Maternal Embryonic Leucine Zipper Kinase (MELK) is listed among clinically used Mammaprint and Prosigna (PAM50) breast cancer signature genes. MELK overexpression has also been reported in other cancers and cancer stem cells. These studies suggested that MELK overexpression predicts poor survival of cancer patients. A small molecule MELK inhibitor OTS167 is currently tested in Phase I clinical trials. However, recent results questioned the specificity of MELK inhibitors, and CRISPR/Cas9 mediated MELK knockout suggested MELK is not an essential kinase for cell proliferation. This has posed a paradox: why then is MELK overexpressed in cancer cells? There is clearly knowledge gap and clinical urgency to better delineate MELK functions. Particularly, we still lack the understanding about MELK action at the individual cell level. Based on literature survey and preliminary data, we propose the central hypothesis that MELK regulates cell cortex stability during late mitosis and controls cell division symmetry. The hypothesis leads to the conceptual innovation that MELK overexpression might not affect proliferation of the mass of cancer cells, but could still exert functional significance through amplifying cancer stem cells by engaging symmetric cell division. The protein level, phosphorylation level and kinase activity of MELK all peak during mitosis. Previously we have identified MELK as a gene co-expressing with core centromere/kinetochore proteins. MELK is also a top-ranking chromosomal instability (CIN) signature gene. We reason that MELK does have some functions during mitosis, and in proper contexts its mitotic activities may impact cell fates. Stem cells including cancer stem cells normally go through asymmetric cell division. However, in certain situations stem cells also divide symmetrically to increase the pool of stem cells. The central hypothesis will be tested in three specific aims.
Aim 1. To elucidate the spatio- temporal control of MELK activity during mitosis;
Aim 2. To test whether MELK amplifies cancer stem cells by regulating cell division symmetry;
Aim 3. To assess surrogate markers for MELK inhibition. The project is expected to bridge mechanistic insights into MELK cell biology and its known overexpression in breast cancers. The project is expected to identify at least one urgently needed surrogate marker to evaluate the efficacy of MELK inhibition in cells. It will be collaborated with several experts and will become a perfect training platform for undergraduate and graduate students in the Department of Biological Sciences at the University of Toledo.
MELK is overexpressed in multiple cancers including breast cancers with poor prognosis and presumed MELK inhibitors are being tested in clinical trials. Nevertheless, how MELK works at cellular level is till poorly understood, which causes confusion and controversy about whether MELK is a valid cancer drug target. The proposed work will provide urgently needed mechanistic information to assess the relevance of MELK and MELK inhibitors in cancer treatment.
