The focus of our laboratory research is to elucidate the mechanisms of therapeutic resistance in brain tumors. We are particularly interested in investigating the role of cellular plasticity in promoting the cancer stem cell niche and disease recurrence.
The Role of Cellular and Epigenetic Plasticity in Brain Tumor Recurrence
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 (GBM). It is hypothesized that CSCs in GBM (GSCs), 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 GSCs and lineage-committed cancer cells. This equilibrium is maintained by regulation of cell differentiation through a balance between asymmetric and symmetric cell division rates within the GSC 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 GSC-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. We hypothesize that cellular plasticity-mediated fate equilibrium shift toward a more stem-like state is responsible for the aggressiveness of recurrent GBMs and their resistance to conventional therapy.
Our goal is to elucidate the mechanisms of how the intratumoral cell fate equilibrium is maintained during gliomagenesis by using PDX models as well as matched primary and recurrent patient GBM samples (Aim 1). Next, we are trying to provide mechanistic insights into the manner by which therapeutic stress can affect the intratumoral cell fate equilibrium and investigate therapy-induced cytokines as a mechanism of regulation for cancer stem cell niche (Aim 2). And finally, we are investigating a novel mechanism of epigenetic regulation for cellular plasticity during anti-cancer therapy and will investigate how such plasticity can promote disease recurrence (Aim 3).
Collectively, these studies will provide us with insight into the role of cellular plasticity in disease recurrence and allow us to formulate novel therapeutic interventions to prevent recurrence. Such findings have direct translational value for a lethal disease that is very much in need of effective therapies.
If you are interested in joining the our lab and would like more information, please fill out our application.
Atique Ahmed, PhD
Assistant Professor of Neurological Surgery