Abstract

The Hes3 Signalling Axis is a recently elucidated molecular mechanism that regulates the growth and function of multiple types of plastic cell. In the living organism, under normal conditions, it is generally turned off, explaining – in part – why it eluded detection until recently. Its function is revealed when a tissue is subjected to damage, which activates the Axis in specialized cells (including multiple types of stem cell), thus contributing to regeneration. In vivo work reveals that disruption of the pathway impairs regeneration, whereas activation promotes it, leading to disease modification in preclinical models of ischemic stroke, Parkinson’s disease, multiple sclerosis, and diabetes (types 1 and 2). Cancer, representing a paradigm of out-of-control regeneration, also utilizes the Axis. Specifically, at least a subpopulation of cancer cells can activate the pathway: in many biopsies, at each moment in time, a percentage of cancer cells express the key biomarker, Hes3. In culture, cancer cells can be forced to turn the Axis on or off, depending on the media formulation, demonstrating that the same cell can switch between the ON and OFF states. This is of relevance to therapy because the drug sensitivities between the two states are very different. In other words, to kill a cell in the ON position, you need different treatments than to kill the same cell in the OFF position. So far, the operation of the Axis has been reported in multiple types of cancer, including brain, pancreas, prostate, breast, lung, and rhabdomyosarcoma. Targeting the Axis has therapeutic potential: Hes3 RNA interference effectively kills cultured cells, specifically in the ON position. In fish, Hes3 promotes cancer progression. In at least two types of cancer, high levels of Hes3 expression predict a shorter patient survival time. The Hes3 Signalling Axis provides a new molecular logic to develop new treatments for a range of disorders.