Treating Brain Tumor by Changing Cell Division Pattern

A major challenge in treating malignant brain tumors is why killing the vast majority of cancer cells does not lead to a cure. The apparent similarity between the ability of cancer cells to proliferate uncontrollably and that of the stem cells to continuously replenish themselves (self-renew) has led to the notion that cancers are diseases of stem cells and that a few cancer stem cells are sufficient to form new tumors to cause relapse and prevent cure. Stem cells can use asymmetric cell division, a process that produces two different daughter cells, to self-renew while simultaneously generating cells that differentiate to perform tissue function. Stem cells can also divide symmetrically to expand themselves by producing two stem cells or deplete themselves by producing two differentiated cells. Findings from our laboratory show that stem cells in the nervous system divide asymmetrically to balance self-renewal and differentiation by segregating two related proteins, Numb and Numbl, to only one of the two daughter cells so that one self-renews and the other becomes a nerve cell (neuron). Neural stem cells lose their ability to self-renew in the absence of Numb and Numbl, whereas their symmetric segregation inhibits neuron production. In this application, we will use a mouse model to explore the possibility of treating brain tumors by manipulating Numb and Numbl segregation to force cancer stem cells to undergo symmetric divisions that lead to their depletion. If successful, our findings will point to fundamentally different targets for devising therapeutic measures to treat brain tumors.