ICC 2022

Alan Prem Kumar

Alan Prem Kumar, Speaker at Cancer Conferences 2022
National University of Singapore, Singapore
Title : Wnt-DP103-GSK3? Cascade Promotes Wnt/?-catenin Signaling in Parental and Stem Cells from Triple Negative Breast Cancer

Abstract:

Breast cancer is a principal cause of death in women globally and a diverse malignancy. Despite recent advances in breast cancer therapeutics, mortality of highly metastatic triple negative breast cancer (TNBC) subtype remains high; due to their lack hormone receptors expression for targeted therapy. Therefore, there is a pressing need to identify new prognostic markers and therapeutic targets for this group of breast cancers. Aberrant activation of Wnt/β-catenin signaling has been associated with breast cancers, where 40% of total breast cancers have elevated β-catenin levels and/or Wnt activity. Herein, we identify DEAD-box RNA helicase DP103 as a novel driver of Wnt/β-catenin pathway in TNBC. The link between DP103 and Wnt/beta-catenin signaling was further validated using in vivo Zebrafish models, where disruption in DDX20 gene splicing mechanisms resulted in severe early embryonic developmental defects such as reduced brain size, tail defects, lack of melanophores formation and cardiac deformities, which phenocopies loss of Wnt/beta-catenin signaling during gastrulation. Interestingly, we also show DP103 drives breast cancer stem cell (CSC) formation, a process regulated by the Wnt/beta-catenin pathway. Depletion of DP103 led to a marked reduction in the percentage of CSC-enriched mammospheres with reduced tumor-initiating ability. Mechanistically, we show DP103’s role in driving Wnt/beta-catenin pathway is independent of caesin kinase I activity but highly dependent on GSK3β activity. More interestingly, from molecular docking data, we found DP103 protein must be phosphorylated at threonine residue 552, when it interacts with GSK3β.  Surprisingly, induction of Wnt/β-catenin signaling also significantly increased DP103 expression, indicating a possible positive feedback loop. Collectively, our data suggest a novel regulatory role of DP103 in the Wnt/β-catenin signaling pathway in parental and CSC derived TNBC - a study which has attracted Pharma company, Rexahn Pharmaceuticals Inc., USA to further develop their Phase I Wnt drug with our group here in Singapore.

 

Biography:

Dr. Alan Prem Kumar earned his Ph.D. from University of North Texas, USA. From his Ph.D. work, he discovered a novel regulatory protein, PyrR for the pyrimidine biosynthetic pathway in Pseudomonas. Dr. Kumar then pursued Postdoctoral training in Cancer Research at Sidney Kimmel Cancer Center, California, USA. He was awarded a Postdoctoral Fellowship for his work on the role of nuclear receptors in the transcriptional regulation of human myeloperoxidase. Dr. Kumar relocated back to Singapore to join the Faculty of Medicine, National University of Singapore as an independent Principal Investigator to continue his expertise on nuclear receptor signaling in cancer biology. His current research focus in the areas of signaling by nuclear receptors and oncogenes in breast cancer. over the past few years , Dr. Kumar and his group have forged relationships with scientists and oncologists in cancer research and with cancer advocacy groups in Singapore.

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