Not all cells in a tumor are equal. They have different genes, proteins and behaviors and while some are easily killed, others are more resistant to cell-destroying therapies. In some cancers, a few of these hardier cells are cancer stem cells and they may be the culprits behind tumor formation and drug resistance. Much like other types of stem cells, cancer stem cells can do two things: self-renew (generating more new stem cells) and differentiate (giving rise to a variety of cell types). The trick to better understanding tumor formation, and designing drugs that specifically target cancer at its root, is figuring out how to pick the stem cell needle out of the tumor haystack. Sanford-Burnham researchers Dr. Alexey Terskikh and Dr. Robert Oshima think a protein called MELK, short for maternal embryonic leucine zipper kinase, might allow them to do just that.
Dr. Terskikh has studied MELK for almost 10 years, but it hasn’t been easy. Early on, researchers would disrupt MELK in mice but see no consequences from that disruption. Now, in a recent paper published in the journal Cancer Research, Dr. Terskikh, Dr. Oshima, and their colleagues show that MELK protein levels are particularly high in tumor-initiating cells found in a mouse model of breast cancer.
“Previous studies provided evidence that high MELK levels correlate with poor prognosis in breast and brain tumors,” Dr. Terskikh says. “Now we show for the first time that MELK does actually play a role in mammary tumor initiation and progression in a relevant animal model of breast cancer.”
What’s more, when the research team inhibited MELK through genetic manipulation, they were able to slow tumor formation in mice, indicating that the MELK protein is a promising target for the development of anti-cancer stem cell therapies, particularly for breast cancer. Drs. Terskikh and Oshima are now trying to unravel exactly how MELK drives tumors and are searching for small molecule inhibitors to stop it.
“Cancer stem cells provide both a challenge and an opportunity,” Dr. Oshima explains. “The challenge is to target a small population of tumor cells without causing collateral damage to normal cells. The opportunity is to instruct these cells to differentiate to a cell type that is no longer dangerous. MELK may be important for either proliferation or differentiation of cancer stem cells.”
Hebbard LW, Maurer J, Miller A, Lesperance J, Hassell J, Oshima RG, & Terskikh AV (2010). Maternal embryonic leucine zipper kinase is upregulated and required in mammary tumor-initiating cells in vivo. Cancer research, 70 (21), 8863-73 PMID: 20861186