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.
|Effective start/end date||4/1/17 → 1/31/22|
- National Institute of Neurological Disorders and Stroke (5R01NS096376-05)
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