Cellular plasticity and equilibrium in GBM progression

Project: Research project

Project Details

Description

A growing body of evidence points to cancer stem cells (CSCs) as the culprit behind persisting
uncontrolled growth in several human malignancies, including one of the most lethal brain tumor
Glioblastoma Multiforme (GBM). It is hypothesized that CSCs, with similar characteristics as normal
tissue stem cells, are resistant to anti-cancer therapeutics and thus instrumental in initiating clinical
relapse. Within the tumor specific “niche”, a dynamic equilibrium exists between CSCs and lineagecommitted
cancer cells. This equilibrium is maintained by regulation of cell differentiation through a
balance between asymmetric and symmetric cell division rates within the CSC compartment. This
intrinsic homoeostatic state is critical for disease progression, as shifts in the equilibrium can influence
the clinical outcome. For example, in the clinical setting CSC-rich tumors are more aggressive and
associated with poor prognosis. It is therefore critical to elucidate the molecular mechanisms of how the
stemness equilibrium state is maintained within the tumor microenvironment, as well as its contribution to
therapeutic resistance and disease recurrence. To this end, we developed models for anti-glioma
chemotherapy-induced recurrent GBM by using patient derived xenograft (PDX), and investigated the
evolutionary path to recurrence. Our data demonstrated that: (i) in the recurrence model, the equilibrium
shifted toward a more stem-like state; (ii) cellular plasticity-mediated conversion of normal GBM cells into
glioma stem cell (GSCs) played a role in this shift; (iii) therapeutic stress induced GSCs (iGSCs) were
highly aggressive with invasive characteristics in the orthotropic xenograft model. Based on this, we
hypothesize that cellular plasticity-mediated fate equilibrium shift towards a more stem-like state is
responsible for the aggressiveness of recurrent GBMs and their resistance to conventional
therapy. By using our PDX derived GBM models we now propose to investigate the molecular
mechanisms of the intratumoral stemness equilibrium state (Aim 1), elucidate the role of the therapy
induced cancer stem cell niche in GBM recurrence (Aim 2) and finally, develop strategies to target
cellular plasticity in order to prevent GBM recurrence (Aim 3). By elucidating the molecular mechanisms
of intratumoral cell fate equilibrium maintenance and the effect of anti-glioma therapies on the CSC niche
will give us insight into their role in disease progression, and aid in identifying novel targets to prevent
GBM recurrence.
StatusActive
Effective start/end date4/1/171/31/22

Funding

  • National Institute of Neurological Disorders and Stroke (5R01NS096376-05)

Fingerprint

Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.