Maternal Embryonic Leucine Zipper Kinase Is Upregulated and Required in Mammary Tumor-Initiating Cells In vivo

Abstract

Maternal Embryonic Leucine zipper Kinase (MELK) is expressed in several developing tissues, in the adult germ line, and in adult neural progenitors. MELK expression is elevated in aggressive undifferentiated tumors correlating with poor patient outcome in human breast cancer. To investigate the role of MELK in mammary tumorigenesis in vivo we used a MELK-GFP reporter mouse, which allows prospective isolation of MELK expressing cells based on GFP fluorescence. We found that in the normal mammary gland, cells expressing high levels of MELK were enriched for proliferating cells, expressing markers of mammary progenitors. The isolation of cells with high levels of MELK in mammary tumors from MMTV-Wnt1/MELK-GFP bitransgenic mice resulted in a significant enrichment of tumorsphere formation in culture and tumor initiation after transplantation into mammary fat pads of syngeneic mice. Furthermore, using lentiviral delivery of MELK-specific shRNA and limiting dilution cell transplantations we demonstrated that MELK function is required for mammary tumorigenesis in vivo. Our findings identify MELK as potential target in breast tumor initiating cells.

MELK inhibitor, novel molecular targeted therapeutics for human cancer stem cells

“…1,5 In addition, we and others have reported that MELK induces expression of oct3/4, a well-known a stem cell marker. 6,7 However, the detailed downstream signaling pathway of MELK in cancer cells is still not fully understood.…”

Cortical localization of Maternal Embryonic Leucine zipper Kinase (MELK) implicated in cytokinesis in early Xenopus embryos

“…MELK was shown to be involved in the control of cell proliferation, 3,4 regulation of apoptosis, 5 inhibition of spliceosome assembly, 6 haematopoiesis, 7 asymmetric cell divisions 8 and cell cycle. of biological processes, its precise function remains elusive.…”

“…5 This lead to the proposal that MELK could be a therapeutic target for several types of cancer. 4,5,11,12 MELK expression is precisely controlled during the cell cycle in two ways. Firstly, the kinase is expressed in cells engaged into the cell cycle, but its amount decreases to undetectable levels in cells that have left the cell cycle to differentiate.…”

Cancer Stem Cells: Prospective Isolation and Progress Toward Functional Biomarker Identification

“…In another example, MELK promoter GFP reporter mice have been exploited to show that in MMTV-Wnt1 induced breast tumors, the GFP ? populations are uniquely enriched for breast CSCs [74]. With the emergence of microRNAs as important regulators of stemness, there have also been efforts to use sensors of their presence as tools to enrich for stem cell populations.…”