Sadhan Majumder, Ph.D.

The research in my laboratory is focused on (1) deciphering the mechanisms that control normal development and how aberrations of such mechanisms produce diseases, and (2) investigating how such knowledge can be translated into improved patient care. We begin by studying molecular mechanisms and then build on the lessons learned from those studies using a multi-disciplinary approach that encompasses genomics, bioinformatics, biochemistry, cell biology and mouse genetics. Our work involves close collaboration between basic scientists and clinicians.

One of the first projects in my laboratory focused on advancing understanding of the childhood brain tumor medulloblastoma (MB) as a foundation for patient-specific therapeutic approaches. In the course of our early work, we discovered that the transcriptional repressor REST has a new function in that it maintains self-renewal and blocks differentiation of normal neural stem cells. REST is aberrantly overexpressed in a subclass of MB tumors, and a unique role of REST in these MB tumors is to block differentiation and maintain stemness of the cerebellar stem/progenitor cells. This work was exciting because others and we suggested that REST inhibitors could be utilized to block MB.

Our work then evolved into an investigation of the mechanisms of stemness in neural stem cells, muscle progenitor cells, embryonic stem cells and glioblastoma stem cells. Based on our understanding of these mechanisms, in one line of work, we converted muscle progenitor cells into functional neurons, with a single recombinant molecule we designed based on REST function (REST-VP16), before the iPS system was published. Genome-wide analyses indicated that REST-VP16 shifted global muscle-specific to neuron-specific transcriptome signature in these engineered neurons. Another line of work resolved some of the contradictions in the literature and showed that the REST-mediated regulation of ES cell pluripotency through a microRNA-mediated pathway depends on the cell-type (not all ES lines are the same) as well as the culture conditions, indicating how various factors form part of an interconnected genome-wide network.

In a third line of work, we discovered that REST regulates glioblastoma (GBM) stem cell (GSC) tumorigenicity by maintaining self-renewal and invasion. Importantly, high levels of REST characterize a class of human GBM patient tumors (HR-GBM). Various labs, including ours, by now have suggested that REST is a potential therapeutic target for stratified HR GBM tumors. Our recent genome-wide chromatin and transcriptome filtering analyses followed by biochemical and biological validations indicated that REST performs its functions in GSCs through a microRNA signature pathway (miR-124, a known REST target, and miR-203, a new target). Parallel to this discovery, we used unbiased genome-wide analyses and discovered a new mechanism (miR-21-Sox2 regulatory axis)-based GBM patient classification with implications for precision medicine. We are currently studying specific innovations in chemotherapy suggested by the REST-miR-124/203 mechanism using exosome-mediated delivery of miRs in HR-stratified mouse tumors. Although REST regulates many genes, many of its biological functions still remain undiscovered. Overexpression (OE) of REST is found in many brain tumors, in ischemic insults, and in neurological diseases and behavioral disorders. However, progress in these areas has been hampered by the continuing absence of a conditional REST OE mouse model. We have now created the first conditional REST OE knockin mouse line enabling study of the role of REST OE in vivo. Our published results confirm that REST expression in these mice is physiologically relevant. Genome-wide analyses followed by quantitative ChIP assays and behavioral assays indicated that REST regulates spontaneous locomotion by repressing a new target, Dopamine Receptor 2.

In a fourth line of work using REST OE mice, we collaborated with Dr. Hui-Lin Pan’s lab to study the role of REST in chronic pain. We are currently studying the central hypothesis that REST in DRG neurons is involved in regulating opioid analgesia in chronic neuropathic pain and in opioid-induced hyperalgesia /analgesic tolerance by governing the opioid receptor expression through epigenomic regulation of these genes. Thus, manipulation of REST in DRG neurons could be utilized to increase opioid analgesic efficacy and reduce opioid consumption.

View a complete list of Dr. Majumder's publications. Visit Dr. Majumder's Lab website.

https://mdanderson.elsevierpure.com/en/persons/sadhan-majumder

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