Microtubule regulation in cancer cells

The notion of microtubule (MT) dynamics relates to the changes in the length of MT polymers in living cells. They are governed by a stochastic process related to the rates and chances of adding or removing tubulin dimers at the ends of MT polymers, termed dynamic instability. The ability of each MT to swiftly switch between stages of adding or removing dimers at the tip of its lattice is critical for the overall success of the mitotic spindle, a molecular machinery built dynamically by MTs and associated molecular motor proteins, in properly segregating the duplicated DNA into the two daughter cells. When changes in the genetic and epigenetic regulation of the cell affect this ability, for example, by increasing the rates of hydrolysis of bound to tubulin dimers incorporated in the MT lattice, that results in segregation errors and is a hallmark of disease.

In cancer, the dysregulation of MT dynamics contributes to drug resistance. Measuring and modeling MT dynamics provides an insight into the regulation of the cell and its susceptibility to drug action. It can also characterize the function of patient immune cells and contribute to improving the success rate of cell therapy.

Our investigation indicates that drug-resistant tumors exhibit particular changes in their regulation at the cellular level that expose cell state vulnerabilities, which can be targeted during therapy. We elucidate mechanisms of oncogenic activity in dividing cells and propose an approach for overcoming drug resistance.

Changes in MT regulation before and after drug treatment of patient cells are indicative of the susceptibility of tumors to particular drug regimens.