buder, Thomas
AU - Nazarov, Petr V.
AU - Muller, Arnaud
AU - Poovathingal, Suresh
AU - Brons, Nicolaas H. C.
AU - Leite, Sonia
AU - Sauvageot, Nicolas
AU - Sarkisjan, Dzjemma
AU - Seyfrid, Mathieu
AU - Fritah, Sabrina
AU - Stieber, Daniel
AU - Michelucci, Alessandro
AU - Hertel, Frank
AU - Herold-Mende, Christel
AU - Azuaje, Francisco
AU - Skupin, Alexander
AU - Bjerkvig, Rolf
AU - Deutsch, Andreas
AU - Voss-Böhme, Anja
AU - Niclou, Simone P.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - The identity and unique capacity of cancer stem cells (CSC) to drive tumor growth and resistance have been challenged in brain tumors. Here we report that cells expressing CSC-associated cell membrane markers in Glioblastoma (GBM) do not represent a clonal entity defined by distinct functional properties and transcriptomic profiles, but rather a plastic state that most cancer cells can adopt. We show that phenotypic heterogeneity arises from non-hierarchical, reversible state transitions, instructed by the microenvironment and is predictable by mathematical modeling. Although functional stem cell properties were similar in vitro, accelerated reconstitution of heterogeneity provides a growth advantage in vivo, suggesting that tumorigenic potential is linked to intrinsic plasticity rather than CSC multipotency. The capacity of any given cancer cell to reconstitute tumor heterogeneity cautions against therapies targeting CSC-associated membrane epitopes. Instead inherent cancer cell plasticity emerges as a novel relevant target for treatment.
AB - The identity and unique capacity of cancer stem cells (CSC) to drive tumor growth and resistance have been challenged in brain tumors. Here we report that cells expressing CSC-associated cell membrane markers in Glioblastoma (GBM) do not represent a clonal entity defined by distinct functional properties and transcriptomic profiles, but rather a plastic state that most cancer cells can adopt. We show that phenotypic heterogeneity arises from non-hierarchical, reversible state transitions, instructed by the microenvironment and is predictable by mathematical modeling. Although functional stem cell properties were similar in vitro, accelerated reconstitution of heterogeneity provides a growth advantage in vivo, suggesting that tumorigenic potential is linked to intrinsic plasticity rather than CSC multipotency. The capacity of any given cancer cell to reconstitute tumor heterogeneity cautions against therapies targeting CSC-associated membrane epitopes. Instead inherent cancer cell plasticity emerges as a novel relevant target for treatment.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85064545608&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30992437
U2 - https://doi.org/10.1038/s41467-019-09853-z
DO - https://doi.org/10.1038/s41467-019-09853-z
M3 - Article
C2 - 30992437
SN - 2041-1723
VL - 10
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1787
ER -